Antioxidants and the Immune System

Molecular Medicine Reports. 2011,4:395-401.
Vaccination with Viral Protein-Mimicking Peptides Postpones Mortality in Domestic Pigs Infected by African Swine Fever Virus.
Ivanov V, Efremov EE, Novikov BV, Balyshev VM, Tsibanov SZh, Kalinovsky T, Kolbasov DV, Niedzwiecki A, Rath M.

Periodic outbreaks of African Swine Fever Virus (ASFV) infection around the world threaten local populations of domestic pigs with lethal disease and provide grounds for pandemic spread. Effective vaccination might bring this threat under control. We investigated the effectiveness of select peptides mimicking viral protein in raising a protective immune response. Forty six synthetic peptides were based on the analysis of the complete nucleotide sequence of ASFV and tested for immunogenicity in mice. The seventeen best immune response-inducing peptide candidates were selected for further investigation.

Twenty-four domestic pigs, three-four month old at 20 to 25 kg body weight, were divided into six groups (n=4) and immunized by subcutaneous injections using a standard three-round injection protocol with one of four-peptide combinations prepared from the seventeen peptides (Groups 1-4) or with carrier only (Group 5). Group 6, the control, was not vaccinated. Animal body temperature and behavior were monitored during and post immunization for health assessment. Two weeks after the last round of immunizations, pigs were infected with live ASFV (Espania 70) at 6.0 Ig GAE50/cm3. Survival rate was monitored. Blood samples were collected for analysis the day before infection and on days 3, 7, and 10 post-infection, or from deceased animals. Serum titer of specific immunoglobulins against synthetic peptides and whole inactivated ASFV were determined by enzyme immunoassay before and after infection. Presence of viral DNA in blood serum samples was determined by polymerase chain reaction. Viral infection activity in blood sera was determined by heme absorption in cultured PBM (porcine bone marrow) and PL (porcine leukocyte) cells. Repeating injections of synthetic peptides both in mice and pigs produced an immune response specific to individual peptides, which differed widely on the intensity scale. Specific anti-whole virus immunoglobulin binding activity in swine serum samples was below detection limit in all animals. Viral DNA was positively identified in all animal samples infected with viral preparation. Viral infection activity was present in all infected animals and it steadily increased with time. On day 3 after infection, the viral titer in group 1 and 3 animals vaccinated with peptides was significantly lower than in unvaccinated controls. In deceased animals, the viral titer in groups 1 and 3 was significantly lower than in controls. All infected animals died within 17 days after infection. Average survival rate in groups 1 and 3 was significantly higher (12.0 days and 14.3 days, respectively) than in controls (9.8 days). Vaccination with specific synthetic peptides significantly delayed mortality in domestic pigs infected with ASFV. These results justify further investigation toward development of effective vaccine against ASFV infection.

https://www.drrathresearch.org/attachments/Infectious%20Diseases/398_vaccination_MMR.pdf

Nova Publishers. 2009; In: Global View of the Fight Against Influenza.
Micronutrients in the global fight against influenza.
Jariwalla RJ, Roomi MW, Kalinovsky T, Rath M, Niedzwiecki A.

Influenza remains a major health threat among infectious diseases, affecting a fifth of the world’s population. Current vaccines and drugs have limited efficacy and there is an urgent need for effective therapies. Influenza virus A not only infects susceptible (alveolar) cells in the lungs, but also manifests in extrapulmonary areas, which require basement membrane disruption by matrix metalloproteinases (MMPs) capable of degrading collagen type IV.

Hence an effective strategy in fighting influenza must be targeted not only in blocking virus replication, but also protecting disruption of the connective tissue and inhibiting virus spread without inflicting toxicity to host cells. We have developed an unique micronutrient mixture, containing ascorbic acid, green tea extract, lysine, proline, N-acetyl cysteine, and selenium, which was shown to be effective in controlling critical steps in influenza virus infection. We evaluated its actions on cell-free influenza A virus, viral multiplication in infected cells and induction of cellular metalloproteinases following virus infection. Application of the nutrient mixture to Vero or MDCK cells post infection resulted in dose-dependent inhibition of viral nucleoprotein production in infected cells. Pretreatment of virus with the nutrient mixture enhanced the antiviral effect. Incubation of cell-free virus with the mixture resulted in dose-dependent inhibition of associated neuraminidase. Additionally, the micronutrient mixture inhibited extracellular invasive parameters such as MMP-2 and MMP-9 secretion and Matrigel invasion. In conclusion, a non-toxic micronutrient mixture tested in our investigation has potential in influenza treatment by not only decreasing viral multiplication in infected cells but also by blocking the enzymatic degradation of the extracellular matrix to limit virus spread.

http://www.novapublishers.org/catalog/product_info.php?products_id=10457

The International Journal of Applied Research in Veterinary Medicine. 2009;7(1):43-49.
Efficacy of a nutrient synergy against colibacillosis in poultry.
Barbour EK, Mastori FA, Shaib HA, Yaghi RH, Tayeb IT, Sleiman FT, Kassaify ZG, Sawaya RK, Abdel Nour AM, Sabra AH, Harakeh S, Rath M.

The main objective of this study was to evaluate the efficacy of a nutrient mixture (NS) containing lysine, proline, green tea extract, ascorbic acid and other micronutrients in alleviating the pathologic effects in broilers challenged with a high or low dose of E. coli following a primary challenge with H9N2 avian influenza virus. Six groups of 19 broilers each were treated as follows.

Birds in groups 1-4 received a primary intratracheal challenge of 2 HA units of H9N2 virus at age 20 d. At age 23 d, birds from groups 1 and 3 received a high dose of E. Coli challenge in the right thoracic air sac (1 X 109 cfu/0.5ml/bird), while birds from groups 2 and 4 received a low dose of E. coli challenge in the same route (1.5 X 106 cfu/ml/bird). NS (976 mg/Kg body weight) was administered daily intraesophageally to birds in groups 3, 4, and 5 from age 17 d to 28 d. Group 6 birds were unchallenged and untreated. The average weight and feed conversion at 28 d of age was significantly improved (p<0.05) in the NS-treated groups compared to NM-deprived groups, with a similar low dose E. coli challenge. The frequency of ocular exudate and diarrhea at 2 d post E. coli challenge dropped significantly (p<0.05) in the NS-treated groups in comparison to NS-deprived birds, with a similar dose of E. coli challenge. The frequency of diarrhea was kept low at 5 d post-challenge, with the high dose of E. coli in birds treated with NS (p<0.05). The frequencies of right and left thoracic airsacculitis and the frequency of pancreatitis were reduced significantly in NS-treated birds with low-dose E. coli, in comparison to similarly challenged birds deprived of NS (p<0.05). However, in the highest dose E. coli challenge groups, the NS treatment lowered only the frequency of abdominal airsacculitis (p<0.05). In conclusion, treatment of broilers with nutrients to reduce injurious effects of H9N2/E.coli challenges is important since it targets improving the resistance in the host to this ailment and not the elimination of the infection with toxic chemotherapy.

https://www.drrathresearch.org/attachments/Infectious%20Diseases/263_intern_j_appl_res_vet_med_2009_7_1_43.pdf

Biofactors. 2008;33(2):85-97.
Effects of a nutrient mixture on infectious properties of the highly pathogenic strain of avian influenza virus A/H5N1.
Deryabin PG, Lvov DK, Botikov AG, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.

Numerous outbreaks of avian influenza virus infection (A/H5N1) have occurred recently, infecting domestic birds, chicken and ducks. The possibility of the emergence of a new strain of influenza virus capable of causing a pandemic in humans is high and no vaccine effective against such a strain currently exists. A unique nutrient mixture (NM), containing lysine, proline, ascorbic acid, green tea extract, N-acetyl cysteine, selenium among other micro nutrients, has been shown to exert a wide range of biochemical and pharmacological effects, including an inhibitory effect on replication of influenza virus and HIV. This prompted us to investigate the potential anti-viral activity of a nutrient mixture (NM) and its components on avian influenza virus A/H5N1at viral dosages of 1.0, 0.1 and 0.01 TCID(50). Antiviral activity was studied in cultured cell lines PK, BHK-21, and Vero-E6. Virus lysing activity was determined by co-incubation of virus A/H5N1 with NM for 0-60 min, followed residual virulence titration in cultured SPEV or BHK-21 cells. NM demonstrated high antiviral activity evident even at prolonged periods after infection. NM antiviral properties were comparable to those of conventional drugs (amantadine and oseltamivir); however, NM had the advantage of affecting viral replication at the late stages of the infection process.

https://www.ncbi.nlm.nih.gov/pubmed/19346584

Biofactors. 2008;33(1):61-75.
Inhibition of cellular invasive parameters in influenza A virus-infected MDCK and Vero cells by a nutrient mixture.
Roomi MW, Jariwalla RJ, Kalinovsky T, Roomi N, Niedzwiecki A, Rath M.

Influenza, a long-standing common infection, poses a serious health problem causing significant morbidity and mortality, and imposing substantial economic costs. To date there are no effective antiviral therapies. A unique nutrient mixture (NM), containing lysine, proline, ascorbic acid, green tea extract, N-acetyl cysteine and selenium among other micro nutrients, has been shown to exert a wide range of biochemical and pharmacological effects, among them anti-carcinogenic and anti-atherogenic activity both in vitro and in vivo. In a previous study, NM was found to significantly inhibit influenza virus A associated neuraminidase enzyme as well as production of NP antigen in a dose-dependent manner. Influenza virus A not only infects pulmonary areas, but also manifests in extrapulmonary areas, which require basement membrane disruption by matrix metalloproteinases capable of degrading collagen type IV. This prompted us to study the effect of NM on cellular invasive parameters of virus-infected and non-infected MDCK and Vero cells. NM inhibited extracellular invasive parameters such as MMP-2 and MMP-9 secretion and Matrigel invasion. Results indicated that the relatively non-toxic nutrient mixture tested in this investigation has potential in influenza treatment by not only decreasing viral multiplication in infected cells but also by blocking the enzymatic degradation of the extracellular matrix.

https://www.ncbi.nlm.nih.gov/pubmed/19276537

Biofactors. 2007;31(1):1-15.
Suppression of influenza A virus nuclear antigen production and neuraminidase activity by a nutrient mixture containing ascorbic acid, green tea extract and amino acids.
Jariwalla RJ, Roomi MW, Gangapurkar B, Kalinovsky T, Niedzwiecki A, Rath M.

Influenza, one of the oldest and most common infections, poses a serious health problem causing significant morbidity and mortality, and imposing substantial economic costs. The efficacy of current drugs is limited and improved therapies are needed. A unique nutrient mixture (NM), containing ascorbic acid, green tea extract, lysine, proline, N-acetyl cysteine, selenium among other micronutrients, has been shown to exert anti-carcinogenic and anti-atherogenic activity both in vitro and in vivo. Many of the constituents of NM have been shown to have an inhibitory effect on replication of influenza virus and HIV. This prompted us to study the effect of NM on influenza A virus multiplication in infected cells and neuraminidase activity (NA) in virus particles. Addition of NM to Vero or MDCK cells post infection resulted in dose-dependent inhibition of viral nucleoprotein (NP) production in infected cells. NM-mediated inhibition of viral NP was selective and not due to cytotoxicity towards host cells. This antiviral effect was enhanced by pretreatment of virus with the nutrient mixture. Individual components of NM, namely ascorbic acid and green tea extract, also blocked viral NP production, conferring enhanced inhibition when tested in combination. Incubation of cell-free virus with NM resulted in dose-dependent inhibition of associated NA enzyme activity. In conclusion, the nutrient mixture exerts an antiviral effect against influenza A virus by lowering viral protein production in infected cells and diminishing viral enzymatic activity in cell-free particles.

https://www.ncbi.nlm.nih.gov/pubmed/18806304

The International Journal of Applied Research in Veterinary Medicine. 2007;5(1):9-16.
Allevation of histopathological effects of avian influenza virus by a specific nutrient synergy.
Babour EK, Rayya EG, Shaib H, El Hakim RG, Niedzwiekci A, Abdel Nour AM, Harakeh S, Rath M.

This study focused on the effects of a nutrient mixture containing ascorbic acid, lysine, proline, green tea extract and other micronutrients in alleviating the histopathologic effects of avian influenza virus.

Daily administration of 48.8 mg/ml/bird of the nutrient mixture at 7 -14 days of age to birds challenged at 7 days of age with H9N2 avian influenza virus resulted in improvement in body weigh and significant reduction in feed conversion ratio at 14 days, associated with a significant increase in liver weight index, significant increase in cecal fermentation and complete absence of toxicity signs, In addition, nutrient supplementation had significant improvements in the following parameters: absence of rales at 3 days post H9N2 challenge, absence of tacheitis and enteritis at 7 days spot challenge and significant reduction in mucus accumulation and counts of inclusion bodies-associated heterophils in the trachea.

https://www.drrathresearch.org/publications/infectious-disease/308-allevation-of-histopathological-effects-of-avian-influenza-virus-by-a-specific-nutrient-synergy

Veterinaria Italiana. 2007;43(1):43-54.
Holistic efficacy of specific nutrient synergy against avian flu virus: pathology and immunomodulation.
Babour EK, Rayya EG, Shaib HA, El Hakim RG, Abdel Nour AM, Niedzwiekci A, Harakeh S, Rath M.

The authors evaluated the holistic efficacy of nine specific nutrient synergy (NS) against avian influenza virus (AIV) strain Lebanon 1 (H9N2). The study included two segments; the first was designed to determine the minimum dose among four doses (1X, 2X, 3X and 4X in which X = 24.4 mg/ml/bird) of NS, administered intraoesophageally, once per day between 7 and 14 days of age, resulting in an improvement of chicken performance without any toxic side-effects; the second aimed at reducing pathological effects and inducing immunomodulation by the determined safe dose of NS in chickens exposed to AIV.

The first segment showed that the daily oral administration of the NS to birds between 7 to 14 days of age at the 2X dose-level (320 mg/kg body weight or 48.8 mg/ml/bird) resulted in a consistent and significant improvement in the feed conversion (P<0.05) at 10 and 14 days of age, associated with a significant (P<0.05) increase in the liver weight index. In addition, the administration of NS at 2X level resulted in complete absence of toxicity signs (swollen infraorbital sinuses, ocular exudate, nasal discharge, thick oral saliva, diarrhoea, lameness and huddling) and complete absence of toxicity lesions (airsacculitis, hydropericardium signs, pericarditis, perihepatitis, splenomegaly and tracheitis). The four groups of birds that received levels 1X to 4X levels had significantly higher frequency of birds with gaseous caeca compared to the control group deprived of NS (P<0.05), a sign of higher fermentation activity in this organ. Data from the second segment of this research showed that the daily administration of NS at a level of 48.8 mg/ml/bird, between 7 to 14 days of age, to H9N2-challenged birds reduced specific pathological effects at 14 days of age namely: absence of rales at 3 days post H9N2 challenge and gross lesions (absence of tracheitis and enteritis at 7 days post challenge). Such reductions in signs and gross lesions were associated with a 63.4% reduction in immune responses to the hemagglutinin protein of the AIV, an indication that NS has a reducing effect on the viral infectivity in chickens.

https://www.drrathresearch.org/attachments/Infectious%20Diseases/172_vet_italiana_2007_43-1.pdf

Curr Drug Metab. 2017;18(9):858-867.
Role of Nutrients and Phyto-compounds in the Modulation of Antimicrobial Resistance.
Harakeh S, Khan I, Almasaudi SB, Azhar EI, Al-Jaouni S, Niedzwiecki A.

Background: Antimicrobial resistance is quickly spreading and has become a major public health problem worldwide. If this issue is not resolved, it may cause a shift back to the pre-antibiotics era and infectious disease will again be a serious problem, especially in developing countries. Since the discovery of antibiotics, bacterial resistance has emerged, enabling certain bacteria to withstand antibiotic action. The emergence of antibiotic resistance is fueled by excessive and improper use of antimicrobial agents, especially in developing countries. For this reason, alternatives to or modifications of current treatment methods have been sought. The aim of this review is to highlight the possible synergies of various agents that can augment antibiotic activities.

Methods: A structured literature search was conducted using only papers that have been published in PubMed with the focus on the agents that are likely to modulate antimicrobial resistance. In this review, data was retrieved from the literature regarding the possible synergies that exist between commercially available antimicrobial drugs with agents of interest. The papers included were summarized and analyzed, critiqued and compared for their contents using a conceptual frame-work.

Results: In total, one hundred and twenty six papers were reviewed. The number of papers that dealt with the different topics included are as follows (): emergence of antimicrobial resistance (22), bioactive phyto-compounds (36) (phytobiologics, and phytochemicals), Antioxidants (40) (N-acetylcysteine, Ambroxol, Ascorbic acid, Glutathione and vitamin E), Peptide synergies (14) (Synthetic cationic α-helical AMPs, CopA3, Alafosfalin, PMAP-36, Phosphonopeptide L-norvalyl-L-1-aminoethylphosphonic acid and norcardicin-A), nano-antibiotics (10), drug-compound interactions (4).This review addressed the new strategies using the above compounds in the modulation of antimicrobial resistance to avoid issues related to resistance of bacteria to antibiotics.

Conclusions: The findings of this review confirm that certain compounds can act in synergy with currently used antimicrobials to enhance the potential of antimicrobial agents and thus to reduce the emergence of antimicrobial resistance. Some of these synergies are already being used to enhance the potential of currently used antimicrobial agents. More studies need to be conducted to better understand the mechanism of action of such compounds, and based on the results, new compounds may be sought.

https://www.ncbi.nlm.nih.gov/pubmed/28721833

J CM and NH. 2019 Oct.
HIV infection treated with a multiple micronutrient supplement program: a case report.
Wong AP.

The human immunodeficiency virus (HIV) attacks the body’s immune system by reducing the number of CD4 cells, which are vital to fighting off infection. If left untreated, it leads to severe damage and degeneration of health. Though current HIV treatments – based on the administration of antiretroviral (ARV) drugs – reduce viral load in the bloodstream and extend life, they do not cure HIV infection or restore the affected immune system.

In this report, we describe the case of a 35‑year‑old male HIV patient with clinical symptoms of infection and leucopenia, and the result of treatment with a high dose multiple micronutrient supplement program combined with a prescribed diet. Upon the first consultation in February 2013, the patient presented with severe skin itchiness, pustules with exudations on the back and chest, and sore throat with candidiasis in the mouth. Following an initial symptom exacerbation, the patient experienced complete resolution of all symptoms and a gradual rise of CD4 after adherence to treatment with a high dose multiple micronutrients.

https://www.jcmnh.org/hiv-infection-treated-with-a-multiple-micronutrient-supplement-program-a-case-report/

ResearchGate. 2011 Nov.
Micronutrient Synergy in the Control of HIV Infection and AIDS.
Jariwalla RJ, Niedzwiecki A, Rath M.

Acquired immune deficiency syndrome (AIDS) has become a global health pandemic and the most common cause of death among young adults aged 20-24 years (Patton et al., 2009). According to the UN/AIDS Global Report published in November 2010 (UNAIDS 2010), about 1.8 million persons died from AIDS-related causes in the year 2009 alone. At the end of that year, the epidemic had left behind totally 16.6 million orphans, defined as those under 18 who had lost one or both parents to AIDS. Since the beginning of the epidemic, nearly 30 million people have died from AIDS-related causes.

At the end of 2009, an estimated 30.8 million adults and 2.8 million children were living with HIV, the human immunodeficiency virus linked to AIDS; with women accounting for just over one-half of all adults living with HIV worldwide. During the same year, about 2.6 million persons became newly infected with HIV, including 370,000 children. Of all people living with HIV, about 68% reside in Sub-Saharan Africa (UNAIDS 2010).

Despite these gruesome statistics, there is no cure in sight. Current treatment is based on the use of antiretroviral (ARV) drugs targeted against HIV at various steps in viral replication (Sleaseman and Goodenow 2003). Although ARV drugs can reduce viral load in the bloodstream, they neither cure HIV infection nor restore the immune system to combat AIDS (Roederer 1998, Pakker et al., 1998). Virus is known to persist indefinitely in reservoirs of latently-infected cells and emergence of drug-resistant strains is common. Furthermore, the effectiveness of ARVs in having any clinical benefits at all depends upon a number of factors, particularly the CD4 count and the nutritional status of patients at the point at which ARV treatment is commenced (Hong et al., 2001, Paton et al., 2006). Additionally, drugs are higly toxic and are often associated with adverse side effects to various organs of the body, including the bone marrow and liver, (Fischl et al., 1987, Richman et al., 1987, Costello et al., 1988, Abrescia et al., 2008), cellular mitochondria (Carr et al., 2001), and with lipodystrophy and dyslipidemia (Carr et al., 1998).

Consequently, there is need for safe and effective, nontoxic therapy that can not only restore the immune system and keep virus multiplication/spread in check but also block AIDS progression without harming cells of the host. This review will focus on the relationship of nutrition to infection and immunity and evidence from experimental and clinical studies on the potential value of micronutrients and their combinations in controlling HIV infection and reducing symptoms associated with AIDS.

https://www.researchgate.net/publication/221918868_Micronutrient_Synergy_in_the_Control_of_HIV_Infection_and_AIDS

Mol Med Rep. 2010 May-Jun;3(3):377-85.
Micronutrient cooperation in the suppression of HIV production in chronically and latently infected cells.
Jariwalla RJ, Gangapurkar B, Pandit A, Kalinovsky T, Niedzwiecki A, Rath M.

Nutrients are known to display pharmacologic activity against viruses and to exert cooperative effects in cells. To study the influence of nutrient cooperation on HIV production in chronically infected T lymphocytes, we evaluated the individual and combined effects of nutrients on HIV-1 reverse transcriptase (RT) released into the culture supernatant. In unstimulated cells, low concentrations of single nutrients, namely ascorbic acid (AA), green tea polyphenols (GT) or lysine, did not significantly suppress HIV-1 RT production. However, when GT (25 µg/ml) and AA (32-64 µg/ml) were combined and applied to cells, extracellular RT was significantly reduced relative to the control. Combining GT (25 µg/ml) with lysine (25 µg/ml) also reduced the RT level to a greater extent (51% of control) than was observed wih lysine alone, and the addition of AA (16 µg/ml) to the combination further decreased RT to 17% of the control (p=0.06). Under the same assay conditions, the nucleoside analog azidothymidine did not significantly suppress HIV production at low to moderate concentrations (0.5-1.0 µg/ml), but did reduce the RT level to 40% of the control (p=0.02) at the highest dose tested (2 µg/ml). In unstimulated cells as well as in latently infected cells stimulated with mitogen (PMA or TNF-α), a nutrient mixture containing GT, AA and amino acids imparted significantly greater RT suppression than equivalent concentrations of key individual components. Nutrient effects on RT suppression were virus-specific and were not due to non-specific cellular toxicity. These results suggest that relatively non-toxic micronutrient combinations are more potent than single nutrients in suppressing virus production in chronically infected T cells, indicating that the constituent nutrients have a cooperative effect in HIV inhibition.

https://www.ncbi.nlm.nih.gov/pubmed/21472250

Elsevier Inc, 2010, 22:323-342.
The Essentiality of Nutritional Supplementation in HIV Infection and AIDS: Review of Clinical Studies and Results from a Community Health Micronutrient Program.
Jariwalla RJ, Niedzwiecki A, Rath M.

The evaluation of the effects of a micronutrient program on AIDS-defining symptoms and other symptoms associated with AIDS in different populations of patients living in different townships and different regions of South Africa, which included Cape Town (Khayelitsha and Western Cape), KwaZulu-Natal province (including Durban) and Free State, concludes that: a) Daily supplementation with a nutritional program containing a defined complex of vitamins, minerals, trace elements, selected amino acids, polyphenols, and other essential nutrients by AIDS patients not taking antiretroviral drugs (ARVs) caused significant reduction in all AIDS-defining and other physical symptoms associated with the progression of AIDS. b)

These observed health improvements in AIDS patients were consistent independent of the township location and region of the country. This evaluation, along with clinical studies reviewed in this report, suggests that science based effective, safe and affordable micronutrient supplementation in combination with other measures of improving nutritional status and living conditions can become a basis of public health strategy to fight immune deficiency.

https://www.drrathresearch.org/publications/infectious-disease/298-the-essentiality-of-nutritional-supplementation-in-hiv-infection-and-aids-review-of-clinical-studies-and-results-from-a-community-health-micronutrient-program

Molecular Medicine Reports. 2010;3:377-385.
Micronutrient Cooperation in Suppression of HIV Production in Chronically and Latently Infected Cells.
Jariwalla RJ, Gangapurkar B, Pandit A, Kalinovsky T, Niedzwiecki A, Rath M.

Nutrients are known to display pharmacologic activity against viruses and to exert cooperative effects in cells. To study the influence of nutrient cooperation on HIV production in chronically infected T lymphocytes, we evaluated the individual and combined effects of nutrients on HIV-1 reverse transcriptase (RT) released into the culture supernatant. In unstimulated cells, low concentrations of single nutrients namely, ascorbic acid (AA), green tea polyphenols (GT), or lysine did not significantly suppress HIV-1 RT production. However, when GT (25 μg/ml) and AA (32 μg/ml to 64 μg/ml) were combined and applied to cells, extracellular RT was significantly reduced relative to control. Combining GT (25 μg/ml) with lysine (25 μg/ml), also reduced RT level to a greater extent (51% of control) than that observed with lysine alone, and addition of AA (16 μg/ml) to the same combination decreased RT further to 17% of control (p=0.06).

Under the same assay conditions, the nucleoside analogue AZT did not significantly suppress HIV production at low to moderate concentrations (0.5 – 1.0 μg/ml) but reduced RT to 40% of control (p=0.02) at the highest dose tested (2 μg/ml). In both unstimulated and latently infected cells stimulated with mitogen (PMA or TNF-alpha), a nutrient mixture containing GT, AA and amino acids, gave significantly greater RT suppression than equivalent concentrations of key individual components. Nutrient effects on RT suppression were virus specific and not due to non-specific cellular toxicity. These results suggest that relatively nontoxic micronutrient combinations are more potent than single nutrients in suppressing virus production in chronically infected T cells, indicating cooperative effects of constituent nutrients in HIV inhibition.

https://www.drrathresearch.org/publications/infectious-disease/299-micronutrient-cooperation-in-suppression-of-hiv-production-in-chronically-and-latently-infected-cells

Botanical Medicine in Clinical Practice, eds. Preedy VR and Watson RR. 2008; Chapter 23.
Micronutrients and Nutrient Synergy in Immunodeficiency and Infectious Disease.
Jariwalla RJ, Niedzwiecki A, Rath M.

Good nutrition is vital to immune function and disease resistance. Conversely poor nutritional status or malnutrition can lower immunity and predispose to infection. Nutritional deficiencies are common in disorders of the immune system and in viral and bacterial infections. Experimental studies conducted to date with micronutrients have revealed beneficial effects with the potential to combat both immunodeficiency disease and microbial infection.

In the case of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), studies have shown that the action of micronutrients can be targeted at at least four different levels of nutrient-host interactions, which include: (i) suppression of virus replication or activation in infected cells; (ii) modulation or enhancement of immune cell production or function to fight opportunistic infection; (iii) reduction in rate of disease progression; and (iv) lowering of AIDS-defining or associated physical symptoms. In the case of tuberculosis (TB), micronutrients have been found to be capable of reducing pathological symptoms and controlling the tubercle bacillus. With viral influenza, though evidence points to a role for micronutrients in improving immunity, blocking viral infectivity/multiplication and suppressing the secretion of cellular proteases required for virus spread. Here, we review the salient features of the scientific evidence for micronutrients and their specific combinations in modulating immunodeficiency and infectious diseases.

https://www.drrathresearch.org/publications/infectious-disease/304-micronutrients-and-nutrient-synergy-in-immunodeficiency-and-infectious-disease

The Commonwealth Health Ministers Reference Book. 2007;187-189.
Role of micronutrients in the control of HIV and AIDS.
Jariwalla RJ, Niedzwiecki A, Rath M.

AIDS has become a global health crisis and a leading cause of death in the developing world. Since 1981, more than 25 million people worldwide have died from this immunodeficiency syndrome and 12 million AIDS orphans have been left behind in Africa alone, According to the UNAIDS/World Health Organization (WHO) 2006 AIDS epidemic update, the number of people living with HIV (human immunodeficiency virus), the virus linked to AIDS, has grown from 8 million in 1990 to nearly 40 million at the end of 2006.

Despite improvements in access to antiretroviral (ARV) drugs, the death toll from AIDS in 2006 was close to 3 million, indicating the need for alternative/complementary therapeutic modalities.

https://www.drrathresearch.org/attachments/Infectious%20Diseases/259_role_of_micronutrients_in_the_control_of_hiv_and_aids.pdf

J CM and NH. 2019 Oct.
Periodontal disease and micronutrients – a clinical pilot study
Author: N.N.

The term periodontal disease describes an infectious form of disease in the tooth socket. As with any other infection, diagnosis is determined by symptoms that include swelling, reddening and bleeding gums, and retraction of gums with a significant loss of soft tissue or bone tissue in the tooth socket. In the 20th century, periodontal disease, like cavities, has become a virtually epidemic disease in dentistry.

Aim of the study: This pilot study has been designed to scientifically document the effects of a specific vitamin treatment in patients with symptoms of periodontal disease.

Study design: Nine patients with typical symptoms of chronic periodontal disease took part in the study. All of them were aware of the importance of optimal oral hygiene. The patients took a daily dosage of vitamins and other nutrients for three months. The most important component of these nutrients was vitamin C. As a diagnostic measurement of the progression of periodontal disease, the “Bleeding-on-Probing” method (BoP), which is widely used in the assessment of this disease, was utilized.

Study results: All study participants displayed similar outcomes with the vitamin treatment. The first significant changes were measurable four to six weeks after the beginning of the study. Before the vitamin therapy, the average BoP value was 60%, which corresponds to a very advanced gum infection. From the sixth week, a clear reduction of gum bleeding was evident and by the eighth week, the average BoP had fallen to 14%. After twelve weeks (the end of the three-month pilot study), the average decrease of gum bleeding was estimated at 85%.

In addition, a significant improvement in gum firmness was noted, as was a reduction in visible vascularization, which indicated s a significant reduction of the previously spongy gum tissue fragments of beet-red color. Additional beneficial health effects were spontaneously reported by many patients, including improvement in overall physical condition and vitality.

https://www.jcmnh.org/periodontal-disease-and-micronutrients-a-clinical-pilot-study/

PLoS One. 2019 Apr;14(4):e0214763.
10-undecynoic acid is a new anti-adherent agent killing biofilm of oral Streptococcus spp.
Goc A, Sumera W, Niedzwiecki A, Rath M.

In the search for novel agents against oral pathogens in their planktonic and biofilm form, we have focused our attention on 10-undecynoic acid as the representative of the acetylenic fatty acids. Using macro-broth susceptibility testing method we first established MIC value. Next, the MBC value was determined from a broth dilution minimum inhibitory concentration test by sub-culturing it to BHI agar plates that did not contain the test agent. Anti-biofilm efficacy was tested in 96-well plates coated with saliva using BHI broth supplemented with 1% sucrose as a standard approach. Based on obtained results, MIC value for 10-undecynoic acid was established to be 2.5 mg/ml and the MBC value to be 5 mg/ml. The MBIC90 showed to be 2.5 mg/ml, however completed inhibition of biofilm formation was achieved at 5.0 mg/ml. MBBC concentration revealed to be the same as MBC value, causing approximately 30% reduction at the same time in biomass of pre-existing biofilm, whereas application of 7.0 mg/ml of 10-undecynoic acid crossed the 50% eradication mark. Strong anti-adherent effect was observed upon 10-undecynoic acid application at sub-MBC concentrations as well, complemented with suppression of acidogenicity and aciduricity. Thus, we concluded that 10-undecynoic acid might play an important role in the development of alternative or adjunctive antibacterial and anti-biofilm preventive and/or therapeutic approaches.

https://www.ncbi.nlm.nih.gov/pubmed/30998699

J Nutri Bio. 2019 Apr;5(1):350-363.
Synergistic Anti-Borreliae Efficacy of a Composition of Naturally-occurring Compounds: an In vitro Study.
Goc A, Niedzwiecki A, Rath M.

Background: Borrelia sp., which is a pathogenic agent of Lyme diseases in mammals, has become an increasing problem worldwide due to the emergence of persistence. In this study we investigated whether a defined composition of naturally occurring substances could display a broad and synergistic action in vitro against both active and persistent forms of Borrelia spp.

Methods: A formulation of six plant-derived compounds combined at their 1/32-1/2 MIC values was tested in vitro against two species of Borrelia recognized as causative agents of Lyme disease in North America and Europe.

Results: The results showed that a composition of baicalein, luteolin, rosmarinic acid, monolaurin, cis-2-decenoic acid, and iodine at their 1/8 MIC values has significant synergistic effect against the active and persisting latent forms. This composition revealed anti-oxidative properties affecting Borrelia’s membrane but not DNA. Finally, we observed its inhibitory effect on the release of IL-1α, IL-1β, and IL-6 by human CD14+ monocytes stimulated with live Borrelia sp.

Conclusion: These results suggest that such a formulation of compounds might be considered and further explored for its significant pleotropic anti-Borreliae efficacy. Additional in vivo and human studies are warranted to validate this possibility.

https://www.drrathresearch.org/attachments/Infectious%20Diseases/Synergistic_Anti_Borreliae_Efficacy_of_a_Composition_of_Naturally_occurring_Compounds_an_In_vitro_Study.pdf

BMC Complement Altern Med. 2019 Feb;19(1):40.
Anti-borreliae efficacy of selected organic oils and fatty acids.
Goc A, Niedzwiecki A, Rath M.

Background: Borrelia sp. is a causative pathogen of Lyme disease which has become a worldwide health concern. Non-toxic approaches especially directed toward latent persistent forms of this pathogen are desired. Lipids in the form of volatile and non-volatile oils, and fatty acids with proven anti-borreliae efficacy could become an additional support or an alternative for consideration in treatment approaches.

Methods: In this study we investigated 47 lipids (30 volatile and non-volatile oils, and 17 fatty acids) of plant and animal origin against typical motile, knob/round-shaped persisters, and biofilm-like aggregates of Borrelia burgdorferi s.s. and Borrelia garinii, which are identified as pathogenic factors of Lyme disease in the USA and Europe, using direct microscopic counting and spectrofluorometric measurements.

Results: Out of all examined lipids, 5 oils (Bay leaf oil, Birch oil, Cassia oil, Chamomile oil German, and Thyme oil) at or below 0.25%, and 3 fatty acids (13Z,16Z Docosadienoic acid, erucic acid, and petroselinic acid) at or below 0.75 mg/ml, showed bactericidal activity against typical motile spirochetes and knob/round-shaped persisters. Only Bay leaf oil and Cassia oil, including their major constituents, eugenol and cinnamaldehyde, showed to target biofilm-like aggregates of both tested Borrelia spp. at the same concentration, although with 20-30% eradication mark.

Conclusion: Based on obtained results, volatile oils were more potent than non-volatile oils, and unsaturated fatty acids were more effective than saturated fatty acids. Among all tested oils, Bay leaf oil and Cassia oil, with their major components eugenol and cinnamaldehyde, seem to have the highest anti-borreliae efficacy.

https://www.ncbi.nlm.nih.gov/pubmed/30717726

J Appl Microbiol. 2017 Sep;123(3):637-650.
Reciprocal cooperation of phytochemicals and micronutrients against typical and atypical forms of Borrelia spp.
Goc A, Niedzwiecki A, Rath M.

Aims: Borrelia sp., a causative pathogenic factor of Lyme disease (LD), has become a major public health threat. Current treatments based on antibiotics often lead to relapse after their withdrawal. Naturally derived substances that could work synergistically to display higher efficacy compared with the individual components may serve as a resource for the development of novel approaches to combat both active and latent forms of Borrelia sp.

Methods and Results: Using checkerboard assay, we investigated the anti-borreliae reciprocal cooperation of phytochemicals and micronutrients against two species of Borrelia selected as prevalent causes of LD in the United States and Europe. We tested 28 combinations of phytochemicals such as polyphenols (baicalein, luteolin, rosmarinic acids), fatty acids (monolaurin, cis-2-decenoic acid) and micronutrients (ascorbic acid, cholecalciferol and iodine). The results showed that the combinations of baicalein with luteolin as well as monolaurin with cis-2-decenoic acid expressed synergistic anti-spirochetal effects. Moreover, baicalein and luteolin, when combined with rosmarinic acid or iodine, produced additive bacteriostatic and bactericidal effects against typical corkscrew motile spirochaetes and persistent knob/round-shaped forms, respectively. An additive anti-biofilm effect was noticed between baicalein with luteolin and monolaurin with cis-2-decenoic acid. Finally, application of the combination of baicalein with luteolin increased cytoplasmic permeability of Borrelia sp. but did not cause DNA damage.

Conclusions: These results show that a specific combination of flavones might play a supporting role in combating Borrelia sp. through either synergistic or additive anti-borreliae effects.

Significance and Impact of the Study: Presented here in vitro results might help advancing our knowledge and improving the approach to target Borrelia sp.

https://www.ncbi.nlm.nih.gov/pubmed/28644529

Int J Biol Sci. 2016 Jul;12(9):1093-103.
Cooperation of Doxycycline with Phytochemicals and Micronutrients Against Active and Persistent Forms of Borrelia sp.
Goc A, Niedzwiecki A, Rath M.

Phytochemicals and micronutrients represent a growing theme in antimicrobial defense; however, little is known about their anti-borreliae effects of reciprocal cooperation with antibiotics. A better understanding of this aspect could advance our knowledge and help improve the efficacy of current approaches towards Borrelia sp. In this study, phytochemicals and micronutrients such as baicalein, luteolin, 10-HAD, iodine, rosmarinic acid, and monolaurin, as well as, vitamins D3 and C were tested in a combinations with doxycycline for their in vitro effectiveness against vegetative (spirochetes) and latent (rounded bodies, biofilm) forms of Borrelia burgdorferi and Borrelia garinii. Anti-borreliae effects were evaluated according to checkerboard assays and supported by statistical analysis. The results showed that combination of doxycycline with flavones such as baicalein and luteolin exhibited additive effects against all morphological forms of studied Borrelia sp. Doxycycline combined with iodine demonstrated additive effects against spirochetes and biofilm, whereas with fatty acids such as monolaurin and 10-HAD it produced FICIs of indifference. Additive anti-spirochetal effects were also observed when doxycycline was used with rosmarinic acid and both vitamins D3 and C. Antagonism was not observed in any of the cases. This data revealed the intrinsic anti-borreliae activity of doxycycline with tested phytochemicals and micronutrients indicating that their addition may enhance efficacy of this antibiotic in combating Borrelia sp. Especially the addition of flavones balcalein and luteolin to a doxycycline regimen could be explored further in defining more effective treatments against these bacteria.

https://www.ncbi.nlm.nih.gov/pubmed/27570483

Ther Adv Infect Dis. 2016 Jun;3(3-4):75-82.
The anti-borreliae efficacy of phytochemicals and micronutrients: an update.
Goc A, Rath M.

Naturally occurring substances have been used for centuries to fight against various pathogens. They serve as a source for new chemical entities or provide options to already existing therapeutics. While there is an increasing interest in studying antimicrobial properties of naturally derived agents, little is known about their effects against Borrelia burgdorferi sensu lato, the causative pathogens of Lyme disease. A better understanding of this aspect could advance knowledge about pathophysiology of these bacteria and help improve the efficacy of current approaches against Lyme disease. Here, we review all naturally occurring substances scientifically evaluated to date, including plant extracts, their metabolites, and micronutrients, against vegetative (spirochetes) and latent (rounded bodies, biofilm) forms of Borrelia sp. This summary reveals the potent anti-borreliae activity of several of these natural compounds indicating their potential in enhancing the efficacy of current treatments for Lyme disease, and offering new options to already existing therapeutic regiments.

https://www.ncbi.nlm.nih.gov/pubmed/27536352

J Appl Microbiol. 2015 Dec;119(6):1561-72.
In vitro evaluation of antibacterial activity of phytochemicals and micronutrients against Borrelia burgdorferi and Borrelia garinii.
Goc A, Niedzwiecki A, Rath M.

Aims: Little is known about the effects of phytochemicals against Borrelia sp. causing Lyme disease. Current therapeutic approach to this disease is limited to antibiotics. This study examined the anti-borreliae efficacy of several plant-derived compounds and micronutrients.

Methods and Results: We tested the efficacy of 15 phytochemicals and micronutrients against three morphological forms of Borrelia burgdoferi and Borrelia garinii: spirochetes, latent rounded forms and biofilm. The results showed that the most potent substances against the spirochete and rounded forms of B. burgdorferi and B. garinii were cis-2-decenoic acid, baicalein, monolaurin and kelp (iodine); whereas, only baicalein and monolaurin revealed significant activity against the biofilm. Moreover, cis-2-decenoic acid, baicalein and monolaurin did not cause statistically significant cytotoxicity to human HepG2 cells up to 125 μg ml(-1) and kelp up to 20 μg ml(-1) .

Conclusions: The most effective antimicrobial compounds against all morphological forms of the two tested Borrelia sp. were baicalein and monolaurin. This might indicate that the presence of fatty acid and phenyl groups is important for comprehensive antibacterial activity.

Significance and Impact of the Study: This study reveals the potential of phytochemicals as an important tool in the fight against the species of Borrelia causing Lyme disease.

https://www.ncbi.nlm.nih.gov/pubmed/26457476

Technical Report. 2020 Apr. doi: 10.38018/TildaRe.2020-05
Vitamin D deficiency in Ireland – implications for COVID-19. Results from the Irish Longitudinal Study on Ageing (TILDA).
Laird E, Kenny RA.

This report demonstrates that of those aged 55+ years in Rep. of Ireland, 1 in 5 are vitamin D deficient during the winter and 1 in 12 during the summer. Of particular concern is that nearly 30% of those aged 70+ and 47% of those aged 85+ are deficient in vitamin D. These are the age groups who are considered to be ‘extremely medically vulnerable’ to the adverse health outcomes of COVID-19 and have been advised to participate in ‘cocooning’ during the COVID-19 public health emergency. Of extra concern is the fact that only 10.5% of those aged 70+ actually report taking a vitamin D supplement – because of ‘cocooning’ many may now lack the opportunity for sun exposure and given the low use of supplements, many of this vulnerable group could be at very high risk of deficiency. This of key importance given the usefulness of vitamin D for immune function particularly at this time.
https://tilda.tcd.ie/publications/reports/pdf/Report_Covid19VitaminD.pdf

Nutrients. 2020 Apr;12(4).
Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths.
Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, Bhattoa HP.

The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40-60 ng/mL (100-150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
https://www.ncbi.nlm.nih.gov/pubmed/32252338

Virus Res. 2020 Mar:197936.
Analysis of influenza virus-induced perturbation in autophagic flux and its modulation during Vitamin D3 mediated anti-apoptotic signaling.
Godbole NM, Sinha RA, Tiwari S, Pawar SD, Dhole TN.

Vitamin D3/Calcitriol supplementation in humans is associated with reduced incidence and severity during influenza A virus (IAV) infection. Apoptosis in response to IAV infection is a major contributor to host cell death and tissue damage; however, its modulation by Vitamin D3 remains unclear. In this study, we demonstrate the efficacy of Vitamin D3 in preventing apoptosis induction by pandemic influenza A (H1N1)pdm09 virus in human alveolar cells (A549). Human alveolar epithelial cell line A549 was used to assess the cytotoxic effects of IAV infection. Immunoblotting and fluorescence microscopy were used to study apoptosis and autophagy. The results of the present study demonstrate that IAV induces apoptosis by subversion of host autophagy via down-regulating components of autophagic machinery involved in autophagosome-lysosome fusion and lysosomal activity. Vitamin D3 restores the autophagic flux inhibited by IAV by upregulating the expression of Syntaxin-17 (STX17) and V-type proton ATPase subunit (ATP6V0A2) thereby causing a concomitant decrease in cellular apoptosis via a Vitamin D3 receptor (VDR) dependent mechanism. The present study suggests that Vitamin D3 is a potentially useful agent for limiting IAV-induced cellular injury via its pro-autophagic action.
https://www.ncbi.nlm.nih.gov/pubmed/32234325

Afr J Emerg Med. 2020 Mar;10(1):23-29.
Association between multivitamin supplementation and mortality among patients with Ebola virus disease: An international multisite cohort study.
Yam D, Aluisio AR, Perera SM, Peters JL, Cho DK, Kennedy SB, Massaquoi M, Sahr F, Smit MA, Locks L, Liu T, Levine AC.

Introduction: Micronutrient supplementation is recommended in Ebola Virus Disease (EVD) care; however, there is limited data on its therapeutic effects.

Methods: This retrospective cohort study included patients with EVD admitted to five Ebola Treatment Units (ETU) in Sierra Leone and Liberia during September 2014 to December 2015. A uniform protocol was used to guide ETU care, however, due to supply limitations, only a subset of patients received multivitamins. Data on demographics, clinical characteristics, and laboratory testing was collected. The outcome of interest was facility-based mortality and the primary predictor was multivitamin supplementation initiated within 48 h of admission. The multivitamin formulations included: thiamine, riboflavin, niacin and vitamins A, C, and D₃. Propensity score models (PSM) were used to match patients based on covariates associated with multivitamin administration and mortality. Mortality between cases treated and untreated within 48 h of admission were compared using generalized estimating equations to calculate relative risk with bootstrap methods employed to assess statistical significance.

Results: There were 424 patients with EVD who had sufficient treatment data for analysis, of which 261 (61.6%) had daily multivitamins initiated within 48 h of admission. The mean age of the cohort was 30.5 years and 59.4% were female. In the propensity score matched analysis, mortality was 53.5% among patients receiving multivitamins and 66.2% among patients not receiving multivitamins, resulting in a relative risk for mortality of 0.81 (p = 0.03) for patients receiving multivitamins.

Conclusion: Early multivitamin supplementation was associated with lower overall mortality. Further research on the impact of micronutrient supplementation in EVD is warranted.

https://www.ncbi.nlm.nih.gov/pubmed/32161708

ClinicalTrials.gov. 2020 Feb.
Vitamin C Infusion for the Treatment of Severe 2019-nCoV Infected Pneumonia.
Peng Z.

2019 new coronavirus (2019-nCoV) infected pneumonia, namely severe acute respiratory infection (SARI) has caused global concern and emergency. There is a lack of effective targeted antiviral drugs, and symptomatic supportive treatment is still the current main treatment for SARI. Vitamin C is significant to human body and plays a role in reducing inflammatory response and preventing common cold. In addtion, a few studies have shown that vitamin C deficiency is related to the increased risk and severity of influenza infections. We hypothize that Vitamin C infusion can help improve the prognosis of patients with SARI. Therefore, it is necessary to study the clinical efficacy and safety of vitamin C for the clinical management of SARI through randomized controlled trials during the current epidemic of SARI.
https://clinicaltrials.gov/ct2/show/NCT04264533

Mol Cell Biochem. 2020 Jan;464(1-2):169-180.
Effect of high doses of vitamin D supplementation on dengue virus replication, Toll-like receptor expression, and cytokine profiles on dendritic cells.
Martínez-Moreno J, Hernandez JC, Urcuqui-Inchima S.

Dengue, caused by dengue virus (DENV) infection, is a public health problem worldwide. Although DENV pathogenesis has not yet been fully elucidated, the inflammatory response is a hallmark feature in severe DENV infection. Although vitamin D (vitD) can promote the innate immune response against virus infection, no studies have evaluated the effects of vitD on DENV infection, dendritic cells (DCs), and inflammatory response regulation. This study aimed to assess the impact of oral vitD supplementation on DENV-2 infection, Toll-like receptor (TLR) expression, and both pro- and anti-inflammatory cytokine production in monocyte-derived DCs (MDDCs). To accomplish this, 20 healthy donors were randomly divided into two groups and received either 1000 or 4000 international units (IU)/day of vitD for 10 days. During pre- and post-vitD supplementation, peripheral blood samples were taken to obtain MDDCs, which were challenged with DENV-2. We found that MDDCs from donors who received 4000 IU/day of vitD were less susceptible to DENV-2 infection than MDDCs from donors who received 1000 IU/day of vitD. Moreover, these cells showed decreased mRNA expression of TLR3, 7, and 9; downregulation of IL-12/IL-8 production; and increased IL-10 secretion in response to DENV-2 infection. In conclusion, the administration of 4000 IU/day of vitD decreased DENV-2 infection. Our findings support a possible role of vitD in improving the innate immune response against DENV. However, further studies are necessary to determine the role of vitD on DENV replication and its innate immune response modulation in MDDCs.

https://www.ncbi.nlm.nih.gov/pubmed/31758375

Fish Shellfish Immunol. 2019 Nov;94:769-779.
Functional nutrition modulates the early immune response against viral haemorrhagic septicaemia virus (VHSV) in rainbow trout.
Leal E, Ordás MC, Soleto I, Zarza C, McGurk C, Tafalla C.

Although viruses represent a major threat for cultured fish worldwide, the commercialization of vaccines capable of providing effective and long-lasting protection is still lacking for most of these viral diseases. In this situation, the use of supplemented diets could be a suitable strategy to increase the immune status of the fish and reduce the impact of viral pathogens. Among possible immunostimulants that could be included in these functional feeds, some studies have previously shown that certain β-glucans can significantly increase certain immune parameters of fish and reduce the impact of viral diseases. However, the mechanisms through which β-glucans exert their activity have not been fully elucidated yet. In the current study, we have studied the immune response of different tissues to viral haemorrhagic septicaemia virus (VHSV) in rainbow trout fed with a non-supplemented control diet as well as in fish fed a commercial functional aquafeed (Protec™, Skretting) containing β-glucans, vitamin C, vitamin E and zinc. For this, after 30 days of feeding the fish with one of the two diets, they were subsequently infected with VHSV by bath or mock-infected. After 2 or 6 days post-infection, fish were sacrificed and the levels of transcription of different immune genes such as IgM, IgT, IgD, Mx, interferon γ (IFN γ) and perforin studied in different tissues (kidney, gut and gills). Additionally, the levels of natural IgMs in serum were also determined. Our results demonstrate that fish fed the functional diet were capable of mounting an increased IgM, IgT, IgD and Mx transcriptional response to the virus. Additionally, these fish also showed increased levels of natural IgMs in serum. These results reveal a previously undescribed effect of functional diets on fish Ig production and point to Protec™ as an adequate diet to be incorporated in holistic programs aimed at mitigating the effect of viral diseases.

https://www.ncbi.nlm.nih.gov/pubmed/31580935

J Nutr. 2019 Oct;149(10):1757-1765.
Vitamin A Supplementation Was Associated with Reduced Mortality in Patients with Ebola Virus Disease during the West African Outbreak.
Aluisio AR, Perera SM, Yam D, Garbern S, Peters JL, Abel L, Cho DK, Kennedy SB, Massaquoi M, Sahr F, Brinkmann S, Locks L, Liu T, Levine AC.

Background: Micronutrient supplementation is recommended in Ebola virus disease (EVD); however, there are limited data on therapeutic impacts of specific micronutrients.

Objective: To evaluate the association between vitamin A supplementation and mortality in EVD.

Methods: This retrospective cohort included patients with EVD admitted to 5 International Medical Corps Ebola Treatment Units (ETUs) in 2 countries during 2014-2015. Protocolized treatments with micronutrients were used at all ETUs: however, because of resource constraints, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola viral loads (cycle threshold values) were collected. The outcome of interest was mortality between cases treated with 200,000 IU of vitamin A on care days 1 and/or 2, and those not. Propensity scores based on the first 48 h of care were derived using covariates of age, ETU duration, malaria status, cycle threshold values, and clinical symptoms. Patients were matched 1:1 using nearest neighbors with replacement. Mortality between cases treated and not treated with vitamin A was compared using generalized estimating equations to calculate RR with associated 95% CI.

Results: There were 424 cases analyzed, of which 330 (77.8%) were treated with vitamin A. The mean age was 30.5 y and 40.3% were men. The most common symptoms were diarrhea (85.6%), anorexia (80.7%), and abdominal pain (76.9%). Mortality proportions among cases treated and not treated with vitamin A were 55.0% and 71.9%, respectively. In the propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77, 95% CI: 0.59, 0.99; P = 0.041). In a subgroup analysis of patients treated with multivitamins already containing vitamin A, additional vitamin A supplementation did not impact mortality.

Conclusion: Early vitamin A supplementation was associated with reduced mortality in patients with EVD, and should be further studied and considered for use in future epidemics.

https://www.ncbi.nlm.nih.gov/pubmed/31268140

Eur J Pharmacol. 2019 Oct;860:172543.
Ergosterol peroxide suppresses influenza A virus-induced pro-inflammatory response and apoptosis by blocking RIG-I signaling.
Zhou B, Liang X, Feng Q, Li J, Pan X, Xie P, Jiang Z, Yang Z.

Ergosterol peroxide has been shown to exhibit anti-tumor, antioxidant and anti-bacterial properties. However, the effects of ergosterol peroxide isolated from the herbal Baphicacanthus cusia root on influenza virus infection remain poorly understood. In the present study, ergosterol peroxide (compound 22) was obtained from the B. cusia root and subjected to investigation regarding its immunoregulatory effect on influenza A virus (IAV)-induced inflammation in A549 human alveolar epithelial cells. The structure of compound 22 isolated from B. cusia root. was elucidated by NMR analyses. Structure determination showed that the chemical structure of compound 22 closely resembles that of ergosterol peroxide. We observed that ergosterol peroxide treatment significantly suppressed IAV-induced upregulation of RIG-I expression. Additionally, ergosterol peroxide inhibited the activation of RIG-I downstream signaling pathways, including p38 MAP kinase and NF-κB, which ultimately resulted in the reduced production of an array of pro-inflammatory mediators and interferons (IFN-β and IFN-λ1). Interestingly, inhibitory effects of ergosterol peroxide on the expression of IFNs did not affect the expression of antiviral effectors or enhance viral replication. On the other hand, ergosterol peroxide effectively abolished the amplified production of pro-inflammatory mediators in cells pretreated with IFN-β (500 ng/ml) prior to IAV infection. Moreover, Annexin V and Hoechst 33258 staining revealed that increased apoptosis of IAV-infected cells was reversed by the presence of ergosterol peroxide. Our findings suggest that ergosterol peroxide from the B. cusia root suppressed IAV-associated inflammation and apoptosis via blocking RIG-I signaling, which may serve as a supplementary approach to the treatment of influenza.

https://www.ncbi.nlm.nih.gov/pubmed/31323223

Viruses. 2019 Sep;11(10). pii: E907.
Baseline Serum Vitamin A and D Levels Determine Benefit of Oral Vitamin A&D Supplements to Humoral Immune Responses Following Pediatric Influenza Vaccination.
Patel N, Penkert RR, Jones BG, Sealy RE, Surman SL, Sun Y, Tang L, DeBeauchamp J, Webb A, Richardson J, Heine R, Dallas RH, Ross AC, Webby R, Hurwitz JL.

Maximizing vaccine efficacy is critical, but previous research has failed to provide a one-size-fits-all solution. Although vitamin A and vitamin D supplementation studies have been designed to improve vaccine efficacy, experimental results have been inconclusive. Information is urgently needed to explain study discrepancies and to provide guidance for the future use of vitamin supplements at the time of vaccination. We conducted a randomized, blinded, placebo-controlled study of influenza virus vaccination and vitamin supplementation among 2 to 8 (inclusive) year old children over three seasons, including 2015-2016 (n = 9), 2016-2017 (n = 44), and 2017-2018 (n = 26). Baseline measurements of vitamins A and D were obtained from all participants. Measurements were of serum retinol, retinol-binding protein (RBP, a surrogate for retinol), and 25-hydroxyvitamin D (25(OH)D). Participants were stratified into two groups based on high and low incoming levels of RBP. Children received two doses of the seasonal influenza virus vaccine on days 0 and 28, either with an oral vitamin supplement (termed A&D; 20,000 IU retinyl palmitate and 2000 IU cholecalciferol) or a matched placebo. Hemagglutination inhibition (HAI) antibody responses were evaluated toward all four components of the influenza virus vaccines on days 0, 28, and 56. Our primary data were from season 2016-2017, as enrollment was highest in this season and all children exhibited homogeneous and negative HAI responses toward the Phuket vaccine at study entry. Responses among children who entered the study with insufficient or deficient levels of RBP and 25(OH)D benefited from the A&D supplement (p < 0.001 for the day 28 Phuket response), whereas responses among children with replete levels of RBP and 25(OH)D at baseline were unaffected or weakened (p = 0.02 for the day 28 Phuket response). High baseline RBP levels associated with high HAI titers, particularly for children in the placebo group (baseline RBP correlated positively with Phuket HAI titers on day 28, r = 0.6, p = 0.003). In contrast, high baseline 25(OH)D levels associated with weak HAI titers, particularly for children in the A&D group (baseline 25(OH)D correlated negatively with Phuket HAI titers on day 28, r = -0.5, p = 0.02). Overall, our study demonstrates that vitamin A&D supplementation can improve immune responses to vaccines when children are vitamin A and D-insufficient at baseline. Results provide guidance for the appropriate use of vitamins A and D in future clinical vaccine studies.

https://www.ncbi.nlm.nih.gov/pubmed/31575021

Iran J Kidney Dis. 2019 Jul;13(4):225-231.
The Relationship Between Serum Level of 25-hydroxy Vitamin D and Cytomegalovirus Infection in Kidney Transplant Recipients.
Musavi Mehdiabadi F, Ahmadi F, Lesan Pezeshki M, Razeghi E.

Introduction: Kidney transplant recipients are at risk of opportunisticinfections; previous studies demonstrated the association betweenlow level of vitamin D and the risk of viral infections. This studywas designed to evaluate the relationship between serum 25-hydroxyvitamin D level and active Cytomegalovirus infection / disease inkidney transplant recipients.

Methods: A total number of 83 kidney transplant recipients enrolledin this case-control study from June 2013 to January 2014. 38patients had active CMV infection / disease and 45 patients hadno evidence of active CMV infection. Serum level of 25-hydroxyvitamin D was measured in these two groups and classified asdifferent levels of sufficient (more than 30ng/mL), insufficient (15-30ng/mL), and deficient (less than 15 ng/mL). Data were analyzedin SPSS 21 statistical software by using statistical tests of Pearsoncorrelation coefficient, chi-square and t-test.

Results: Mean serum 25-hydroxy vitamin D level was 14.42 ng/mL in case group and 17.52 ng/mL in control group. There wasno significant difference between the groups in terms of patients’characteristics (P > .05). No significant statistical difference wasfound between mean 25-hydroxy vitamin D level in case and controlgroups (P > .05) but Vitamin D deficiency (serum 25-hydroxy vitaminD less than 15 ng/mL) was noticed in 63.1% of CMV infected groupversus 42.2% of control group. Thus vitamin D deficiency was seenmore prevalent in the CMV infected group (P > .05).

Conclusion: Although we did not find a statistically significantrelationship between vitamin D levels and the CMV infection, CMVinfected patients had lower vitamin D level compared with noninfectedrecipients, hence vitamin D deficiency can be consideredas a risk factor for CMV reactivation after renal transplantation.

https://www.ncbi.nlm.nih.gov/pubmed/31422387

Int J Mol Sci. 2019 Jul;20(14). pii: E3562.
Vitamin D Alleviates Rotavirus Infection through a Microrna-155-5p Mediated Regulation of the TBK1/IRF3 Signaling Pathway In Vivo and In Vitro.
Zhao Y, Ran Z, Jiang Q, Hu N, Yu B, Zhu L, Shen L, Zhang S, Chen L, Chen H, Jiang J, Chen D.

(1) Background: Vitamin D (VD) plays a vital role in anti-viral innate immunity. However, the role of VD in anti-rotavirus and its mechanism is still unclear. The present study was performed to investigate whether VD alleviates rotavirus (RV) infection through a microRNA-155-5p (miR-155-5p)-mediated regulation of TANK-binding kinase 1 (TBK1)/interferon regulatory factors 3 (IRF3) signaling pathway in vivo and in vitro. (2) Methods: The efficacy of VD treatment was evaluated in DLY pig and IPEC-J2. Dual-luciferase reporter activity assay was performed to verify the role of miR-155-5p in 1α,25-dihydroxy-VD₃ (1,25D3) mediating the regulation of the TBK1/IRF3 signaling pathway. (3) Results: A 5000 IU·kg^-1 dietary VD₃ supplementation attenuated RV-induced the decrease of the villus height and crypt depth (p < 0.05), and up-regulated TBK1, IRF3, and IFN-β mRNA expressions in the jejunum (p < 0.05). Incubation with 1,25D3 significantly decreased the RV mRNA expression and the RV antigen concentration, and increased the TBK1 mRNA and protein levels, and the phosphoprotein IRF3 (p-IRF3) level (p < 0.05). The expression of miR-155-5p was up-regulated in response to an RV infection in vivo and in vitro (p < 0.05). 1,25D3 significantly repressed the up-regulation of miR-155-5p in vivo and in vitro (p < 0.05). Overexpression of miR-155-5p remarkably suppressed the mRNA and protein levels of TBK1 and p-IRF3 (p < 0.01), while the inhibition of miR-155-5p had an opposite effect. Luciferase activity assays confirmed that miR-155-5p regulated RV replication by directly targeting TBK1, and miR-155-5p suppressed the TBK1 protein level (p < 0.01). (4) Conclusions: These results indicate that miR-155-5p is involved in 1,25D3 mediating the regulation of the TBK1/IRF3 signaling pathway by directly targeting TBK1.

https://www.ncbi.nlm.nih.gov/pubmed/31330869

Inflamm Bowel Dis. 2019 May;25(6):1088-1095.
Randomized Trial of Vitamin D Supplementation to Prevent Seasonal Influenza and Upper Respiratory Infection in Patients With Inflammatory Bowel Disease.
Arihiro S, Nakashima A, Matsuoka M, Suto S, Uchiyama K, Kato T, Mitobe J, Komoike N, Itagaki M, Miyakawa Y, Koido S, Hokari A, Saruta M, Tajiri H, Matsuura T, Urashima M.

Background: We evaluated whether oral vitamin D supplementation during the winter and early spring reduces the incidence of influenza and upper respiratory infections in patients with inflammatory bowel disease (IBD).

Methods: A randomized, double-blind, controlled trial was conducted to compare the effects of vitamin D supplementation (500 IU/day) and a placebo. The primary outcome was the incidence of influenza; the secondary outcome was the incidence of upper respiratory infection. Prespecified subgroup analyses were performed according to 25-hydroxyvitamin D (25-OHD) levels (low <20 ng/mL or high ≥20 ng/mL) and whether ulcerative colitis (UC) or Crohn’s disease (CD) was present. We also used the Lichtiger clinical activity index for patients with UC and the Crohn’s Disease Activity Index (CDAI) for patients with CD before and after interventions.

Results: We included 223 patients with IBD and randomized them into 2 groups: vitamin D supplementation (n = 108) and placebo (n = 115). The incidence of influenza did not differ between the groups. However, the incidence of upper respiratory infection was significantly lower in the vitamin D group (relative risk [RR], 0.59; 95% confidence interval (CI), 0.35-0.98; P = 0.042). This effect was enhanced in the low 25-OHD level subgroup (RR, 0.36; 95% CI, 0.14-0.90; P = 0.02). With respect to adverse events, the Lichtiger clinical activity index score was significantly worse in the vitamin D group (P = 0.002) and remained significant only in the high 25-OHD level subgroup.

Conclusions: Vitamin D supplementation may have a preventative effect against upper respiratory infection in patients with IBD but may worsen the symptoms of UC.

https://www.ncbi.nlm.nih.gov/pubmed/30601999

Dermatol Ther. 2019 May;32(3):e12882.
Effectiveness of intralesional vitamin D₃ injection in the treatment of common warts: Single-blinded placebo-controlled study.
Kareem IMA, Ibrahim IM, Mohammed SFF, Ahmed AA.

Warts are common viral infection of the skin, usually treated with destructive methods like electrocautery, cryotherapy or laser ablation. Topical vitamin D has been used to treat warts with variable success is to evaluate the efficacy of intralesional vitamin D₃ injection in the treatment of common warts. Fifty patients were divided into two groups: 30 patients as cases group who received intralesional injection of 0.2 mL of vitamin D₃ (300,000 IU) into the base of mother wart for two sessions and another 20 patients as a control group who were injected with normal saline solution. Standardized photographs were taken before the procedure, and 1 month and 3 months after the procedure. The degree of the response was classified into complete, partial, and no response. Complete clearance of the target injected warts occurred in 40% of patients in cases group while it occurred only in 5% of patients in control group (p ≤ .001) that was statistically significant. Intralesional injection of vitamin D₃ may be considered a good and safe modality for the treatment of common warts.

https://www.ncbi.nlm.nih.gov/pubmed/30920098

Vet Microbiol. 2019 Apr;231:24-32.
Immunological and pathological effects of vitamin E with Fetomune Plus^® on chickens experimentally infected with avian influenza virus H9N2.
Awadin WF, Eladl AH, El-Shafei RA, El-Adl MA, Ali HS.

Avian influenza virus (AIV) H9N2 infection causes economic losses on poultry farms, and immunostimulants are essential for improving chicken immunity. This study evaluated the immunological and pathological effects of vitamin E with Fetomune Plus^® (a commercial product based on a yeast extract and vitamins) on chickens experimentally infected with AIV H9N2. Three groups of white Hy-Line chicks were included. The G1 group was kept as an uninfected untreated control, the G2 group was intranasally infected with the AIV H9N2 strain (0.5 ml of 10⁶ 50% egg infectious dose (EID₅₀)), and the G3 group was infected and treated with vitamin E (200 mg/kg of diet) and Fetomune Plus^® (1 ml/liter of drinking water) for four weeks. The gene expression of interferon-gamma (IFN-γ), interleukin (IL)-6, and IL-2 was determined at 3, 5 and 7 days post-infection (PI). Virus shedding titers and rates and haemagglutination inhibition (HI) antibody titers were detected. Clinical signs, mortalities and post-mortem lesions were recorded. The birds were weighed, and relative organ weights were calculated. Tissue specimens were taken for histopathological examination and immunohistochemistry (IHC). The expression of IFN-γ in the duodenum revealed a significant increase in G2 compared to G3 at 3 days PI, while the duodenal and splenic expression of IL-6 was significantly increased in G2 compared to G3 at 5 days PI. IL-2 was overexpressed in the duodenum in G3 compared to G2 at 3 and 5 days PI. A significant decrease (P ≤ 0.05) in the virus shedding titer and an increase in the HI titers were detected in G3 compared to G2. The clinical signs and the mortality rate were clearly appeared in G2 than in G3. By IHC, lower H9N2 staining intensity was observed in the examined organs from G3 than in those from G2. In conclusion, as a first report, vitamin E with Fetomune Plus^® supplementation for four weeks could improve the immunological and pathological effects of H9N2 infection on chickens.

https://www.ncbi.nlm.nih.gov/pubmed/30955817

Rev Med Virol. 2019 Mar;29(2):e2032.
The interplay between vitamin D and viral infections.
Teymoori-Rad M, Shokri F, Salimi V, Marashi SM.

The pleiotropic role of vitamin D has been explored over the past decades and there is compelling evidence for an epidemiological association between poor vitamin D status and a variety of diseases. While the potential anti-viral effect of vitamin D has recently been described, the underlying mechanisms by which vitamin D deficiency could contribute to viral disease development remain poorly understood. The possible interactions between viral infections and vitamin D appear to be more complex than previously thought. Recent findings indicate a complex interplay between viral infections and vitamin D, including the induction of anti-viral state, functional immunoregulatory features, interaction with cellular and viral factors, induction of autophagy and apoptosis, and genetic and epigenetic alterations. While crosstalk between vitamin D and intracellular signalling pathways may provide an essential modulatory effect on viral gene transcription, the immunomodulatory effect of vitamin D on viral infections appears to be transient. The interplay between viral infections and vitamin D remains an intriguing concept, and the global imprint that vitamin D can have on the immune signature in the context of viral infections is an area of growing interest.

https://www.ncbi.nlm.nih.gov/pubmed/30614127

J Assoc Physicians India. 2019 Mar;67(3):42-45.
High Prevalence of Vitamin D Deficiency in HIV Infected on Antiretroviral Therapy in a Cohort of Indian Patients.
Deshwal R, Arora S.

Objectives: The main aim of this study was to assess vitamin D [25(OH)D]levels in an HIV infected adult population and to define HIV and antiretroviral-related factors associated with vitamin D deficiency.

Methods: This observational analytical study was conducted on 475 adult patients on follow up at Apex Immunodeficiency Center of Base Hospital, Delhi Cantt. We estimated the prevalence of vitamin D insufficiency/deficiency(<30 ng/ml). Age, gender, BMI, CD4 count, plasma viral load, HBV/HCV coinfection, smoking status, time since diagnosis of HIV infection and selected liver enzymes were recorded. Antiretroviral therapy regimen was taken into account and its relationship with vitamin D levels were noted.

Results: Vitamin D insufficiency/deficiency was noted in 92.63% of patients out of which 65.68 % were males. Median age of vitamin D sufficient group was slightly higher(52.11 vs 49.95). Patients with higher body mass index (BMI) had a slightly higher rates of Vitamin D insufficiency(24.2 vs 22.3). More the time interval from the date of diagnosis higher were the chances of deficiency/insufficiency. Co-infected patients with hepatitis B and C had sufficient vitamin D levels in 71.92% patients. Efavirenz(66.93%), nevirapine(79.02%), tenofovir(64.84%) and ritonavir(84.90%) containing regimens had consistently low levels of vitamin D. Abnormal liver enzymes viz alanine aminotransferase, alkaline phosphatase and gamma glutamyl transferase were associated with higher rates of deficient vitamin D levels.

Conclusions: Vitamin D deficiency is very high in HIV patients on antiretroviral therapy. . Efavirenz (EFV), Nevirapine (NVP), Tenofovir (TDF) and Protease Inhibitors (PI’s) were associated with high levels of deficiency/insufficiency of vitamin D levels. Vitamin D supplementation as a global strategy in all HIV positive patients on antiretroviral therapy is advocated.

https://www.ncbi.nlm.nih.gov/pubmed/31304705

Medicine (Baltimore). 2019 Jan;98(3):e12735.
Effects of selenium supplementation on pregnancy outcome and disease progression in HIV-infected pregnant women in Lagos, Nigeria: Study protocol for a randomised, double-blind, placebo-controlled trial.
Okunade KS, John-Olabode S, Akinsola OJ, Akinajo O, Akanmu SA, Kanki PJ.

Background: Micronutrient deficiencies are common during pregnancy, especially in pregnant women from economically disadvantaged settings where diets with low content of minerals and vitamins are consumed. Selenium is a non-metallic chemical element of great importance to human health. This study will assess the effect of selenium supplementation on major pregnancy outcomes and disease progression among HIV-infected pregnant women in Lagos, Nigeria.

Methods: A randomized, double-blind, placebo-controlled trial involving confirmed HIV-positive pregnant women at the Lagos University Teaching Hospital (LUTH) between September 2018 and February 2019. Eligible participants are HIV-infected pregnant women aged 15 to 49 years and have a singleton gestation at 14 to 27 weeks’ gestation. At enrolment, 90 women will be randomly assigned into each intervention arm to receive either a daily tablet of 200 μg elemental selenium or placebo. Relevant participants’ data will be collected at enrolment and at delivery. Statistical analyses will be carried out using SPSS version 23.0 for Windows. The associations between any 2 groups of continuous variables will be tested using the t test or the Mann-Whitney U test and that of 2 groups of categorical variables with chi-square or Fishers exact test where appropriate. A series of multivariable analyses will also be carried out to identify and control for several possible confounders of the major pregnancy outcomes and HIV disease progression. Statistical significance will be defined as P < .05. Ethical approval for the study was obtained from the LUTH’s Health Research and Ethics Committee (Approval number: ADM/DCST/HREC/APP/2438; 30th August 2018).

Discussion: This trial will assess the effect of selenium supplementation on pregnancy outcome and HIV disease progression among HIV-infected pregnant women in Lagos. This will help to determine if routine selenium supplementation in HIV-infected pregnant women will contribute to the improvement in the major adverse pregnancy outcomes such as preterm birth and low birth weight and the HIV disease surrogate markers such as CD4+ cells count and viral load.

https://www.ncbi.nlm.nih.gov/pubmed/30653086

Front Immunol. 2018 Mar;9:458.
Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease.
Jiménez-Sousa MÁ, Martínez I, Medrano LM, Fernández-Rodríguez A, Resino S.

People living with human immunodeficiency virus (HIV) infection typically have hypovitaminosis D, which is linked to a large number of pathologies, including immune disorders and infectious diseases. Vitamin D (VitD) is a key regulator of host defense against infections by activating genes and pathways that enhance innate and adaptive immunity. VitD mediates its biological effects by binding to the Vitamin D receptor (VDR), and activating and regulating multiple cellular pathways. Single nucleotide polymorphisms in genes from those pathways have been associated with protection from HIV-1 infection. High levels of VitD and VDR expression are also associated with natural resistance to HIV-1 infection. Conversely, VitD deficiency is linked to more inflammation and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients. VitD supplementation and restoration to normal values in HIV-infected patients may improve immunologic recovery during combination antiretroviral therapy, reduce levels of inflammation and immune activation, and increase immunity against pathogens. Additionally, VitD may protect against the development of immune reconstitution inflammatory syndrome events, pulmonary tuberculosis, and mortality among HIV-infected patients. In summary, this review suggests that VitD deficiency may contribute to the pathogenesis of HIV infection. Also, VitD supplementation seems to reverse some alterations of the immune system, supporting the use of VitD supplementation as prophylaxis, especially in individuals with more severe VitD deficiency.

https://www.ncbi.nlm.nih.gov/pubmed/29593721

Environ Sci Pollut Res Int. 2018 Mar;25(9):8836-8842.
Supplementing dietary rosemary (Rosmarinus officinalis L.) powder and vitamin E in broiler chickens: evaluation of humoral immune response, lymphoid organs, and blood proteins.
Rostami H, Seidavi A, Dadashbeiki M, Asadpour Y, Simões J, Shah AA, Laudadio V, Losacco C, Perillo A, Tufarelli V.

The aim of the present study was to evaluate the effect rosemary (Rosmarinus officinalis L.) powder (RP) and vitamin E (VE) at different levels on humoral immunity of broilers during a 42-day production cycle. A total of 270 1-day-old male chicks were assigned to nine groups with three replicates of ten birds each, and diets were supplemented with 0, 0.5, or 1.0% RP and 0, 100, or 200 mg/kg VE, respectively. Commercial-inactivated vaccines against avian influenza (AI) and Newcastle disease (ND) viruses, and living infectious bronchitis virus (IBV) vaccine were administered by spray method. Sheep red blood cells (SRBC) were administered subcutaneously. Blood samples were collected from birds 1 week after each vaccination to determine antibody titers. At the 42nd day, blood samples were also assessed for globulin level, and lymphoid tissues (thymus, spleen, and bursa) were weighed. Neither antibody titers against viruses nor lymphoid tissues weight were affected by RP and/or VE (P > 0.05) treatments. However, broilers supplemented with 0 mg/kg of VE had lower antibody titers against SRBC than those fed 100 mg/kg of VE (P < 0.05) at the 24th day. A significant RP × VE interaction effect (P < 0.05) on plasma globulin level was observed. The findings of our study suggest that dietary RP and VE additives can interact and modulate the humoral immunity of broilers, but not sufficiently to improve antibody titers against specific virus during a 42-day production cycle.

https://www.ncbi.nlm.nih.gov/pubmed/29330815

J Pharm Pharmacol. 2016 Mar;68(3):406-20.
Red ginseng and vitamin C increase immune cell activity and decrease lung inflammation induced by influenza A virus/H1N1 infection.
Kim H, Jang M, Kim Y, Choi J, Jeon J, Kim J, Hwang YI, Kang JS, Lee WJ.

Objectives: Because red ginseng and vitamin C have immunomodulatory function and anti-viral effect, we investigated whether red ginseng and vitamin C synergistically regulate immune cell function and suppress viral infection.

Methods: Red ginseng and vitamin C were treated to human peripheral blood mononuclear cells (PBMCs) or sarcoma-associated herpesvirus (KSHV)-infected BCBL-1, and administrated to Gulo(-/-) mice, which are incapable of synthesizing vitamin C, with or without influenza A virus/H1N1 infection.

Key Findings: Red ginseng and vitamin C increased the expression of CD25 and CD69 of PBMCs and natural killer (NK) cells. Co-treatment of them decreased cell viability and lytic gene expression in BCBL-1. In Gulo(-/-) mice, red ginseng and vitamin C increased the expression of NKp46, a natural cytotoxic receptor of NK cells and interferon (IFN)-γ production. Influenza infection decreased the survival rate, and increased inflammation and viral plaque accumulation in the lungs of vitamin C-depleted Gulo(-/-) mice, which were remarkably reduced by red ginseng and vitamin C supplementation.

Conclusions: Administration of red ginseng and vitamin C enhanced the activation of immune cells like T and NK cells, and repressed the progress of viral lytic cycle. It also reduced lung inflammation caused by viral infection, which consequently increased the survival rate.

https://www.ncbi.nlm.nih.gov/pubmed/26898166

Transfusion. 2016 Dec;56(12):2948-2952.
Inactivation of Middle East respiratory syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment.
Keil SD, Bowen R, Marschner S.

Background: Middle East respiratory syndrome coronavirus (MERS-CoV) has been identified as a potential threat to the safety of blood products. The Mirasol Pathogen Reduction Technology System uses riboflavin and ultraviolet (UV) light to render blood-borne pathogens noninfectious while maintaining blood product quality. Here, we report on the efficacy of riboflavin and UV light against MERS-CoV when tested in human plasma.

Study Design and Methods: MERS-CoV (EMC strain) was used to inoculate plasma units that then underwent treatment with riboflavin and UV light. The infectious titers of MERS-CoV in the samples before and after treatment were determined by plaque assay on Vero cells. The treatments were initially performed in triplicate using pooled plasma (n = 3) and then repeated using individual plasma units (n = 6).

Results: In both studies, riboflavin and UV light reduced the infectious titer of MERS-CoV below the limit of detection. The mean log reductions in the viral titers were ≥4.07 and ≥4.42 for the pooled and individual donor plasma, respectively.

Conclusion: Riboflavin and UV light effectively reduced the titer of MERS-CoV in human plasma products to below the limit of detection, suggesting that the treatment process may reduce the risk of transfusion transmission of MERS-CoV.

https://www.ncbi.nlm.nih.gov/pubmed/27805261

Transfusion. 2015 Apr;55(4):858-63.
Riboflavin and ultraviolet light for pathogen reduction of murine cytomegalovirus in blood products.
Keil SD, Saakadze N, Bowen R, Newman JL, Karatela S, Gordy P, Marschner S, Roback J, Hillyer CD.

BACKGROUND: Two studies were performed to test the effectiveness of riboflavin and ultraviolet (UV) light treatment (Mirasol PRT, Terumo BCT) against murine cytomegalovirus (MCMV). The first study utilized immune-compromised mice to measure the reduction of cell-free MCMV. A second study used a murine model to evaluate the ability of Mirasol PRT to prevent transfusion-transmitted (TT)-MCMV infection.
STUDY DESIGN AND METHODS: Human plasma was inoculated with MCMV and then treated with Mirasol PRT. The viral titer was measured using an infectious dose 50% assay in nude mice. Mice were euthanized on Day 10 posttransfusion, and their spleens were tested for the presence of MCMV DNA using polymerase chain reaction (PCR). Mirasol PRT was also evaluated to determine its effectiveness in preventing TT-MCMV in platelets (PLTs) stored in PLT additive solution. PLTs were inoculated with either cell-associated MCMV or cell-free MCMV and then treated with Mirasol PRT. Mice were transfused with treated or untreated product and were euthanized 14 days posttransfusion. Blood and spleens were assayed for MCMV DNA by real-time-PCR.
RESULTS: Using nude mice to titer MCMV, a modest 2.1-log reduction was observed in plasma products after Mirasol PRT treatment. TT-MCMV was not observed in the mouse transfusion model when either cell-free or cell-associated MCMV was treated with Mirasol PRT; MCMV transmission was uniformly observed in mice transfused with untreated PLTs.
CONCLUSIONS: These results suggest that using riboflavin and UV light treatment may be able to reduce the occurrence of transmission of human CMV from infectious PLTs and plasma units.

https://www.ncbi.nlm.nih.gov/pubmed/25438832

Int J Biometeorol. 2014 Dec;58(10):2153-7.
Performance traits and immune response of broiler chicks treated with zinc and ascorbic acid supplementation during cyclic heat stress.
Chand N, Naz S, Khan A, Khan S, Khan RU.

This research was conducted to investigate the effect of supplementation of zinc (Zn) and ascorbic acid (AA) in heat-stressed broilers. A total of 160-day-old broiler chicks of approximately the same weight and appearance were divided into four treatment groups (control, T1, T2, and T3). Control group was fed a standard diet without any supplementation. T1 was supplemented with Zn at the rate of 60 mg/kg of feed, T2 was supplemented with 300 mg/kg of feed AA, and T3 was supplemented with combination of Zn and AA. From week 3 to 5, heat stress environment was provided at the rate of 12 h at 25 °C, 3 h at 25 to 34 °C, 6 h at 34 °C, and 3 h at 34 to 25 °C daily. The results revealed that feed intake, body weight and feed conversion ratio (FCR), and weight of thymus, spleen, and bursa of Fabricius improved significantly (P < 0.05) in T3 compared to the other treatments. Antibody titer against Newcastle disease (ND), infectious bursal disease (IBD), and infectious bronchitis (IB) increased significantly (P < 0.05) in T2 and T3 groups. However, total leucocytes count, lymphocytes, and monocytes increased (P < 0.05) in all treated groups compared to control. The results indicated that the supplementation of Zn or AA alone or in combination improved the performance and immune status of broilers reared under heat stress.

https://www.ncbi.nlm.nih.gov/pubmed/24676574

Int J Infect Dis. 2010 Dec;14(12):e1099-105.
The seasonality of pandemic and non-pandemic influenzas: the roles of solar radiation and vitamin D.
Juzeniene A, Ma LW, Kwitniewski M, Polev GA, Lagunova Z, Dahlback A, Moan J.

OBJECTIVES: Seasonal variations in ultraviolet B (UVB) radiation cause seasonal variations in vitamin D status. This may influence immune responses and play a role in the seasonality of influenza.
METHODS: Pandemic and non-pandemic influenzas in Sweden, Norway, the USA, Singapore, and Japan were studied. Weekly/monthly influenza incidence and death rates were evaluated in view of monthly UVB fluences.
RESULTS: Non-pandemic influenzas mostly occur in the winter season in temperate regions. UVB calculations show that at high latitudes very little, if any, vitamin D is produced in the skin during the winter. Even at 26°N (Okinawa) there is about four times more UVB during the summer than during the winter. In tropical regions there are two minor peaks in vitamin D photosynthesis, and practically no seasonality of influenza. Pandemics may start with a wave in an arbitrary season, while secondary waves often occur the following winter. Thus, it appears that a low vitamin D status may play a significant role in most influenzas.
CONCLUSIONS: In temperate latitudes even pandemic influenzas often show a clear seasonality. The data support the hypothesis that high fluences of UVB radiation (vitamin D level), as occur in the summer, act in a protective manner with respect to influenza.

https://www.ncbi.nlm.nih.gov/pubmed/21036090

Am J Clin Nutr. 2010 May;91(5):1255-60.
Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren.
Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H.

BACKGROUND: To our knowledge, no rigorously designed clinical trials have evaluated the relation between vitamin D and physician-diagnosed seasonal influenza.
OBJECTIVE: We investigated the effect of vitamin D supplements on the incidence of seasonal influenza A in schoolchildren.
DESIGN: From December 2008 through March 2009, we conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D(3) supplements (1200 IU/d) with placebo in schoolchildren. The primary outcome was the incidence of influenza A, diagnosed with influenza antigen testing with a nasopharyngeal swab specimen.
RESULTS: Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D(3) group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P = 0.04]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D(3) compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; P = 0.006).
CONCLUSION: This study suggests that vitamin D(3) supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren. This trial was registered at https://center.umin.ac.jp as UMIN000001373.

https://www.ncbi.nlm.nih.gov/pubmed/20219962

Epidemiol Infect. 2006 Dec;134(6):1129-40.
Epidemic influenza and vitamin D.
Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E.

In 1981, R. Edgar Hope-Simpson proposed that a ‘seasonal stimulus’ intimately associated with solar radiation explained the remarkable seasonality of epidemic influenza. Solar radiation triggers robust seasonal vitamin D production in the skin; vitamin D deficiency is common in the winter, and activated vitamin D, 1,25(OH)2D, a steroid hormone, has profound effects on human immunity. 1,25(OH)2D acts as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the ‘oxidative burst’ potential of macrophages. Perhaps most importantly, it dramatically stimulates the expression of potent anti-microbial peptides, which exist in neutrophils, monocytes, natural killer cells, and in epithelial cells lining the respiratory tract where they play a major role in protecting the lung from infection. Volunteers inoculated with live attenuated influenza virus are more likely to develop fever and serological evidence of an immune response in the winter. Vitamin D deficiency predisposes children to respiratory infections. Ultraviolet radiation (either from artificial sources or from sunlight) reduces the incidence of viral respiratory infections, as does cod liver oil (which contains vitamin D). An interventional study showed that vitamin D reduces the incidence of respiratory infections in children. We conclude that vitamin D, or lack of it, may be Hope-Simpson’s ‘seasonal stimulus’.

https://www.ncbi.nlm.nih.gov/pubmed/16959053

Poult Sci. 2001 Nov;80(11):1590-9.
Relationship between the level of dietary vitamin E and the immune response of broiler chickens.
Leshchinsky TV, Klasing KC.

The relationship between the dietary level of vitamin E (VE) and the immune response of broilers was studied in three experiments. Immunity was assessed as antibody production to infectious bronchitis virus (IBV), SRBC, and Brucella abortus (BA) antigens, mitogenic response to phytohemagglutinin A (PHA) and concanavalin A (Con A), cutaneous basophil hypersensitivity (CBH) to PHA, and lipopolysaccharide induction of acute-phase proteins (APP) and heterophilia. A range of VE (0, 10, 17.5, 25, 37.5, 50, 100, and 200 IU/kg) levels were supplemented to a basal diet (corn-soy) containing 10.2 IU of VE/kg. We found a dose-dependent increase in antibody production in response to attenuated IBV between 0 and 25 IU/kg of supplemented VE and no further increase at higher levels. Antibody levels to SRBC were higher in birds supplemented with 50 IU of VE/kg compared to those supplemented with 0 or 200 IU/kg of VE. Antibody production in response to BA antigens was not influenced by VE. Mitogenic responses were suppressed by supplemented VE in Experiment 1 for PHA (25 IU/kg diet) and Con A (25 and 50 IU/kg diets). CBH and APP levels were not affected by VE. Heterophilia was lowest at 50 IU/kg 6 h after lipopolysaccharide injection (Experiment 1). Our study showed that moderate (25 to 50 IU/kg) levels of VE supplementation were most immunomodulatory and that high levels were less effective.

https://www.ncbi.nlm.nih.gov/pubmed/11732676

Immunology. 2000 Aug;100(4):487-93.
Vitamin E Supplementation Increases T Helper 1 Cytokine Production in Old Mice Infected With Influenza Virus.
Han SN, Wu D, Ha WK, Beharka A, Smith DE, Bender BS, Meydani SN.

Compared with young mice, old mice infected with influenza virus have significantly higher pulmonary viral titres, although these can be reduced significantly with dietary vitamin E supplementation. T helper 1 (Th1) cytokines, especially interferon-gamma (IFN-gamma), play an important role in defending against influenza infection. However, there is an age-associated loss of Th1 cytokine production. Prostaglandin E2 (PGE2) production, which increases with age, can modulate the T helper cell function by suppressing Th1 cytokine production. To investigate the mechanism of vitamin E supplementation on reduction of influenza severity in old mice, we studied the cytokine production by splenocytes, and PGE2 production by macrophages (Mphi), in young and old C57BL mice fed semipurified diets containing 30 (control) or 500 parts per million (ppm) (supplemented) vitamin E for 8 weeks, and then infected with influenza A/PC/1/73 (H3N2). Old mice fed the control diet had significantly higher viral titres than young mice; old mice fed the vitamin E-supplemented diet had significantly lower pulmonary viral titres than those fed the control diet (P = 0.02 and 0.001 for overall age and diet effect, respectively). Following influenza infection, interleukin (IL)-2 and IFN-gamma production was significantly lower in old mice than in young mice. Vitamin E supplementation increased production of IL-2 and IFN-gamma in old mice; higher IFN-gamma production was associated with lower pulmonary viral titre. Old mice fed the control diet showed significantly higher lipopolysaccharide (LPS)-stimulated Mphi PGE2 production than old mice fed the vitamin E diet or young mice fed either diet. There was no significant age difference in IL-6, IL-1beta, or tumour necrosis factor-alpha (TNF-alpha) production by splenocytes. Young mice fed the vitamin E-supplemented diet had significantly lower IL-1beta (day 7) and TNF-alpha production (day 5) compared with those fed the control diet. Old mice fed the vitamin E-supplemented diet had significantly lower TNF-alpha production (day 2) than those fed the control diet. Our results indicate that the vitamin E-induced decrease in influenza viral titre is mediated through enhancement of Th1 cytokines, which may be the result of reduced PGE2 production caused by vitamin E.

https://pubmed.ncbi.nlm.nih.gov/10929076/

Arch Virol. 1978;56(3):195-9.
The effect of ascorbic acid on infection chick-embryo ciliated tracheal organ cultures by coronavirus.
Atherton JG, Kratzing CC, Fisher A.

Chick embryo tracheal organ cultures showed increased resistance to infection by a coronavirus after exposure to ascorbate, while chick respiratory epithelium and allantois-on-shell preparations showed no increase in resistance to infection by an influenza virus or a paramyxovirus.

https://www.ncbi.nlm.nih.gov/pubmed/205194

World J Crit Care Med. 2017 Feb;6(1):85-90.
Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome.
Fowler Iii AA, Kim C, Lepler L, Malhotra R, Debesa O, Natarajan R, Fisher BJ, Syed A, DeWilde C, Priday A, Kasirajan V.

We report a case of virus-induced acute respiratory distress syndrome (ARDS) treated with parenteral vitamin C in a patient testing positive for enterovirus/rhinovirus on viral screening. This report outlines the first use of high dose intravenous vitamin C as an interventional therapy for ARDS, resulting from enterovirus/rhinovirus respiratory infection. From very significant preclinical research performed at Virginia Commonwealth University with vitamin C and with the very positive results of a previously performed phase I safety trial infusing high dose vitamin C intravenously into patients with severe sepsis, we reasoned that infusing identical dosing to a patient with ARDS from viral infection would be therapeutic. We report here the case of a 20-year-old, previously healthy, female who contracted respiratory enterovirus/rhinovirus infection that led to acute lung injury and rapidly to ARDS. She contracted the infection in central Italy while on an 8-d spring break from college. During a return flight to the United States, she developed increasing dyspnea and hypoxemia that rapidly developed into acute lung injury that led to ARDS. When support with mechanical ventilation failed, extracorporeal membrane oxygenation (ECMO) was initiated. Twelve hours following ECMO initiation, high dose intravenous vitamin C was begun. The patient’s recovery was rapid. ECMO and mechanical ventilation were discontinued by day-7 and the patient recovered with no long-term ARDS sequelae. Infusing high dose intravenous vitamin C into this patient with virus-induced ARDS was associated with rapid resolution of lung injury with no evidence of post-ARDS fibroproliferative sequelae. Intravenous vitamin C as a treatment for ARDS may open a new era of therapy for ARDS from many causes.

https://www.ncbi.nlm.nih.gov/pubmed/28224112

Cochrane Database Syst Rev. 2013 Jan;(1):CD000980.
Vitamin C for preventing and treating the common cold.
Hemilä H, Chalker E.

Background: Vitamin C (ascorbic acid) for preventing and treating the common cold has been a subject of controversy for 70 years.
Objectives: To find out whether vitamin C reduces the incidence, the duration or severity of the common cold when used either as a continuous regular supplementation every day or as a therapy at the onset of cold symptoms.
Search Methods: We searched CENTRAL 2012, Issue 11, MEDLINE (1966 to November week 3, 2012), EMBASE (1990 to November 2012), CINAHL (January 2010 to November 2012), LILACS (January 2010 to November 2012) and Web of Science (January 2010 to November 2012). We also searched the U.S. National Institutes of Health trials register and WHO ICTRP on 29 November 2012.
Selection Criteria: We excluded trials which used less than 0.2 g per day of vitamin C and trials without a placebo comparison. We restricted our review to placebo-controlled trials.
Data Collection and Analysis: Two review authors independently extracted data. We assessed ‘incidence’ of colds during regular supplementation as the proportion of participants experiencing one or more colds during the study period. ‘Duration’ was the mean number of days of illness of cold episodes.
Main Results: Twenty-nine trial comparisons involving 11,306 participants contributed to the meta-analysis on the risk ratio (RR) of developing a cold whilst taking vitamin C regularly over the study period. In the general community trials involving 10,708 participants, the pooled RR was 0.97 (95% confidence interval (CI) 0.94 to 1.00). Five trials involving a total of 598 marathon runners, skiers and soldiers on subarctic exercises yielded a pooled RR of 0.48 (95% CI 0.35 to 0.64).Thirty-one comparisons examined the effect of regular vitamin C on common cold duration (9745 episodes). In adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds by 18%. The severity of colds was also reduced by regular vitamin C administration.Seven comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent effect of vitamin C was seen on the duration or severity of colds in the therapeutic trials.The majority of included trials were randomised, double-blind trials. The exclusion of trials that were either not randomised or not double-blind had no effect on the conclusions.
Authors’ Conclusions: The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted.

https://www.ncbi.nlm.nih.gov/pubmed/23440782

Br J Nutr. 1992 Jan;67(1):3-16.
Vitamin C and the common cold.
Hemilä H.

The effect of vitamin C on the common cold has been the subject of several studies. These studies do not support a considerable decrease in the incidence of the common cold with supplemental vitamin C. However, vitamin C has consistently decreased the duration of cold episodes and the severity of symptoms. The benefits that have been observed in different studies show a large variation and, therefore, the clinical significance may not be clearly inferred from them. The biochemical explanation for the benefits may be based on the antioxidant property of vitamin C. In an infection, phagocytic leucocytes become activated and they produce oxidizing compounds which are released from the cell. By reacting with these oxidants, vitamin C may decrease the inflammatory effects caused by them. Scurvy, which is caused by a deficiency in vitamin C, is mostly attributed to the decreased synthesis of collagen. However, vitamin C also participates in several other reactions, such as the destruction of oxidizing substances. The common cold studies indicate that the amounts of vitamin C which safely protect from scurvy may still be too low to provide an efficient rate for other reactions, possibly antioxidant in nature, in infected people.

https://www.ncbi.nlm.nih.gov/pubmed/1547201

Scott Med J. 1973 Jan;18(1):3-7.
Changes in leucocyte ascorbic acid during the common cold.
Hume R, Weyers E.

Leucocyte ascorbic acid was measured in 7 subjects during the common cold. There was a significant fall in L.A.A. to scorbutic levels within 24 hours of the onset of symptoms. By the fifth day the L.A.A. had returned to normal, which coincided with the cessation of symptoms. Absorption studies suggested 1g. ascorbic acid per day as a prophylactic dose and 6g. ascorbic acid per day as a therapeutic dose. The effect of such supplements of ascorbic acid in 4 episodes of the common cold in 3 subjects suggests that the L.A.A. pattern can be changed by this therapy. The implications are discussed.

https://www.ncbi.nlm.nih.gov/pubmed/4717661

Biochem Med. 1979 Feb;21(1):78-85.
Metabolism of ascorbic acid (vitamin C) in subjects infected with common cold viruses.
Davies JE, Hughes RE, Jones E, Reed SE, Craig JW, Tyrrell DA.

The influence of experimentally induced rhinovirus infection on the excretion of ascorbic acid (AA) and two of its possible metabolites, diketogulonic acid (DKG) and oxalic acid was determined in human volunteers receiving a controlled daily intake of AA. There was a significant fall in the excretion of both AA and DKG in the infected subjects but no change in the oxalic acid excretion. A simple absorption test provided no evidence of any impairment of gastrointestinal absorption of AA during infection. Possible mechanisms of this infection-induced change in AA metabolism are discussed.

https://www.ncbi.nlm.nih.gov/pubmed/222262

Nutrients. 2020 Apr;12(4).
Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections.
Calder PC, Carr AC, Gombart AF, Eggersdorfer M.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.

https://pubmed.ncbi.nlm.nih.gov/32340216/

J Ethnopharmacol. 2020 Jan;251:112569.
A review of Penthorum chinense Pursh for hepatoprotection: Traditional use, phytochemistry, pharmacology, toxicology and clinical trials.
Wang A, Li M, Huang H, Xiao Z, Shen J, Zhao Y, Yin J, Kaboli PJ, Cao J, Cho CH, Wang Y, Li J, Wu X.

Ethnopharmacological Relevance: In China, Penthorum chinense Pursh (P. chinense) has been used for hundreds of years traditionally for alleviating symptoms by excessive intake of alcohol as well as in the treatment of traumatic injury, edema and liver diseases. Recently, P. chinense and its extract have been developed into tea, drinks or medicines for treatment of liver diseases, including hepatic virus infections, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and liver fibrosis.

Aim of the Study: The main purpose of this review is to provide a critical appraisal of the existing knowledge on the phytochemical data, quality control aspect, pharmacological, as well as toxicological and clinical studies performed on P. chinense, including the identification of scientific gaps.

Materials and Methods: A detailed literature search was conducted using various online search engines, such as Pubmed, Scopus, Google Scholar, Mendeley, Web of Science as well as China National Knowledge Infrastructure (CNKI) database.

Results: In the pharmacological studies, there clearly are links between local/traditional uses and the biomedical investigations. Most pharmacological studies indicated potential liver protective effects in experimental models of chemicals-induced liver injury, acute and chronic alcoholic liver injury, NAFLD, liver fibrosis and viral infection, potentially through antioxidant effects, balancing key liver enzyme levels, inhibition of hepatic virus DNA replication, inhibition of hepatic stellate cells activation and inflammation either in vitro or in vivo. In some models, the effects of P. chinense is comparable with the one of silymarin. Clinical studies have suggested that P. chinense is safe and effective in treating several liver diseases, although most of them are not double-blinded and placebo-controlled studies. Toxicology studies show that P. chinense has no obvious toxicity or side effects in animals or human. Flavonoids, lignans, coumarins, polyphenols and organic acids have been identified. However, only a few studies have investigated the active compounds (mainly flavonoids and lignans) and molecular mechanisms of P. chinense.

Conclusion: P. chinense seems to be safe and shows relevant liver protecting effects. Therefore, it might be a promising candidate for developing as new hepatoprotective agents. However, a lack of understanding of the active compounds and mechanisms of action needs further attention.

https://www.ncbi.nlm.nih.gov/pubmed/31935496

Food Microbiol. 2019 Sep;82:202-208.
Antiviral effects of blueberry proanthocyanidins against Aichi virus.
Joshi SS, Howell AB, D’Souza DH.

Blueberry polyphenols are known for their high antioxidant and antimicrobial potential. Aichi virus (AiV) is an emerging human enteric virus that causes gastroenteritis outbreaks worldwide. This study aimed to (1) determine the time- and dose-dependent effects of blueberry proanthocyanidins (B-PAC) against AiV over 24 h at 37 °C; (2) gain insights on their mode of action using pre- and post-treatment of host cells and Transmission Electron Microscopy; and (3) determine their anti-AiV effects in model foods and under simulated gastric conditions. AiV at ∼5 log PFU/ml was incubated with equal volumes of commercial blueberry juice (BJ, pH 2.8), neutralized BJ (pH 7.0), B-PAC (2, 4, and 10 mg/ml) prepared either in 10% ethanol, apple juice (AJ), 2% milk, simulated gastric fluid (SGF, pH 1.5) or simulated intestinal fluid (SIF, pH 7.5), and controls (malic acid (pH 3.0), phosphate buffered saline (pH 7.2), apple juice (pH 3.6) and 2% milk) over 24 h at 37 °C, followed by standard plaque assays. Each experiment was replicated thrice and data were statistically analyzed. Differences in AiV titers with 1 mg/ml B-PAC were 2.13 ± 0.06 log PFU/ml lower after 24 h and ≥3 log PFU/ml (undetectable levels) lower with 2 and 5 mg/ml B-PAC compared to AiV titers in PBS after 24 h and 3 h, respectively. BJ at 37 °C resulted in titer differences (lower titers compared to PBS) of 0.17 ± 0.06, 1.27 ± 0.01, and 1.73 ± 0.23 log PFU/ml after 1, 3, and 6 h and ≥3 log PFU/ml after 24 h. Pre- and post-treatment of host cells with 0.5 mg/ml B-PAC caused titer decreases of 0.62 ± 0.33 and 0.30 ± 0.06 log PFU/ml, respectively suggesting a moderate effect on viral-host cell binding. B-PAC at 2 mg/ml in AJ caused titer differences of ≥3 log PFU/ml after 0.5 h, while differences of 0.84 ± 0.03 log PFU/ml with 5 mg/ml B-PAC in milk, and ≥3 log PFU/ml with B-PAC at 5 mg/ml in SIF after 30 min were obtained. This study shows the ability of BJ and B-PAC to decrease AiV titers to potentially prevent AiV-related illness and outbreaks.

https://www.ncbi.nlm.nih.gov/pubmed/31027775

Int J Mol Med. 2019 Aug;44(2):737-749.
Resveratrol‑loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress‑mediated ERS/autophagy pathway.
Du N, Li XH, Bao WG, Wang B, Xu G, Wang F.

A number of studies have demonstrated that resveratrol (RES) has a variety of biological functions, including cardiovascular protective effects, treatment of mutations, and anti‑inflammatory, anti‑tumor and antiviral effects. In the present study, RES‑loaded nanoparticles (RES‑NPs) were used to protect rhabdosarcoma (RD) cells from enterovirus 71 (EV71) infection, and the relevant mechanisms were also explored. An amphiphilic copolymer, monomethoxy poly (ethylene glycol)‑b‑poly (D,L‑lactide), was used as vehicle material, and RES‑NPs with necessitated drug‑loading content and suitable sizes were prepared under optimized conditions. RES‑NPs exhibited the ability to inhibit the increase of intracellular oxidative stress. The prospective mechanism for the function of RES‑NPs suggested was that RES‑NPs may inhibit the oxidative stress‑mediated PERK/eIF2α/ATF4 signaling pathway, downregulate the autophagy pathway and resist EV71‑induced RD cells injury. Furthermore, RES‑NPs treatment markedly inhibited the secretion of inflammatory factors, including interleukin (IL)‑6, IL‑8 and tumor necrosis factor‑α elicited by EV71 infection. Concomitantly, inhibitors of oxidative stress, endoplasmic reticulum stress (ERS) or autophagy were demonstrated to negate the anti‑inflammatory and antiviral effects of RES‑NPs on EV71‑infected RD cells. These results demonstrated that RES‑NPs attenuated EV71‑induced viral replication and inflammatory effects by inhibiting the oxidative stress‑mediated ERS/autophagy signaling pathway. In view of their safety and efficiency, these RES‑NPs have potential applications in protecting RD cells from EV71 injury.

https://www.ncbi.nlm.nih.gov/pubmed/31173159

Curr Drug Discov Technol. 2019 Jul. doi: 10.2174/1570163816666190715114741.
Effective antiviral medicinal plants and biological compounds against central nervous system infections: A mechanistic review.
Malekmohammad K, Rafieian-Kopaei M, Sardari S, Sewell RDE.

Background and Objective: Infectious diseases are amongst the leading causes of death in the world and central nervous system infections produced by viruses may either be fatal or generate a wide range of symptoms that affect global human health. Most antiviral plants contain active phytoconstituents such as alkaloids, flavonoids, and polyphenols, some of which play an important antiviral role. Herein, we present a background to viral central nervous system (CNS) infections, followed by a review of medicinal plants and bioactive compounds that are effective against viral pathogens in CNS infections.

Method: A comprehensive literature search was conducted on scientific databases including: PubMed, Scopus, Google Scholar and Web of Science. The relevant key words used as search terms were: “myelitis”, “encephalitis”, “meningitis”, “meningoencephalitis”, “encephalomyelitis”, “central nervous system”, “brain”, “spinal cord”, “infection”, “virus”, “medicinal plants” and “biological compounds”.

Results: The most significant viruses involved in central nervous system infections are: Herpes simplex virus (HSV), Varicella zoster virus (VZV), West Nile virus (WNV), Enterovirus 71 (EV71), Japanese encephalitis virus (JEV) and Dengue virus (DENV). The inhibitory activity of medicinal plants against CNS viruses are mostly active through prevention of viral binding to cell membranes, blocking viral genome replication, prevention of viral protein expression, scavenging reactive oxygen species (ROS) and reduction of plaque formation.

Conclusion: Due to the increased resistance of microorganisms (bacteria, viruses and parasites) to antimicrobial therapies, alternative treatments, especially using plant sources and their bioactive constituents, appear to be more fruitful.

https://www.ncbi.nlm.nih.gov/pubmed/31309894

Int J Mol Sci. 2019 May;20(10). pii: E2382.
Doratoxylon apetalum, an Indigenous Medicinal Plant from Mascarene Islands, Is a Potent Inhibitor of Zika and Dengue Virus Infection in Human Cells.
Haddad JG, Koishi AC, Gaudry A, Nunes Duarte Dos Santos C, Viranaicken W, Desprès P, El Kalamouni C.

Zika virus (ZIKV) and Dengue virus (DENV) are mosquito-borne viruses of the Flavivirus genus that could cause congenital microcephaly and hemorrhage, respectively, in humans, and thus present a risk to global public health. A preventive vaccine against ZIKV remains unavailable, and no specific antiviral drugs against ZIKV and DENV are licensed. Medicinal plants may be a source of natural antiviral drugs which mostly target viral entry. In this study, we evaluate the antiviral activity of Doratoxylum apetalum, an indigenous medicinal plant from the Mascarene Islands, against ZIKV and DENV infection. Our data indicated that D. apetalum exhibited potent antiviral activity against a contemporary epidemic strain of ZIKV and clinical isolates of four DENV serotypes at non-cytotoxic concentrations in human cells. Time-of-drug-addition assays revealed that D. apetalum extract acts on ZIKV entry by preventing the internalisation of virus particles into the host cells. Our data suggest that D. apetalum-mediated ZIKV inhibition relates to virus particle inactivation. We suggest that D. apetalum could be a promising natural source for the development of potential antivirals against medically important flaviviruses.

https://www.ncbi.nlm.nih.gov/pubmed/31091703

Int J Mol Sci. 2019 Apr;20(8). pii: E1860.
The Polyphenol-Rich Extract from Psiloxylon mauritianum, an Endemic Medicinal Plant from Reunion Island, Inhibits the Early Stages of Dengue and Zika Virus Infection.
Clain E, Haddad JG, Koishi AC, Sinigaglia L, Rachidi W, Desprès P, Duarte Dos Santos CN, Guiraud P, Jouvenet N, El Kalamouni C.

The recent emergence and re-emergence of viral infections transmitted by vectors, such as the Zika virus (ZIKV) and Dengue virus (DENV), is a cause for international concern. These highly pathogenic arboviruses represent a serious health burden in tropical and subtropical areas of the world. Despite the high morbidity and mortality associated with these viral infections, antiviral therapies are missing. Medicinal plants have been widely used to treat various infectious diseases since millenaries. Several compounds extracted from plants exhibit potent effects against viruses in vitro, calling for further investigations regarding their efficacy as antiviral drugs. Here, we demonstrate that an extract from Psiloxylon mauritianum, an endemic medicinal plant from Reunion Island, inhibits the infection of ZIKV in vitro without exhibiting cytotoxic effects. The extract was active against different ZIKV African and Asian strains, including an epidemic one. Time-of-drug-addition assays revealed that the P. mauritianum extract interfered with the attachment of the viral particles to the host cells. Importantly, the P. mauritianum extract was also able to prevent the infection of human cells by four dengue virus serotypes. Due to its potency and ability to target ZIKV and DENV particles, P. mauritianum may be of value for identifying and characterizing antiviral compounds to fight medically-important flaviviruses.

https://www.ncbi.nlm.nih.gov/pubmed/30991717

Emerg Microbes Infect. 2018 Sep;7(1):162.
Small molecules targeting coxsackievirus A16 capsid inactivate viral particles and prevent viral binding.
Lin CJ, Liu CH, Wang JY, Lin CC, Li YF, Richardson CD, Lin LT.

Coxsackievirus A16 (CVA16) is an etiologic agent of hand, foot, and mouth disease (HFMD) that affects young children, and although typically self-limited, severe complications, and fatal cases have been reported. Due to the lack of specific medication and vaccines against CVA16, there is currently a need to develop effective antivirals to better control CVA16 infections in epidemic areas. In this study, we identified the tannins chebulagic acid (CHLA) and punicalagin (PUG) as small molecules that can efficiently disrupt the CVA16 infection of human rhabdomyosarcoma cells. Both compounds significantly reduced CVA16 infectivity at micromolar concentrations without apparent cytotoxicity. A mechanistic analysis revealed that the tannins particularly targeted the CVA16 entry phase by inactivating cell-free viral particles and inhibiting viral binding. Further examination by molecular docking analysis pinpointed the targets of the tannins in the fivefold axis canyon region of the CVA16 capsid near the pocket entrance that functions in cell surface receptor binding. We suggest that CHLA and PUG are efficient antagonists of CVA16 entry and could be of value as antiviral candidates or as starting points for developing molecules to treat CVA16 infections.

https://www.ncbi.nlm.nih.gov/pubmed/30254193

Curr Pharm Biotechnol. 2018;19(15):1221-1231.
Comparison of Anti-HCV Activity of Multiple Punica granatum Extracts and Fractions in Virus-infected Human Hepatocytes.
Rehman S, Ashfaq UA, Ijaz B, Jabeen Z, Riazuddin S.

Background: Plants extracts and their bioactive constituents can provide an alternative approach for new treatment. Pakistani flora reveals a huge, largely untapped source of potential antiviral constituents.

Objective: High-cost concerns of direct-acting anti-HCV drugs limit their employment specifically in developing countries like Pakistan. Therefore, discovery of inexpensive and nontoxic agents is needed for HCV treatment.

Methodology: In this study, we used plasmid constructs of pCR3.1/FLAGtag/HCV NS3/4A (genotype 1a & 3a) and Punica granatum extracts (PK AV 003) and semi-purified fractions (P1-P11) were evaluated for their anti-HCV activity. Acetone extract along with two fractions (P4 & P11) revealed a useful therapeutic index.

Results: The fractions P4 (IC50=28.5±0.02 µg/ml; IC25=16±0.02 µg/ml) and P11 (IC50=72±0.02 µg/ml; IC25=41±0.03 μg/ml) dramatically suppressed HCV replication as measured by quantitative PCR (qPCR) and HCV NS3 protein expression level in transient transfection model. Consistent with suppression in genome replication, inhibition of HCV infectious particles by PK AV 003 extract was also judged in an infectious model system. This data is the first description of Pakistani indigenous cultivated fruit-producing plant, Punica granatum, possessing anti-HCV activity. Further analyses are being performed for investigating the mechanistic studies and structural characterization of purified fractions of PK AV 003.

Conclusion: Our findings suggest that PK AV 003 fruit extract might be useful as an add-on therapeutic candidate for treating HCV infection.

https://www.ncbi.nlm.nih.gov/pubmed/30608038

Microb Pathog. 2018 Aug;121:198-209.
Anti-hepatitis C virus activity and synergistic effect of Nymphaea alba extracts and bioactive constituents in liver infected cells.
Rehman S, Ashfaq UA, Ijaz B, Riazuddin S.

Background: Without an effective vaccine, hepatitis C virus (HCV) remains a global threat, inflicting 170-300 million carriers worldwide at risk of cirrhosis and hepatocellular carcinoma (HCC). Though various direct acting antivirals have been redeemed the hepatitis C treatment, a few restraints persist including possible side effects, viral resistance emergence, excessive cost which restricts its availability to a common person.

Hypothesis: There is no preventive HCV vaccine available today so the discovery of potent antiviral natural flora and their bioactive constituents may help to develop preventive cures against HCV infection.

Study Design: In current study, we aim to clarify anti-HCV activity of methanol and acetone extracts along with the purified fractions of Pakistani local plant, Nymphaea alba L (N. alba) using Huh-7 cell line as transfection model. Synergistic study of purified fractions with interferon was performed using MDBK cell line (expressing interferon receptors) as transfection model.

Materials and Methods: Recent study by our research group has observed potent anti-HCV NS3 protease activity of methanol and acetone extracts of N. alba. Effect of N. alba extracts, its fractions precisely, the N1 and N8 fractions on HCV replication was demonstrated by analyzing viral gene expression using in vitro transfection model. Considering NS3 protease as a dynamic drug target, fourteen phytochemicals of N. alba were selected as ligands for interaction with NS3 protein using Molecular Operating Environment (MOE) software. Boceprevir, FDA approved NS3 protease inhibitor, was used as standard for comparative study in docking screening.

Results: Herein we report 84% and 94% reduction of 3a genotype of HCV NS3/4A gene expression at mRNA level at non-toxic concentration. Specifically, two fractions ‘N1’ & ‘N8’ isolated from acetone extract suppressed HCV NS3 gene expression in transfected target cells with an EC₅₀ value of 37 ± 0.03 μg/ml and 20 ± 0.02 μg/ml respectively. Similarly, viral genotype 1a replication is strongly suppressed in target cells by N. alba flower extracts and purified fractions. Moreover, combination of fractions with standard antiviral drug displayed synergistic effects for inhibition of HCV replication. Phytochemicals including Isoquercetin, Hyperoside, Quercetin, Reynoutrin, Apigenin and Isokaempferide displayed minimum binding energies as compared to standard protease inhibitor.

Conclusion: N. alba and its purified phytochemicals with new scaffolds might significantly serve as valuable and alternative regimen against HCV either alone or in combination with other potential anti-HCV agents.

https://www.ncbi.nlm.nih.gov/pubmed/29775725

PLoS One. 2018 Jul;13(7):e0199612.
Quercetin prevents rhinovirus-induced progression of lung disease in mice with COPD phenotype.
Farazuddin M, Mishra R, Jing Y, Srivastava V, Comstock AT, Sajjan US.

Acute exacerbations are the major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Rhinovirus, which causes acute exacerbations may also accelerate progression of lung disease in these patients. Current therapies reduces the respiratory symptoms and does not treat the root cause of exacerbations effectively. We hypothesized that quercetin, a potent antioxidant and anti-inflammatory agent with antiviral properties may be useful in treating rhinovirus-induced changes in COPD. Mice with COPD phenotype maintained on control or quercetin diet and normal mice were infected with sham or rhinovirus, and after 14 days mice were examined for changes in lung mechanics and lung inflammation. Rhinovirus-infected normal mice showed no changes in lung mechanics or histology. In contrast, rhinovirus-infected mice with COPD phenotype showed reduction in elastic recoiling and increase in lung inflammation, goblet cell metaplasia, and airways cholinergic responsiveness compared to sham-infected mice. Interestingly, rhinovirus-infected mice with COPD phenotype also showed accumulation of neutrophils, CD11b+/CD11c+ macrophages and CD8+ T cells in the lungs. Quercetin supplementation attenuated rhinovirus-induced all the pathologic changes in mice with COPD phenotype. Together these results indicate that quercetin effectively mitigates rhinovirus-induced progression of lung disease in a mouse model of COPD. Therefore, quercetin may be beneficial in the treatment of rhinovirus-associated exacerbations and preventing progression of lung disease in COPD.

https://www.ncbi.nlm.nih.gov/pubmed/29975735

Microb Pathog. 2018 May;118:301-309.
Study on antiviral activities, drug-likeness and molecular docking of bioactive compounds of Punica granatum L. to Herpes simplex virus – 2 (HSV-2).
Arunkumar J, Rajarajan S.

Herpes simplex virus – 2 (HSV-2) causes lifelong persisting infection in the immunocompromised host and intermittent in healthy individuals with high morbidity in neonatals and also increase the transmission of HIV. Acyclovir is widely used drug to treat HSV-2 infection but it unable to control viral latency and recurrent infection and prolonged usage lead to drug resistance. Plant-based bioactive compounds are the lead structural bio-molecules play an inevitable role as a potential antiviral agent with reduced toxicity. Therefore, there is an urgent need to develop anti-HSV-2 bioactive molecules to prevent viral resistance and control of latent infection. Punica granatum fruit is rich in major bioactive compounds with potential antimicrobial properties. Hence, we evaluated the anti-HSV-2 efficacy of lyophilized extracts and bioactive compounds isolated from fruit peel of P. granatum. As a result, ethanolic peel extract showed significant inhibition at 62.5 μg/ml. Hence, the fruit peel ethanolic extract was subjected for the isolation of bioactive compounds isolation by bioactivity-guided fractionation. Among isolated bioactive compounds, punicalagin showed 100% anti-HSV-2 activity at 31.25 μg/ml with supportive evidence of desirable in silico ADMET properties and strong interactions to selected protein targets of HSV-2 by docking analysis.

https://www.ncbi.nlm.nih.gov/pubmed/29604421

PLoS One. 2017 Jun;12(6):e0179291.
Potentiated virucidal activity of pomegranate rind extract (PRE) and punicalagin against Herpes simplex virus (HSV) when co-administered with zinc (II) ions, and antiviral activity of PRE against HSV and aciclovir-resistant HSV.
Houston DMJ, Bugert JJ, Denyer SP, Heard CM.

Erratum in
Correction: Potentiated virucidal activity of pomegranate rind extract (PRE) and punicalagin against Herpes simplex virus (HSV) when co-administered with zinc (II) ions, and antiviral activity of PRE against HSV and aciclovir-resistant HSV. [PLoS One. 2017]

Background: There is a clinical need for new therapeutic products against Herpes simplex virus (HSV). The pomegranate, fruit of the tree Punica granatum L, has since ancient times been linked to activity against infection. This work probed the activity of pomegranate rind extract (PRE) and co-administered zinc (II) ions.

Materials and Methods: PRE was used in conjunction with zinc (II) salts to challenge HSV-1 and aciclovir-resistant HSV in terms of virucidal plaque assay reduction and antiviral activities in epithelial Vero host cells. Cytotoxicity was determined by the MTS assay using a commercial kit.

Results: Zinc sulphate, zinc citrate, zinc stearate and zinc gluconate demonstrated similar potentiated virucidal activity with PRE against HSV-1 by up to 4-fold. A generally parabolic relationship was observed when HSV-1 was challenged with PRE and varying concentrations of ZnSO4, with a maximum potentiation factor of 5.5. Punicalagin had 8-fold greater virucidal activity than an equivalent mass of PRE. However, antiviral data showed that punicalagin had significantly lower antiviral activity compared to the activity of PRE (EC50 = 0.56 μg mL-1) a value comparable to aciclovir (EC50 = 0.18 μg mL-1); however, PRE also demonstrated potency against aciclovir-resistant HSV (EC50 = 0.02 μg mL-1), whereas aciclovir showed no activity. Antiviral action of PRE was not influenced by ZnSO4. No cytotoxicity was detected with any test solution.

Conclusions: The potentiated virucidal activity of PRE by coadministered zinc (II) has potential as a multi-action novel topical therapeutic agent against HSV infections, such as coldsores.

https://www.ncbi.nlm.nih.gov/pubmed/28665969

BMC Complement Altern Med. 2017 Feb;17(1):110.
Anti-HSV-2 activity of Terminalia chebula Retz extract and its constituents, chebulagic and chebulinic acids.
Kesharwani A, Polachira SK, Nair R, Agarwal A, Mishra NN, Gupta SK.

Background: Development of new and effective therapeutics for sexually transmitted herpes simplex virus-2 (HSV-2) infection is important from public health perspective. With an aim to identify natural products from medicinal plants, in the present study, the potential of Terminalia chebula Retz was investigated for its activity against HSV-2.

Methods: Fruits of Terminalia chebula Retz were used to prepare 50% ethanolic extract. In addition, chebulagic acid and chebulinic acid both purified from T. chebula were also used. The extract as well as purified compounds were first used to determine their in vitro cytotoxicity on Vero cells by MTT assay. T. chebula extract, chebulagic acid, chebulinic acid along with acyclovir were subsequently assessed for direct anti-viral activity, and their ability to inhibit attachment and penetration of HSV-2 to the Vero cells. In addition, their anti-HSV-2 activity was also determined by in vitro post-infection plaque reduction assay.

Results: Cytotoxicity assay using Vero cells revealed CC₅₀ = 409.71 ± 47.70 μg/ml for the extract whereas chebulagic acid and chebulinic acid showed more than 95% cell viability up to 200 μg/ml. The extract from T. chebula (IC₅₀ = 0.01 ± 0.0002 μg/ml), chebulagic (IC₅₀ = 1.41 ± 0.51 μg/ml) and chebulinic acids (IC₅₀ = 0.06 ± 0.002 μg/ml) showed dose dependent potent in vitro direct anti-viral activity against HSV-2. These also effectively prevented the attachment as well as penetration of the HSV-2 to Vero cells. In comparison, acyclovir showed poor direct anti-viral activity and failed to significantly (p > 0.05) prevent the attachment as well as penetration of HSV-2 to Vero cells when tested upto 50 μg/ml. However, in post-infection plaque reduction assay, T. chebula extract, chebulagic and chebulinic acids showed IC₅₀ values of 50.06 ± 6.12, 31.84 ± 2.64, and 8.69 ± 2.09 μg/ml, respectively, which were much lower than acyclovir (71.80 ± 19.95 ng/ml).

Conclusions: The results presented herein suggest that T. chebula extract, chebulagic and chebulinic acids have higher direct antiviral activity against HSV-2 and efficacy to inhibit virus attachment and penetration to the host cells as compared to acyclovir. However, acyclovir is more potent to inhibit post-infection virus replication. Hence, T. chebula may be a useful candidate for developing alternative therapy for prevention of sexually transmitted HSV-2 infection.

https://www.ncbi.nlm.nih.gov/pubmed/28196487

Eur J Pharm Sci. 2017 Jan;96:99-106.
In vitro permeation and biological activity of punicalagin and zinc (II) across skin and mucous membranes prone to Herpes simplex virus infection.
Houston DMJ, Robins B, Bugert JJ, Denyer SP, Heard CM.

Coadministration of pomegranate rind extract (PRE) and zinc (II) ions has recently been reported as a potential new topical treatment for Herpes simplex virus (HSV) infections. In the current work we examined the in vitro topical delivery of punicalagin (major phytochemical of PRE) and zinc from hydrogels across epithelial membranes that can become infected with HSV. Porcine epidermal, buccal and vaginal mucous membranes were excised and mounted in Franz diffusion cells and dosed with a simple hydrogel containing PRE and zinc sulphate (ZnSO₄). The permeation of punicalagin and zinc were determined by HPLC and ICPMS respectively; punicalagin was also determined in the basal layers by reverse tape stripping. Receptor phases from the epidermal membrane experiment were also used to challenge HSV-1 in Vero host cells, and ex vivo porcine skin was used to probe COX-2 modulation. Punicalagin and zinc permeated each of the three test membranes, with significantly greater amounts of both delivered across the epidermal membrane. The amounts of punicalagin permeating the buccal and vaginal membranes were similar, although the amount of zinc permeating the vaginal membrane was comparatively very large – it is known that zinc interacts with vaginal mucosa. The punicalagin recovered by reverse tape stripping of the epidermal, buccal and vaginal membranes gave 0.47±0.016, 0.45±0.052 and 0.51±0.048nMcm^-2 respectively, and were statistically the same (p<0.05). A 2.5 log reduction was achieved against HSV-1 using diffusion cell receptor phase, and COX-2 expression was reduced by 64% in ex vivo skin after 6h. Overall, a hydrogel containing 1.25mgmL^-1 PRE and 0.25M ZnSO₄ was able to topically deliver both the major bioactive compound within PRE and Zn (II) across all membranes and into the site specific region of Herpes simplex vesicular clusters, while maintaining potentiated virucidal and anti-inflammatory properties. This novel therapeutic system therefore has potential for the topical treatment of HSV infections.

https://www.ncbi.nlm.nih.gov/pubmed/27516148

Biomed Pharmacother. 2016 Oct;83:881-891.
Therapeutic potential of Taraxacum officinale against HCV NS5B polymerase: In-vitro and In silico study.
Rehman S, Ijaz B, Fatima N, Muhammad SA, Riazuddin S.

Discovery of alternative and complementary regimens for HCV infection treatment is a need of time from clinical as well as economical point of views. Low cost of bioactive natural compounds production, high biochemical diversity and inexistent/milder side effects contribute to new therapies. Aim of this study is to clarify anti-HCV role of Taraxacum officinale, a natural habitat plant rich of flavonoids. In this study, methanol extract of T. officinale leaves was initially analyzed for its cytotoxic activity in human hepatoma (Huh-7) and CHO cell lines. Hepatoma cells were transfected with pCR3.1/Flagtag/HCV NS5B gene cloned vector (genotype 1a) along with T. officinale extract. Considering NS5B polymerase as potential therapeutic drug target, twelve phytochemicals of T. officinale were selected as ligands for molecular interaction with NS5B protein using Molecular Operating Environment (MOE) software. Sofosbuvir (Sovaldi: brand name) currently approved as new anti-HCV drug, was used as standard in current study for comparative analysis in computational docking screening. HCV NS5B polymerase as name indicates plays key role in viral genome replication. On the basis of which NS5B gene is targeted for determining antiviral role of T. officinale extract and 65% inhibition of NS5B expression was documented at nontoxic dose concentration (200μg/ml) using Real-time PCR. In addition, 57% inhibition of HCV replication was recorded when incubating Huh-7 cells with high titer serum of HCV infected patients along with leaves extract. Phytochemicals for instance d-glucopyranoside (-31.212 Kcal/mol), Quercetin (-29.222 Kcal/mol), Luteolin (-26.941 Kcal/mol) and some others displayed least binding energies as compared to standard drug Sofosbuvir (-21.0746 Kcal/mol). Results of our study strongly revealed that T. officinale leaves extract potentially blocked the viral replication and NS5B gene expression without posing any toxic effect on normal fibroblast cells of body.

https://www.ncbi.nlm.nih.gov/pubmed/27513212

Drug Discov Today. 2016 Feb;21(2):333-41.
Natural polyphenols: potential in the prevention of sexually transmitted viral infections.
Date AA, Destache CJ.

Sexually transmitted viral infections represent a major public health concern due to lack of effective prevention strategies. Efforts are ongoing to develop modalities that can enable simultaneous prevention of multiple sexually transmitted infections. In the present review, we discuss the potential of natural polyphenols to prevent sexually transmitted viral infections. The review gives an account of various in vitro and in vivo studies carried out on epigallocatechin gallate, theaflavins (black tea polyphenols), resveratrol, genistein and curcumin to highlight their potential to prevent sexually transmitted infections caused by HIV (human immunodeficiency virus), HSV (herpes simplex virus) and HPV (human papilloma virus).

https://www.ncbi.nlm.nih.gov/pubmed/26546859

Animal. 2015 Sep;9(9):1473-80.
Improved performance and immunological responses as the result of dietary genistein supplementation of broiler chicks.
Rasouli E, Jahanian R.

The present study aimed to investigate the effect of supplemental genistein (an isoflavonoid) on performance, lymphoid organs’ development, and cellular and humoral immune responses in broiler chicks. A total of 675-day-old male broiler chicks (Ross 308) were randomly assigned to the five replicate pens (15 chicks each) of nine experimental diets. Dietary treatments included a negative (not-supplemented) control diet, two positive control groups (virginiamycin or zinc-bacitracin, 20 mg/kg), and diets containing 10, 20, 40, 80, 160 and 320 mg/kg of genistein. The cutaneous basophil hypersensivity (CBH) test was measured at day 10 of age after toe web injection with phytohemagglutinin-P. In addition, sera samples were collected after different antigen inoculations to investigate antibody responses. At day 28 of age, three randomly selected birds from each pen were euthanized to evaluate the relative weights of lymphoid organs. Results showed that dietary supplementation of both antibiotics increased (P<0.01) feed intake during 1 to 42 days of age. Furthermore, daily weight gain was influenced (P<0.01) by dietary treatments throughout the trial, so that the birds fed on antibiotics and 20 to 80 mg/kg genistein diets revealed the greater weight gains compared with other experimental groups. The best (P<0.05) feed conversion ratio assigned to the birds fed on diets containing antibiotics and moderate levels (40 to 80 mg/kg) of genistein. Although the relative weights of thymus (P<0.05) and bursa of Fabricius (P<0.01) were greater in birds fed on genistein-supplemented diets compared with antibiotics-supplemented birds, the spleen weight was not affected by experimental diets. Similarly, CBH response and antibody titers against Newcastle and infectious bronchitis disease viruses were markedly (P<0.05) greater in chicks fed on diets supplemented with 20 to 80 mg/kg of genistein. Interestingly, the higher dosages of genistein suppressed CBH and antibody responses to the levels seen by control and antibiotics chicks. Dietary inclusion of genistein increased (P<0.05) lymphocytes and subsequently reduced (P<0.01) heterophil to lymphocyte ratio. The present findings indicate that dietary genistein supplementation at the levels of 20 to 80 mg/kg not only improves growth performance, but also could beneficially affect immunological responses in broiler chicks.

https://www.ncbi.nlm.nih.gov/pubmed/25998982

BMC Complement Altern Med. 2015 Jun;15:179.
Novel antiviral activity of mung bean sprouts against respiratory syncytial virus and herpes simplex virus -1: an in vitro study on virally infected Vero and MRC-5 cell lines.
Hafidh RR, Abdulamir AS, Abu Bakar F, Sekawi Z, Jahansheri F, Jalilian FA.

Background: New sources for discovering novel antiviral agents are desperately needed. The current antiviral products are both expensive and not very effective.

Methods: The antiviral activity of methanol extract of mung bean sprouts (MBS), compared to Ribavarin and Acyclovir, on respiratory syncytial virus (RSV) and Herpes Simplex virus -1 (HSV-1) was investigated using cytotoxicity, virus yield reduction, virucidal activity, and prophylactic activity assays on Vero and MRC-5 cell lines. Moreover, the level of antiviral cytokines, IFNβ, TNFα, IL-1, and IL-6 was assessed in MBS-treated, virally infected, virally infected MBS-treated, and control groups of MRC-5 cells using ELISA.

Results: MBS extract showed reduction factors (RF) 2.2 × 10 and 0.5 × 10(2) for RSV and HSV-1, respectively. The 2 h incubation virucidal and prophylactic selectivity indices (SI) of MBS on RSV were 14.18 and 12.82 versus Ribavarin SI of 23.39 and 21.95, respectively, and on HSV-1, SI were 18.23 and 10.9 versus Acyclovir, 22.56 and 15.04, respectively. All SI values were >10 indicating that MBS has a good direct antiviral and prophylactic activities on both RSV and HSV-1. Moreover, interestingly, MBS extract induced vigorously IFNβ, TNFα, IL-1, and IL-6 cytokines in MRC-5 infected-treated group far more than other groups (P < 0.05) and induced TNFα and IL-6 in treated group more than infected group (P < 0.05).

Conclusions: MBS extract has potent antiviral and to a lesser extent, prophylactic activities against both RSV and HSV-1, and in case of HSV-1, these activities were comparable to Acyclovir. Part of the underlying mechanism(s) of these activities is attributed to MBS potential to remarkably induce antiviral cytokines in human cells. Hence, we infer that MBS methanol extract could be used as such or as purified active component in protecting and treating RSV and HSV-1 infections. More studies are needed to pinpoint the exact active components responsible for the MBS antiviral activities.

https://www.ncbi.nlm.nih.gov/pubmed/26062546

BMC Microbiol. 2013 Aug;13:187.
Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry.
Lin LT, Chen TY, Lin SC, Chung CY, Lin TC, Wang GH, Anderson R, Lin CC, Richardson CD.

Background: We previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry.

Results: Extensive analysis of the tannins’ mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses.

Conclusions: CHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified.

https://www.ncbi.nlm.nih.gov/pubmed/23924316

Antiviral Res. 2012 Jun;94(3):258-71.
Quercetin inhibits rhinovirus replication in vitro and in vivo. Ganesan S, Faris AN, Comstock AT, Wang Q, Nanua S, Hershenson MB, Sajjan US.

Rhinovirus (RV), which is responsible for the majority of common colds, also causes exacerbations in patients with asthma and chronic obstructive pulmonary disease. So far, there are no drugs available for treatment of rhinovirus infection. We examined the effect of quercetin, a plant flavanol on RV infection in vitro and in vivo. Pretreatment of airway epithelial cells with quercetin decreased Akt phosphosphorylation, viral endocytosis and IL-8 responses. Addition of quercetin 6h after RV infection (after viral endocytosis) reduced viral load, IL-8 and IFN responses in airway epithelial cells. This was associated with decreased levels of negative and positive strand viral RNA, and RV capsid protein, abrogation of RV-induced eIF4GI cleavage and increased phosphorylation of eIF2α. In mice infected with RV, quercetin treatment decreased viral replication as well as expression of chemokines and cytokines. Quercetin treatment also attenuated RV-induced airway cholinergic hyperresponsiveness. Together, our results suggest that quercetin inhibits RV endocytosis and replication in airway epithelial cells at multiple stages of the RV life cycle. Quercetin also decreases expression of pro-inflammatory cytokines and improves lung function in RV-infected mice. Based on these observations, further studies examining the potential benefits of quercetin in the prevention and treatment of RV infection are warranted.

https://www.ncbi.nlm.nih.gov/pubmed/22465313

J Virol. 2011 May;85(9):4386-98.
Hydrolyzable tannins (chebulagic acid and punicalagin) target viral glycoprotein-glycosaminoglycan interactions to inhibit herpes simplex virus 1 entry and cell-to-cell spread.
Lin LT, Chen TY, Chung CY, Noyce RS, Grindley TB, McCormick C, Lin TC, Wang GH, Lin CC, Richardson CD.

Herpes simplex virus 1 (HSV-1) is a common human pathogen that causes lifelong latent infection of sensory neurons. Non-nucleoside inhibitors that can limit HSV-1 recurrence are particularly useful in treating immunocompromised individuals or cases of emerging acyclovir-resistant strains of herpesvirus. We report that chebulagic acid (CHLA) and punicalagin (PUG), two hydrolyzable tannins isolated from the dried fruits of Terminalia chebula Retz. (Combretaceae), inhibit HSV-1 entry at noncytotoxic doses in A549 human lung cells. Experiments revealed that both tannins targeted and inactivated HSV-1 viral particles and could prevent binding, penetration, and cell-to-cell spread, as well as secondary infection. The antiviral effect from either of the tannins was not associated with induction of type I interferon-mediated responses, nor was pretreatment of the host cell protective against HSV-1. Their inhibitory activities targeted HSV-1 glycoproteins since both natural compounds were able to block polykaryocyte formation mediated by expression of recombinant viral glycoproteins involved in attachment and membrane fusion. Our results indicated that CHLA and PUG blocked interactions between cell surface glycosaminoglycans and HSV-1 glycoproteins. Furthermore, the antiviral activities from the two tannins were significantly diminished in mutant cell lines unable to produce heparan sulfate and chondroitin sulfate and could be rescued upon reconstitution of heparan sulfate biosynthesis. We suggest that the hydrolyzable tannins CHLA and PUG may be useful as competitors for glycosaminoglycans in the management of HSV-1 infections and that they may help reduce the risk for development of viral drug resistance during therapy with nucleoside analogues.

https://www.ncbi.nlm.nih.gov/pubmed/21307190

Fitoterapia. 2011 Apr;82(3):408-13.
Inhibition of viral adsorption and penetration by an aqueous extract from Rhododendron ferrugineum L. as antiviral principle against herpes simplex virus type-1.
Gescher K, Kühn J, Hafezi W, Louis A, Derksen A, Deters A, Lorentzen E, Hensel A.

The polyphenol-enriched aqueous extract RF from the aerial parts of Rhododendron ferrugineum exhibited strong antiviral activity against herpes simplex virus type-1 while adenovirus 3 was not affected. RF exhibited an IC(50) of 7.4 μg/mL and a selectivity index of 64 when added to the virus inoculum prior to infection. RF abolished virus entry into the host cell by blocking attachment to the cell surface. When added after attachment at a concentration of >25 μg/mL, RF inhibited also penetration of HSV-1 into the host cell. RF directly interacts with viral envelope proteins as demonstrated for the viral glycoprotein gD.

https://www.ncbi.nlm.nih.gov/pubmed/21129454

J Ethnopharmacol. 2011 Mar;134(2):468-74.
Proanthocyanidin-enriched extract from Myrothamnus flabellifolia Welw. exerts antiviral activity against herpes simplex virus type 1 by inhibition of viral adsorption and penetration.
Gescher K, Kühn J, Lorentzen E, Hafezi W, Derksen A, Deters A, Hensel A.

Aim of the Study: Extracts from the aerial parts of the South African resurrection plant Myrothamnus flabellifolia Welw. have been used traditionally against infections of the upper respiratory tract and skin diseases. A polyphenol-enriched extract was investigated for potential antiviral effects against herpes simplex virus type 1 (HSV-1) and adenovirus, and the underlying mode of action was to be studied.

Materials and Methods: Antiviral effects of an acetone-water extract (MF) from Myrothamnus flabellifolia on HSV-1 and adenovirus type 3 were tested in infected Vero cells by plaque reduction assay, MTT test and immunofluorescence. The influence of the extract on the HSV-1 envelope glycoprotein D was shown by Western blot. Organotypic full thickness skin models consisting of multilayer skin equivalents were used for the investigation of MF effects on HSV-1 replication.

Results: MF exhibited strong antiviral activity against HSV-1. The HSV-1-specific inhibitory concentration (IC(50)) was determined as 0.4 μg/mL and the cytotoxic concentration (CC(50)) against Vero cells as 50 μg/mL. A selectivity index (SI) (ratio of CC(50) to IC(50)) of approximately 120 was calculated when MF was added to the virus inoculum for 1h at 37°C prior to infection. The replication of adenovirus 3 was not affected by MF. MF abolished virus entry into the host cell by blocking viral attachment to the cell surface. When added after attachment at a concentration of >6 μg/mL, the extract also inhibited penetration of HSV-1 into the host cell. Polyphenolic compounds from MF directly interacted with viral particles, leading to the oligomerisation of envelope proteins as demonstrated for the essential viral glycoprotein D (gD). Using organotypic full thickness tissue cultures, it was shown that treatment of HSV-1 infected cultures with the MF resulted in reduced viral spread.

Conclusions: A polyphenol-enriched extract from Myrothamnus flabellifolia strongly acts against HSV-1 by blocking viral entry into the cells.

https://www.ncbi.nlm.nih.gov/pubmed/21211557

BMC Complement Altern Med. 2011 Feb;11:15.
Effects of Green Tea Catechins and Theanine on Preventing Influenza Infection Among Healthcare Workers: A Randomized Controlled Trial.
Matsumoto K, Yamada H, Takuma N, Niino H, Sagesaka YM.

Background: Experimental studies have revealed that green tea catechins and theanine prevent influenza infection, while the clinical evidence has been inconclusive. This study was conducted to determine whether taking green tea catechins and theanine can clinically prevent influenza infection.
Design, setting, and participants: A randomized, double-blind, placebo-controlled trial of 200 healthcare workers conducted for 5 months from November 9, 2009 to April 8, 2010 in three healthcare facilities for the elderly in Higashimurayama, Japan.
Interventions: The catechin/theanine group received capsules including green tea catechins (378 mg/day) and theanine (210 mg/day). The control group received placebo.
Main outcome measures: The primary outcome was the incidence of clinically defined influenza infection. Secondary outcomes were (1) laboratory-confirmed influenza with viral antigen measured by immunochromatographic assay and (2) the time for which the patient was free from clinically defined influenza infection, i.e., the period between the start of intervention and the first diagnosis of influenza infection, based on clinically defined influenza infection.
Results: Eligible healthcare workers (n = 197) were enrolled and randomly assigned to an intervention; 98 were allocated to receive catechin/theanine capsules and 99 to placebo. The incidence of clinically defined influenza infection was significantly lower in the catechin/theanine group (4 participants; 4.1%) compared with the placebo group (13 participants; 13.1%) (adjusted OR, 0.25; 95% CI, 0.07 to 0.76, P = 0.022). The incidence of laboratory-confirmed influenza infection was also lower in the catechin/theanine group (1 participant; 1.0%) than in the placebo group (5 participants; 5.1%), but this difference was not significant (adjusted OR, 0.17; 95% CI, 0.01 to 1.10; P = 0.112). The time for which the patient was free from clinically defined influenza infection was significantly different between the two groups (adjusted HR, 0.27; 95% CI, 0.09 to 0.84; P = 0.023).
Conclusions: Among healthcare workers for the elderly, taking green tea catechins and theanine may be effective prophylaxis for influenza infection.

https://pubmed.ncbi.nlm.nih.gov/21338496/

Antiviral Res. 2010 Nov;88(2):227-35.
Inhibition of influenza virus replication by plant-derived isoquercetin.
Kim Y, Narayanan S, Chang KO.

Influenza virus infects the respiratory system of human and animals causing mild to severe illness which could lead to death. Although vaccines are available, there is still a great need for influenza antiviral drugs to reduce disease progression and virus transmission. Currently two classes (M2 channel blockers and neuraminidase inhibitors) of FDA-approved influenza antiviral drugs are available, but there are great concerns of emergence of viral resistance. Therefore, timely development of new antiviral drugs against influenza viruses is crucial. Plant-derived polyphenols have been studied for antioxidant activity, anti-carcinogenic, and cardio- and neuroprotective actions. Recently, some polyphenols, such as resveratrol and epigallocatechin gallate, showed significant anti-influenza activity in vitro and/or in vivo. Therefore we investigated selected polyphenols for their antiviral activity against influenza A and B viruses. Among the polyphenols we tested, isoquercetin inhibited the replication of both influenza A and B viruses at the lowest effective concentration. In a double treatment of isoquercetin and amantadine, synergistic effects were observed on the reduction of viral replication in vitro. The serial passages of virus in the presence of isoquercetin did not lead to the emergence of resistant virus, and the addition of isoquercetin to amantadine or oseltamivir treatment suppressed the emergence of amantadine- or oseltamivir-resistant virus. In a mouse model of influenza virus infection, isoquercetin administered intraperitoneally to mice inoculated with human influenza A virus significantly decreased the virus titers and pathological changes in the lung. Our results suggest that isoquercetin may have the potential to be developed as a therapeutic agent for the treatment of influenza virus infection and for the suppression of resistance in combination therapy with existing drugs.

https://www.ncbi.nlm.nih.gov/pubmed/20826184

Antivir Chem Chemother. 2004 May;15(3):153-9.
Inhibitory effect of medicinal herbs against RNA and DNA viruses.
Ruffa MJ, Wagner ML, Suriano M, Vicente C, Nadinic J, Pampuro S, Salomón H, Campos RH, Cavallaro L.

Fifteen Argentine medicinal plants were tested for their antiviral activity in vitro against herpes simplex viruses types 1 and 2 (HSV-1 and 2), bovine viral diarrhoea virus type 1 (BVDV-1), influenza virus type A (Inf A) and human immunodeficiency virus type 1 (HIV-1). Antiviral activity was evaluated by a reduction in cytopathic effect, plaque-forming units and p24 HIV-1 antigen. The Selective Index of the active extract (SI(extract) = CC50(extract)/EC50(extract)) of Coronopus didymus (SI(extract) = 110.7), Juglans australis (SI(extract) = 8.1) and Lippia alba (SI(extract) = 19.2) against BVDV-1, HSV-1 and influenza A virus, respectively, justify a further analysis. None of the seven plants assayed against HIV-1 displayed any antiviral activity. The results of this study justify the continuing isolation and characterization of the antiviral components present.

https://www.ncbi.nlm.nih.gov/pubmed/15266897

Chemotherapy. 2002 Jul;48(3):144-7.
Antiviral activity of Petiveria alliacea against the bovine viral diarrhea virus.
Ruffa MJ, Perusina M, Alfonso V, Wagner ML, Suriano M, Vicente C, Campos R, Cavallaro L.

Background: Natural products are a relevant source of antiviral drugs. Five medicinal plants used in Argentina have been assayed to detect inhibition of viral growth.

Methods: Antiviral activity of the infusions and methanolic extracts of Aristolochia macroura, Celtis spinosa, Plantago major, Schinus areira, Petiveria alliacea and four extracts obtained from the leaves and stems of the last plant were evaluated by the plaque assay.

Results: P. alliacea, unlike A. macroura, C. spinosa, P. major and S. areira, inhibited bovine viral diarrhea virus (BVDV) replication. Neither P. alliacea nor the assays of the other plants were active against herpes simplex virus type 1, poliovirus type 1, adenovirus serotype 7 and vesicular stomatitis virus type 1. Four extracts of P. alliacea were assayed to detect anti-BVDV activity. Ethyl acetate (EC(50) of 25 microg/ml) and dichloromethane (EC(50) of 43 microg/ml) extracts were active; moreover, promising SI (IC(50)/EC(50)) values were obtained.

Conclusion: BVDV is highly prevalent in the cattle population, there are no antiviral compounds available; additionally, it is a viral model of the hepatitis C virus. For these reasons and in view of the results obtained, the isolation and characterization of the antiviral components present in the P. alliacea extracts is worth carrying out in the future.

https://www.ncbi.nlm.nih.gov/pubmed/12138331

J Basic Clin Physiol Pharmacol. 2020 Mar. pii: /j/jbcpp.ahead-of-print/jbcpp-2019-0206/jbcpp-2019-0206.xml.
Silymarin: not just another antioxidant.
Camini FC, Costa DC.

Silymarin (Silybum marianum; SM), popularly known as milk thistle, is an extract that has been used for many centuries to treat liver diseases. In recent years, several studies have shown that SM is not only just another antioxidant but also a multifunctional compound that exhibits several beneficial properties for use in the treatment and prevention of different types of pathologies and disorders. This review aims at demonstrating the main protective activities of SM in diseases, such as cancer, diabetes, hepatitis, non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis C virus, hepatitis B virus, metabolic syndrome, depression, cardiovascular diseases and thalassemia, in addition to its photoprotective activity in in vitro tests and preclinical studies. Its main functions include antioxidant and anti-inflammatory effects, and it acts as modulator of signaling pathways. It has been suggested that SM presents great multifunctional potential and is capable of achieving promising results in different types of research. However, caution is still needed regarding its indiscriminate use in humans as there are only a few clinical studies relating to the adequate dose and the actual efficacy of this extract in different types of diseases.

https://www.ncbi.nlm.nih.gov/pubmed/32134732

Evid Based Complement Alternat Med. 2020 Feb;2020:7259267.
Chrysophyllum cainito: A Tropical Fruit with Multiple Health Benefits.
Doan HV, Le TP.

Chrysophyllum cainito is a tropical fruit tree with multiple benefits to human health. C. cainito possesses strong antioxidant properties either in vitro or in vivo. Extracts from the leaves, stem bark, fruits, peel, pulp, or seed of C. cainito are promising candidates in traditional medicine for curing diabetes and fighting against bacterial, fungal, and viral infections. C. cainito leaf extract alone or in a complex formula exhibits anti-inflammatory responses by reducing hypersensitivity, acts as inflammatory markers, and has antinociceptive effects. The leaf extract also increases wound healing speed and assists in regulating fat uptake. In addition, the C. cainito fruit shows anticancer activity against osteosarcoma. In conclusion, the aerial parts of C. cainito have strong beneficial biological effects on human health.

https://www.ncbi.nlm.nih.gov/pubmed/32148550

Food Chem Toxicol. 2020 Jan;135:110985.
Probing the effect of quercetin 3-glucoside from Dianthus superbus L against influenza virus infection- In vitro and in silico biochemical and toxicological screening.
Nile SH, Kim DH, Nile A, Park GS, Gansukh E, Kai G.

Investigation of antiviral and cytotoxic effect of quercetin 3-glucoside (Q3G) from Dianthus superbus L over influenza virus infection and replication were studied. Moreover, anti-influenza mechanism was screened by time-dependent antiviral assay, virus-induced symptoms and related gene expressions. The blockade of cap-binding domain of polymerase basic protein subunit were analysed by molecular docking study. The Q3G demonstrated potent antiviral activity showing 4.93, 6.43, 9.94, 8.3, and 7.1 μg/mL of IC₅₀ for A/PR/8/34, A/Victoria/3/75, A/WS/33, B/Maryland/1/59, and B/Lee/40, respectively. The cellular toxicity of Q3G and oseltamivir (control) were tested and >100 μg/mL of CC₅₀ value considered as nontoxic. Influenza A virus infection induced a higher ROS production, however potentially reduced by Q3G treatment and significantly blocked virus infection induced acidic vesicular organelles (AVO). Moreover, Q3G has no inhibitory effect for neuraminidase activity but blocked virus replication through time dependent assay and showed more competitive binding affinity (-8.0 kcal/mal) than GTP (-7.0 kcal/mol) to block polymerase basic protein-2 subunit of influenza virus. Q3G from D. superbus showed potent antiviral activity against influenza A and B viruses with suppressive effect on virus-induced cellular ROS generation and AVO formation. Thus, this study provided a new line of research for Q3G to develop possible natural anti-influenza drug.

https://www.ncbi.nlm.nih.gov/pubmed/31765700

Vet Microbiol. 2019 Nov;238:108431.
Therapeutic effect of Xanthohumol against highly pathogenic porcine reproductive and respiratory syndrome viruses.
Liu X, Bai J, Jiang C, Song Z, Zhao Y, Nauwynck H, Jiang P.

The infection by porcine reproductive and respiratory syndrome virus (PRRSV) has a severe impact on the world swine industry. However, commercially available vaccines provide only incomplete protection against this disease. Thus, novel approaches to control PRRSV infection are essential for the robust and sustainable swine industry. In our previous study, Xanthohumol (Xn), a prenylated flavonoid extracted for hops (Humulus lupulus L), was screened from 386 natural products to inhibit PRRSV proliferation and alleviate oxidative stress induced by PRRSV via the Nrf2-HMOX1 axis in Marc-145 cells. In this study, we furtherly found that Xn could inhibit PRRSV different sub-genotype strains infection with a low IC₅₀ value in porcine primary alveolar macrophages (PAMs). In addition, it caused decreased expression of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α in PAMs infected with PRRSV or treated with lipopolysaccharide. Animal challenge experiments showed that Xn effectively alleviated clinical signs, lung pathology, and inflammatory responses in lung tissues of pigs induced by highly pathogenic PRRSV infection. The results demonstrate that Xn is a promising therapeutic agent to combat PRRSV infections.

https://www.ncbi.nlm.nih.gov/pubmed/31648725

BMC Infect Dis. 2019 Nov;19(1):944.
Glutathione, glutathione peroxidase and some hematological parameters of HIV-seropositive subjects attending clinic in University of Calabar teaching hospital, Calabar, Nigeria.
Coco-Bassey SB, Asemota EA, Okoroiwu HU, Etura JE, Efiong EE, Inyang IJ, Uko EK.

Background: Despite the numerous intervention programmes, HIV still remains a public health concern with a high impact in Sub-Saharan Africa region. Oxidative stress has been documented in HIV subjects as viral infection promotes prolonged activation of immune system, hence, production of increased reactive oxygen species.

Methods: We studied 180 subjects. Of these, 60 were HIV-infected on antiretroviral therapy (ART), 40 were ART naïve HIV-infected and 80 were apparent healthy non HIV-infected subjects. The complete blood count was performed by automated hemoanalyzer, the CD4⁺ T-cell count was performed by cyflow cytometer, while the antioxidant assay was performed using ELISA technique.

Result: All evaluated parameters; glutathione (GSH), glutathione peroxidase (GPX), CD4⁺ T-cell count, haemoglobin (Hb), total white blood cell count (WBC) and platelet count were significantly (P < 0.05) reduced in the HIV-infected subjects. All assessed parameters were found to be significantly (P < 0.5) reduced in the HIV-infected subjects that are ART naive when compared with those on ART. HIV-infected subjects with CD4⁺ T-cell count < 200 cells/mm³ had significantly (P < 0.05) reduced values in all assessed parameters when compared to those with CD4⁺ T-cell count ≥200 cells/mm³. GSH and WBC were found to be significantly (P < 0.05) increased in the female HIV-infected subjects when compared with the male counterpart. Anemia prevalence of 74 and 33% were recorded for the HIV-infected and control subjects, respectively. Gender and ART treatment were found to be associated with anemia in HIV. Male HIV-infected subjects on ART were found to be more likely to have anemia.

Conclusion: Antioxidants; GSH and GPX were found to be significantly reduced in HIV infection. Further probe showed that the antioxidant status was improved in the HIV-infected group on ART.

https://www.ncbi.nlm.nih.gov/pubmed/31703562

Inflammation. 2019 Oct;42(5):1585-1594.
The Protection Potential of Antioxidant Vitamins Against Acute Respiratory Distress Syndrome: a Rat Trial.
Erol N, Saglam L, Saglam YS, Erol HS, Altun S, Aktas MS, Halici MB.

Acute respiratory distress syndrome (ARDS) is a fatal disease that includes inflammation formed by septic and non-septic causes. Reactive oxygen radicals (ROS) play a key role in ARDS pathophysiology and constitute the base of damage process. Antioxidant vitamins are used for inhibiting hazardous effects of radicals. Therefore, effects of antioxidant vitamins such as α-lipoic acid (ALA), vitamin E (VITE), and C (VITC) were investigated on oleic acid (OA)-induced ARDS rat model. Furthermore, high and low dose of methylprednisolone (HDMP, LDMP) was used for comparing effects of the vitamins. In this study, 42 male rats were divided to seven groups named control, OA, ALA, VITE, VITC, LDMP, and HDMP. OA was intravenously administered to all groups except control group and other compounds were orally administered (ALA, VITE, and VITC: 100 mg/kg, LDMP: 5 mg/kg, HDMP: 50 mg/kg) after OA injections. OA increased MDA level in lung tissue and TNF-α and IL-1β cytokine levels in serum. ALA, VITE, VITC, and both dose of MP significantly decreased the cytokine levels. Although OA reduced SOD, CAT, and GSH levels in lung tissue, the vitamins and LDMP markedly enhanced the levels except for HDMP. Furthermore, OA showed thickening in bronchi and alveolar septum, hyperemia in vessels, and inflammatory cell infiltrations in lung tissue histopathological examinations. Antioxidant vitamins may be useful for premedication of ARDS and similar disorders. However, methylprednisolone was not found sufficient for being a therapeutic agent for ARDS

https://www.ncbi.nlm.nih.gov/pubmed/31081527

BMC Plant Biol. 2019 Oct;19(1):450.
Tomato glycosyltransferase Twi1 plays a role in flavonoid glycosylation and defence against virus.
Campos L, López-Gresa MP, Fuertes D, Bellés JM, Rodrigo I, Lisón P.

Background: Secondary metabolites play an important role in the plant defensive response. They are produced as a defence mechanism against biotic stress by providing plants with antimicrobial and antioxidant weapons. In higher plants, the majority of secondary metabolites accumulate as glycoconjugates. Glycosylation is one of the commonest modifications of secondary metabolites, and is carried out by enzymes called glycosyltransferases.

Results: Here we provide evidence that the previously described tomato wound and pathogen-induced glycosyltransferase Twi1 displays in vitro activity toward the coumarins scopoletin, umbelliferone and esculetin, and the flavonoids quercetin and kaempferol, by uncovering a new role of this gene in plant glycosylation. To test its activity in vivo, Twi1-silenced transgenic tomato plants were generated and infected with Tomato spotted wilt virus. The Twi1-silenced plants showed a differential accumulation of Twi1 substrates and enhanced susceptibility to the virus.

Conclusions: Biochemical in vitro assays and transgenic plants generation proved to be useful strategies to assign a role of tomato Twi1 in the plant defence response. Twi1 glycosyltransferase showed to regulate quercetin and kaempferol levels in tomato plants, affecting plant resistance to viral infection.

https://www.ncbi.nlm.nih.gov/pubmed/31655554

Molecules. 2019 Sep;24(19). pii: E3475.
Anti-Hepatitis B Virus Activity of Esculetin from Microsorium fortunei In Vitro and In Vivo.
Huang SX, Mou JF, Luo Q, Mo QH, Zhou XL, Huang X, Xu Q, Tan XD, Chen X, Liang CQ.

Coumarins are widely present in a variety of plants and have a variety of pharmacological activities. In this study, we isolated a coumarin compound from Microsorium fortunei (Moore) Ching; the compound was identified as esculetin by hydrogen and carbon spectroscopy. Its anti-hepatitis B virus (HBV) activity was investigated in vitro and in vivo. In the human hepatocellular liver carcinoma 2.2.15 cell line (HepG2.2.15) transfected with HBV, esculetin effecting inhibited the expression of the HBV antigens and HBV DNA in vitro. Esculetin inhibited the expression of Hepatitis B virus X (HBx) protein in a dose-dependent manner. In the ducklings infected with duck hepatitis B virus (DHBV), the levels of DHBV DNA, duck hepatitis B surface antigen (DHBsAg), duck hepatitis B e-antigen (DHBeAg), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) decreased significantly after esculetin treatment. Summing up the above, the results suggest that esculetin efficiently inhibits HBV replication both in vitro and in vivo, which provides an opportunity for further development of esculetin as antiviral drug.

https://www.ncbi.nlm.nih.gov/pubmed/31557836

Vet Res. 2019 Sep;50(1):61.
Xanthohumol inhibits PRRSV proliferation and alleviates oxidative stress induced by PRRSV via the Nrf2-HMOX1 axis.
Liu X, Song Z, Bai J, Nauwynck H, Zhao Y, Jiang P.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen that causes significant economic losses in the global swine industry. Commercial vaccines provide limited protection against this virus, and no highly effective therapeutic drugs are yet available. In this study, we first screened a library of 386 natural products and found that xanthohumol (Xn), a prenylated flavonoid found in hops, displayed high anti-PRRSV activity by inhibiting PRRSV adsorption onto and internalization into cells. Transcriptome sequencing revealed that Xn treatment stimulates genes associated with the antioxidant response in the nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. Xn causes increased expression of Nrf2, HMOX1, GCLC, GCLM, and NQO1 in Marc-145 cells. The action of Xn against PRRSV proliferation depends on Nrf2 in Marc-145 cells and porcine alveolar macrophages (PAMs). This finding suggests that Xn significantly inhibits PRRSV proliferation and decreases viral-induced oxidative stress by activating the Nrf2-HMOX1 pathway. This information should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV infection.

https://www.ncbi.nlm.nih.gov/pubmed/31506103

BMC Complement Altern Med. 2019 Aug;19(1):202.
Influence of curcumin supplementation on metabolic and lipid parameters of people living with HIV/AIDS: a randomized controlled trial.
Silva TAL, Medeiros DC, Medeiros GCBS, Medeiros RCSC, de Souza Araújo J, Medeiros JA, Ururahy MAG, Santos RVT, Medeiros RMV, Leite-Lais L, Dantas PMS.

Background: Scientific studies have shown that the potential therapeutic efficacy of curcumin in several diseases is due to its potent antioxidant and anti-inflammatory properties. Consequently, curcumin supplementation seems to be a valuable alternative for HIV-infected individuals. The aim of this study is to evaluate the influence of curcumin supplementation on substrate oxidation at rest, body composition, and the lipid profile of physically active people living with HIV/AIDS under antiretroviral therapy.

Methods: This double-blind, crossover, randomized clinical trial was comprised of 20 subjects divided into experimental (EG) and control (CG) groups, receiving 1000 mg curcumin/day and placebo, respectively, during a 30-day period. Substrate oxidation at rest was assessed by indirect calorimetry, body composition was measured by dual-energy x-ray absorptiometry, and the lipid profile was evaluated by blood tests. Data analysis was performed by independent samples and paired t-tests to compare the differences between groups and times. A p-value < 0.05 was accepted as significant.

Results: There were no differences between groups regarding substrate oxidation at rest or body composition. However, serum triglyceride levels were increased after curcumin supplementation (182 vs. 219 mg/dL; p = 0.004).

Conclusion: Curcumin supplementation promoted the elevation of serum triglyceride levels in HIV-infected subjects. Further studies with a larger sample cohort, different curcumin doses, and longer intervention times are needed to validate current observations. In addition, the influence of physical activity, dietary intake, and genetic polymorphisms must be considered in future studies to better understand the impact of curcumin supplementation on the lipid profile of people living with HIV/AIDS under antiretroviral therapy.

https://www.ncbi.nlm.nih.gov/pubmed/31387592

Evid Based Complement Alternat Med. 2019 Aug;2019:1475163.
Zeaxanthin Dipalmitate in the Treatment of Liver Disease.
Bahaji Azami NL, Sun M.

Goji berry, Lycium barbarum, has been widely used in traditional Chinese medicine (TCM), but its properties have not been studied until recently. The fruit is a major source of zeaxanthin dipalmitate (ZD), a xanthophyll carotenoid shown to benefit the liver. Liver disease is one of the most prevalent diseases in the world. Some conditions, such as chronic hepatitis B virus, liver cirrhosis, and hepatocellular carcinoma, remain incurable. Managing them can constitute an economic burden for patients and healthcare systems. Hence, development of more effective pharmacological drugs is warranted. Studies have shown the hepatoprotective, antifibrotic, antioxidant, anti-inflammatory, antiapoptotic, antitumor, and chemopreventive properties of ZD. These findings suggest that ZD-based drugs could hold promise for many liver disorders. In this paper, we reviewed the current literature regarding the therapeutic effects of ZD in the treatment of liver disease.

https://www.ncbi.nlm.nih.gov/pubmed/31531108

Phytother Res. 2019 Mar;33(3):856-858.
Impact of curcumin on energy metabolism in HIV infection: A case study.
da Silva TAL, Medeiros RMV, de Medeiros DC, Medeiros RCSC, de Medeiros JA, de Medeiros GCBS, de Andrade RD, Lais LL, Silva Dantas PM.

Prolonged use of antiretroviral therapy (ART) has been associated with dyslipidemia and impaired energy substrate oxidation (SOxi). Curcumin is a natural bioactive compound, which interacts with molecular targets and holds important metabolic properties. The aim of this study was to evaluate the effect of curcumin supplementation on energetic metabolism of an adult female with HIV/AIDS and under ART. The intervention was performed with 500 mg/day of curcumin for 27 days. Glycemic and lipid profile and SOxi at rest were evaluated before and after intervention. After intervention, improvement of lipid profile and insulin sensibility was observed. Moreover, there was a positive modulation of SOxi at rest. Oral curcumin supplementation can positively modulate the energy metabolism of people living with HIV/AIDS using the ART. However, clinical studies are required in order to confirm our findings in a representative sample.

https://www.ncbi.nlm.nih.gov/pubmed/30648299

Food Chem Toxicol. 2019 Mar;125:313-321.
Utilization of Dianthus superbus L and its bioactive compounds for antioxidant, anti-influenza and toxicological effects.
Kim DH, Park GS, Nile AS, Kwon YD, Enkhtaivan G, Nile SH.

Dianthus superbus (DS) is a traditional medicinal herb well known for its medicinal and therapeutic potential and widely distributed in various Asian countries. The ethyl acetate (EA), butanol (Bu) and distilled water (DW) extracts of DS assessed for extraction of bioactive compounds and their biological activities. The chemical analysis was done using LC-MS/MS and antioxidant, anticancer and antiviral activities were determined. EA extracts showed strong anticancer activity with IC₅₀ of 9.5, 13.8 and 69.9 μg/mL on SKOV, NCL-H1299 and Caski cancer cell lines, respectively. The Bu extracts exhibited strongest antiviral activity with respect to both influenza A and B viruses with IC₅₀ values of 4.97 and 3.9 μg/mL, respectively. Also the metabolic profile for EA, Bu and DW extracts shows high variations and influence precisely the antioxidant, anticancer and antiviral properties. The quercetin 3- rutinoside and isorhamnetin 3- glucoside showed higher neuraminidase inhibition activity in dose dependent manner. Molecular docking study revealed that flavonol glycosides have higher binding activities towards influenza polymerase membrane glycoprotein. Correlation study showed that flavonol glycosides were linked to anti-influenza activity and cyclic peptides with anticancer activities. This study provides vital information for effective utilization of DS for medicinal, food and therapeutic purposes.

https://www.ncbi.nlm.nih.gov/pubmed/30654095

Antiviral Res. 2018 Oct;158:52-62.
Multiple Antiviral Approaches Of (-)-Epigallocatechin-3-Gallate (EGCG) Against Porcine Reproductive And Respiratory Syndrome Virus Infection In Vitro.
Ge M, Xiao Y, Chen H, Luo F, Du G, Zeng F.

Porcine reproductive and respiratory syndrome virus (PRRSV) remains an economically important pathogen in the global pig industry, effective measures to control the virus are still lacking. (-)-Epigallocatechin-3-gallate (EGCG), the most abundant and bioactive catechin in green tea, has been reported to have antiviral effect against the diverse groups of viruses. In this study, the comprehensive anti-PRRSV activity of EGCG was investigated using various in vitro assays. EGCG effectively inhibited PRRSV infection and replication in porcine alveolar macrophages (PAMs), regardless of whether it was administrated pre- or post-infection, and the cytotoxicity to PAMs was low. Next, anti-PRRSV approaches of EGCG were characterized in MARC-145 cells. EGCG was demonstrated to be able to significantly prevent PRRSV from infecting MARC-145 cells either through blocking of EGCG-treated viruses docking to susceptible cells involving a direct virus-EGCG interaction or by blocking of the infective virus binding to EGCG pre-treated cells via triggering down-regulation of viral receptors and/or related proteins required for infection. In addition, PRRSV replication was suppressed in MARC-145 cells treated with EGCG post-infection, likely because of down-regulation of pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-8. Taken together, these data showed that treatment of primary PAMs with EGCG can inhibit PRRSV infection and revealed that multiple antiviral approaches of EGCG operate in PRRSV-susceptible MARC-145 cells.

https://www.ncbi.nlm.nih.gov/pubmed/30048655

Nat Prod Res. 2018 May;32(10):1224-1228.
Anti-influenza effect of the major flavonoids from Salvia plebeia R.Br. via inhibition of influenza H1N1 virus neuraminidase.
Bang S, Li W, Ha TKQ, Lee C, Oh WK, Shim SH.

To determine the compounds responsible for its anti-influenza activities, we isolated the three flavonoids, 6-hydroxyluteolin 7-O-β-d-glucoside (1), nepitrin (2), homoplantaginin (3) from the MeOH extract of Salvia plebeia R.Br. and identified them by comparing the spectroscopic data with that reported in the literature. The contents of the three flavonoids in the whole extract were 108.74 ± 0.95, 46.26 ± 2.19, and 69.35 ± 1.22 mg/g for 6-hydroxyluteolin 7-O-β-d-glucoside, nepitrin, and homoplantaginin, respectively, which demonstrates that they are the major constituents of this plant. The three flavonoids were evaluated for their inhibitory activities against influenza virus H1N1 A/PR/9/34 neuraminidase and H1N1-induced cytopathic effect (CPE) on Madin-Darby canine kidney (MDCK) cells. Our results demonstrated the following arrangement for their anti-influenza activities: nepitrin (2) > 6-hydroxyluteolin 7-O-β-d-glucoside (1) > homoplantaginin (3). The potent inhibitory activities of these flavonoids against influenza suggested their potential to be developed as novel anti-influenza drugs in the future.

https://www.ncbi.nlm.nih.gov/pubmed/28504013

Viruses. 2018 Apr;10(4).
Vitamin E Supplementation Ameliorates Newcastle Disease Virus-Induced Oxidative Stress and Alleviates Tissue Damage in the Brains of Chickens.
Rehman ZU, Qiu X, Sun Y, Liao Y, Tan L, Song C, Yu S, Ding Z, Munir M, Nair V, Meng C, Ding C.

Newcastle disease (ND), characterized by visceral, respiratory, and neurological pathologies, causes heavy economic loss in the poultry industry around the globe. While significant advances have been made in effective diagnosis and vaccine development, molecular mechanisms of ND virus (NDV)-induced neuropathologies remain elusive. In this study, we report the magnitude of oxidative stress and histopathological changes induced by the virulent NDV (ZJ1 strain) and assess the impact of vitamin E in alleviating these pathologies. Comparative profiling of plasma and brains from mock and NDV-infected chicken demonstrated alterations in several oxidative stress makers such as nitric oxide, glutathione, malondialdehyde, total antioxidant capacity, glutathione S-transferase, superoxide dismutase, and catalases. While decreased levels of glutathione and total antioxidant capacity and increased concentrations of malondialdehyde and nitric oxide were observed in NDV-challenged birds at all time points, these alterations were eminent at latter time points (5 days post infection). Additionally, significant decreases in the activities of glutathione S-transferase, superoxide dismutase, and catalase were observed in the plasma and brains collected from NDV-infected chickens. Intriguingly, we observed that supplementation of vitamin E can significantly reduce the alteration of oxidative stress parameters. Under NDV infection, extensive histopathological alterations were observed in chicken brain including neural inflammation, capillary hyperemia, necrosis, and loss of prominent axons, which were reduced with the treatment of vitamin E. Taken together, our findings highlight that neurotropic NDV induces extensive tissue damage in the brain and alters plasma oxidative stress profiles. These findings also demonstrate that supplementing vitamin E ameliorates these pathologies in chickens and proposes its supplementation for NDV-induced stresses.

https://www.ncbi.nlm.nih.gov/pubmed/29614025

Cell Physiol Biochem. 2018;47(4):1655-1666.
Supplementation of Vitamin E Protects Chickens from Newcastle Disease Virus-Mediated Exacerbation of Intestinal Oxidative Stress and Tissue Damage.
Rehman ZU, Che L, Ren S, Liao Y, Qiu X, Yu S, Sun Y, Tan L, Song C, Liu W, Ding Z, Munir M, Nair V, Meng C, Ding C.

BACKGROUND/AIMS: Newcastle disease virus (NDV) causes a highly devastating and contagious disease in poultry, which is mainly attributed to extensive tissue damages in the digestive, respiratory and nervous systems. However, nature and dynamics of NDV-induced oxidative stresses in the intestine of chickens remain elusive.
METHODS: In this study, we examined the magnitude of intestinal oxidative stress and histopathological changes caused by the virulent NDV infection, and explored the protective roles of vitamin E (vit. E) in ameliorating these pathological changes. For these purposes, chickens were divided into four groups namely i) non supplemented and non-challenged (negative control, CON); ii) no supplementation of vit. E but challenged with ZJ1 (positive control, NS+CHA); iii) vit. E supplementation at the dose of 50 IU/day/Kg body weight and ZJ1 challenge (VE50+CHA); and 4) vit. E supplementation at the dose of 100 IU/day/Kg body weight and ZJ1 challenge (VE100+CHA). In all groups, we analyzed concentrations of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (T-AOC), and activity of glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) using biochemical methods. The virus loads were determined by quantitative RT-PCR and antibody titers by hemagglutination inhibition assays. We also examined the histopathological changes in the duodenal and jejunal mucosa at 3 and 5-day post infection (dpi) with NDV.
RESULTS: A significant elevation in the NO level was observed in NDV challenged chickens compared to the CON chickens at 2 dpi. The MDA contents were significantly increased whereas GSH was significantly decreased in NDV-challenged chickens compared to control. Furthermore, activities of GST, CAT, SOD, as well as the TOAC were markedly decreased in challenged chickens in comparison with control. Virus copy numbers were higher in NDV infected NS+CHA group compared to other groups. Severe histopathological changes including inflammation, degeneration and broken villi were observed in the intestine of NDV challenged chickens. However, all these malfunctions of antioxidant system and pathological changes in the intestine were partially or completely reversed by the vit. E supplementation.
CONCLUSIONS: Our results suggest that NDV infection causes oxidative stress and histopathological changes in the duodenum and jejunum of chickens, which can be partially or fully ameliorated by supplementation of vit. E. Additionally, these findings suggest that oxidative stress contributes to the intestinal damages in NDV infected chickens. These findings will help to understand the pathogenesis of NDV and further investigation of therapeutic agents for control of Newcastle disease.

https://www.ncbi.nlm.nih.gov/pubmed/29949793

Nutrition. 2017 Nov-Dec;43-44:61-68.
Effect of chocolate and mate tea on the lipid profile of individuals with HIV/AIDS on antiretroviral therapy: A clinical trial.
Souza SJ, Petrilli AA, Teixeira AM, Pontilho PM, Carioca AA, Luzia LA, Souza JM, Damasceno NR, Segurado AA, Rondó PH.

Objective: HIV/AIDS is generally associated with dyslipidemia and oxidative imbalance, which are caused by the infection itself and by antiretroviral therapy (ART). The flavonoids, found in cocoa and yerba mate, have antioxidant and hypolipidemic properties. The aim of this study was to evaluate the effects of the consumption of dark chocolate and mate tea on the lipid profiles of individuals with HIV/AIDS who are undergoing ART.

Methods: A randomized, double-blind, placebo-controlled crossover clinical trial was conducted with 92 patients receiving ART for ≥6 mo and with viral suppression. The participants were randomized to receive either 65 g of chocolate (with 2148 mg polyphenols) or placebo chocolate (without polyphenols) or 3 g of mate tea (with 107 mg total phenols and 84.24 mg chlorogenic acid) or placebo mate (without polyphenols) for 15 d each, separated by a washout period of 15 d. The lipid profile, including determination of electronegative low-density lipoprotein, was determined after each intervention. The data were analyzed by analysis of variance using the pkcross procedure of the Stata 11.0 software.

Results: Analysis of variance revealed a significant overall difference in mean high-density lipoprotein cholesterol (HDL-C) between all supplements (P = 0.047). Using the paired t test, the effect was attributed to the consumption of dark chocolate (P = 0.046). The other parameters investigated were not improved.

Conclusions: The consumption of dark chocolate for 15 d improved HDL-C concentrations of individuals with HIV/AIDS undergoing ART, possibly due to the presence of fatty acids (stearic acid), polyphenols, and theobromine. This fact is important for the cardiovascular protection of these individuals.

https://www.ncbi.nlm.nih.gov/pubmed/28935146

Virol J. 2017 Sep;14:178.
Fucoidan from Fucus vesiculosus suppresses hepatitis B virus replication by enhancing extracellular signal-regulated Kinase activation.
Li H, Li J, Tang Y, Lin L, Xie Z, Zhou J, Zhang L, Zhang X, Zhao X, Chen Z, Zuo D.

Background: Hepatitis B virus (HBV) infection is a serious public health problem leading to cirrhosis and hepatocellular carcinoma. As the clinical utility of current therapies is limited, the development of new therapeutic approaches for the prevention and treatment of HBV infection is imperative. Fucoidan is a natural sulfated polysaccharide that extracted from different species of brown seaweed, which was reported to exhibit various bioactivities. However, it remains unclear whether fucoidan influences HBV replication or not.

Methods: The HBV-infected mouse model was established by hydrodynamic injection of HBV replicative plasmid, and the mice were treated with saline or fucoidan respectively. Besides, we also tested the inhibitory effect of fucoidan against HBV infection in HBV-transfected cell lines.

Results: The result showed that fucoidan from Fucus vesiculosus decreased serum HBV DNA, HBsAg and HBeAg levels and hepatic HBcAg expression in HBV-infected mice. Moreover, fucoidan treatment also suppressed intracellular HBcAg expression and the secretion of the HBV DNA as well as HBsAg and HBeAg in HBV-expressing cells. Furthermore, we proved that the inhibitory activity by fucoidan was due to the activation of the extracellular signal-regulated kinase (ERK) pathway and the subsequent production of type I interferon. Using specific inhibitor of ERK pathway abrogated the fucoidan-mediated inhibition of HBV replication.

Conclusion: This study highlights that fucoidan might be served as an alternative therapeutic approach for the treatment of HBV infection.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603053/

Sci Rep. 2017 Jan;7:40760.
Inhibition of Influenza A Virus Infection by Fucoidan Targeting Viral Neuraminidase and Cellular EGFR Pathway.
Wang W, Wu J, Zhang X, Hao C, Zhao X, Jiao G, Shan X, Tai W, Yu G.

Development of novel anti-influenza A virus (IAV) drugs with high efficiency and low toxicity is critical for preparedness against influenza outbreaks. Herein, we investigated the anti-IAV activities and mechanisms of fucoidan in vitro and in vivo. The results showed that a fucoidan KW derived from brown algae Kjellmaniella crassifolia effectively blocked IAV infection in vitro with low toxicity. KW possessed broad anti-IAV spectrum and low tendency of induction of viral resistance, superior to the anti-IAV drug amantadine. KW was capable of inactivating virus particles before infection and blocked some stages after adsorption. KW could bind to viral neuraminidase (NA) and inhibit the activity of NA to block the release of IAV. KW also interfered with the activation of EGFR, PKCα, NF-κB, and Akt, and inhibited both IAV endocytosis and EGFR internalization in IAV-infected cells, suggesting that KW may also inhibit cellular EGFR pathway. Moreover, intranasal administration of KW markedly improved survival and decreased viral titers in IAV-infected mice. Therefore, fucoidan KW has the potential to be developed into a novel nasal drop or spray for prevention and treatment of influenza in the future.

https://www.ncbi.nlm.nih.gov/pubmed/28094330

J Ethnopharmacol. 2016 Nov;192:398-405.
Antiviral activities of compounds from aerial parts of Salvia plebeia R. Br.
Bang S, Quy Ha TK, Lee C, Li W, Oh WK, Shim SH.

Ethnopharmacological Relevance: Salvia plebeia R. Br. is an edible plant widely spread in many countries. It has been used as a traditional medicine to treat common cold, flu, cough, hepatitis, hemorrhoids, etc. The purpose of the study is to explicate antiviral compounds responsible for its traditional use for the common cold or flu.

Materials and Methods: The methanolic extract of the aerial parts of S. plebeia was extracted with CHCl₃, EtOAc, and n-BuOH, successively. The EtOAc and CHCl₃ fractions were subjected to a successive of chromatographic method, which led to the isolation of fourteen compounds. Inhibition activities of the isolated compounds were evaluated against.

Results: Chemical investigation of the methanolic extracts of S. plebeia resulted in the isolation of two novel benzoylated monoterpene glycosides, named as plebeiosides A (1) and B (2), together with twelve known compounds including four flavonoids (4-5, 7, 10), two sesquiterpenoids (8, 12), four phenolics (9-10, 13-14), a steroid (6), and a triterpenoid (3). Their chemical structures were elucidated based on spectroscopic data and absolute stereochemistries of 1 and 2 were determined by comparison of optical rotations of their hydrolysates with literature values. Compounds 5, 7, 9, and 11 exhibited potent enzymatic inhibition against H1N1 neuraminidase (IC₅₀ values ranging from 11.18±1.73 to 19.83±2.28μM). Furthermore, two flavonoids (5 and 7) and one rosmarinic acid methyl ester (9) reduced cytopathic effects of the H1N1 virus during replication.

Conclusions: The antiviral activities of the flavonoids and phenolics isolated from the extracts of S. plebeia supported the traditional application of this medicine on common cold or flu. In this study, benzoylated monoterpene glycosides were first found to exist in this species. Moreover, the present study suggested potential of three compounds (5, 7, and 9) to be new lead structures for the development of new neuraminidase inhibitors in the future.

https://www.ncbi.nlm.nih.gov/pubmed/27647011

Phytomedicine. 2016 Aug;23(9):958-67.
Probing the impact of quercetin-7-O-glucoside on influenza virus replication influence.
Gansukh E, Kazibwe Z, Pandurangan M, Judy G, Kim DH.

Background: Influenza virus is still at large and seriously affects social welfare and health. Dianthus superbus is a well-known medicinal plant widely used in Mongolian and Chinese traditional medicine for anti-inflammatory purposes.

Purpose: To investigate the influence of this novel herbal medicinal product over virus infection and virus-induced symptoms

Method: Quercetin-7-O-glucoside was isolated by bioassay (anti-influenza)-guided fractionation. The structural elucidation was made with 1H-NMR and 13C-NMR. Influenza A/Vic/3/75 (H3N2), A/PR/8/34 (H1N1), B/Maryland/1/59 and B/Lee/40 viruses were used for the evaluation of the antiviral activity. Virus-induced reactive oxygen species and autophagy formation levels were studied. The antiviral mechanism was elucidated via time-dependent, pre-, post-incubation assay methods. The viral RNA replication inhibition of Q7G was analyzed using quantitative RT-PCR method. The blocking of polymerase basic protein subunits of influenza viral RNA polymerase by Q7G was detected by in silico molecular docking assays using AutoDock Vina program with m(7)GTP. Additionally, Q7G was tested against M-MuLV RNA polymerase.

Results: Q7G was not cytotoxic (CC50>100µg/ml) in MDCK cells and it showed 3.1µg/ml, 6.61µg/ml, 8.19µg/ml and 5.17µg/ml IC50 values against influenza A/PR/8/34, A/Vic/3/75, B/Lee/40 and B/Maryland/1/59 virus strains, respectively. Treatment of Q7G highly reduced ROS and autophagy formation induced by influenza virus infection. Q7G did not reduce NA activity and did not directly interact with the virus particles. Since viral RNA synthesis was blocked by treatment of Q7G. We targeted viral RNA polymerase for further probing. Interestingly, the binding energy of Q7G on viral PB2 protein was -9.1kcal/mol and was higher than m(7)GTP recorded as -7.5kcal/mol. It also was observe to block M-MuLV RNA polymerase.

Conclusion: Isolated compound Q7G showed strong inhibition activity against influenza A and B viruses. It also reduced virus-induced ROS and autophagy formation. Q7G does not directly bind to the virus particles and did not affect NA activity. These results indicated that Q7G inhibits viral RNA polymerase, and that it occupies the binding site of m(7)GTP on viral PB2 protein.

https://www.ncbi.nlm.nih.gov/pubmed/27387404

J Ethnopharmacol. 2016 Jul;188:144-52.
Antiviral activity of hydroalcoholic extract from Eupatorium perfoliatum L. against the attachment of influenza A virus.
Derksen A, Kühn J, Hafezi W, Sendker J, Ehrhardt C, Ludwig S, Hensel A.

Ethnopharmacological Relevance: Aerial parts of Eupatorium perfoliatum have been traditionally used by American natives as a treatment for fever and infections. Also modern phytotherapy in Europe documents the use of hydroalcoholic extracts of this herbal material for the treatment of infections of the upper respiratory tract.

Aim of the Study: The aim of the present study was to characterize the anti-influenza A virus (IAV) potential of extracts derived from the aerial parts of E. perfoliatum and to identify their antiviral mode of action and potential active fraction’s compounds of the extract.

Materials and Methods: The inhibitory effects of extracts obtained by different organic solvents with different polarities on the cytopathic effect induced by IAV replication was determined in a Madin-Darby Canine Kidney Epithelial (MDCK II) cell-based assay measuring cell viability by MTT stain (MTTIAV assay). Plaque reduction assays were used for investigation of antiviral activity. The mode of action was investigated by different incubation and treatment cycles as well as hemagglutination inhibition assays. Influence of the test extract on tumor necrosis factor (TNF-α) and epidermal growth factor (EGF)-induced cell signaling was analyzed in human lung epithelial (A549) cells. Analytical characterization of extract and fractions obtained from the extract was performed by UHPLC-MS.

Results: Hydroalcoholic extracts from the aerial parts of E. perfoliatum were shown to inhibit growth of a clinical isolate of IAV(H1N1)pdm09 I1 and the influenza virus A/Puerto Rico/8/34 (PR8; H1N1) with a half-maximal inhibitory concentration (IC50) of 7µg/mL and 14µg/mL, and a selectivity index (SI) (half-maximal cytotoxic concentration (CC50)/IC50)) of 52 and 26, respectively. Extracts prepared with dichloromethane and methanol were inactive. At concentrations >1-10µg/mL of the hydroalcoholic extract plaque formation of IAV(H1N1)pdm09 was abrogated. The extract was also active against an oseltamivir-resistant isolate of IAV(H1N1)pdm09. The extract blocked attachment of IAV and interfered with virus-induced hemagglutination. TNF-α-induced signal transduction in A549 cells was not affected, while the EGF-induced signaling to phosphorylated ERK was slightly upregulated by the extract. Bioassay-guided fractionation and subsequent LC-MS analysis indicated that the antiviral activity might be due to polyphenolic compounds with higher molecular weights, which strongly interact with stationary phases of different chromatographic systems. These still unknown compounds with probably high molecular weight could not be isolated in the present study. A variety of different flavonoid glycosides and caffeoyl quinic acids obtained from E. perfoliatum did definitely not contribute to the antiviral effect of the extract and its respective fractions.

Conclusion: Hydroalcoholic extracts from the aerial parts of E. perfoliatum and its main active polyphenolic constituents protect cells from IAV infection by inhibiting viral attachment to the host cells. The extract appears to be a promising expansion of the currently available anti-influenza agents.

https://www.ncbi.nlm.nih.gov/pubmed/27178637

J Microbiol. 2014 Apr;52(4):340-4.
Antiviral effect of flavonol glycosides isolated from the leaf of Zanthoxylum piperitum on influenza virus.
Ha SY, Youn H, Song CS, Kang SC, Bae JJ, Kim HT, Lee KM, Eom TH, Kim IS, Kwak JH.

The ethanol extract of Zanthoxylum piperitum (L.) DC. showed in vitro antiviral activity against influenza A virus. Three flavonol glycosides were isolated from the EtOAc fraction of Z. piperitum leaf by means of activity-guided chromatographic separation. Structures of isolated compounds were identified as quercetin 3-O-β-D-galactopyranoside (1), quercetin 3-O-α-L-rhamnopyranoside (2), kaempferol 3-O-α-L-rhamnopyranoside (3) by comparing their spectral data with literature values. The anti-influenza viral activity of isolates was evaluated using a plaque reduction assay against influenza A/NWS/33 (H1N1) virus. The compounds also were subjected to neuraminidase inhibition assay in influenza A/NWS/33 virus. Compounds 1-3 exhibited antiviral activity against an influenza A virus in vitro, and inhibited the neuraminidase activity at relatively high concentrations.

https://www.ncbi.nlm.nih.gov/pubmed/24682996

Viruses. 2014 Feb;6(2):938-50.
In vitro evaluation of the antiviral activity of the synthetic epigallocatechin gallate analog-epigallocatechin gallate (EGCG) palmitate against porcine reproductive and respiratory syndrome virus.
Zhao C, Liu S, Li C, Yang L, Zu Y.

In this study, epigallocatechin gallate (EGCG) palmitate was synthesized and its anti-porcine reproductive and respiratory syndrome virus (PRRSV) activity was studied. Specifically, EGCG palmitate was evaluated for its ability to inhibit PRRSV infection in MARC-145 cells when administered as pre-, post-, or co-treatment. EGCG and ribavirin were used as controls. The results showed that a 50% cytotoxic concentration (CC50) of EGCG, EGCG palmitate, and ribavirin was achieved at 2,359.71, 431.42, and 94.06 μM, respectively. All three drugs inhibited PRRSV in a dose-dependent manner regardless of the treatment protocol. EGCG palmitate exhibited higher cytotoxicity than EGCG, but lower cytotoxicity than ribavirin. EGCG palmitate anti-PRRSV activity was significantly higher than that of EGCG and ribavirin, both as pre-treatment and post-treatment. Under the former conditions and a tissue culture infectious dose of 10 and 100, the selectivity index (SI) of EGCG palmitate in the inhibition of PRRSV was 3.8 and 2.9 times higher than that of ribavirin when administered as a pre-treatment, while the SI of EGCG palmitate in the inhibition of PRRSV was 3.0 and 1.9 times higher than ribavirin when administered as a post-treatment. Therefore, EGCG palmitate is potentially effective as an anti-PRRSV agent and thus of interest to the pharmaceutical industry.

https://www.ncbi.nlm.nih.gov/pubmed/24566281

Antiviral Res. 2019 Dec:104699.
N-Acetyl cysteine effectively alleviates Coxsackievirus B-Induced myocarditis through suppressing viral replication and inflammatory response.
Wang Y, Zhao S, Chen Y, Wang Y, Wang T, Wo X, Dong Y, Zhang J, Xu W, Qu C, Feng X, Wu X, Wang Y, Zhong Z, Zhao W.

Viral myocarditis caused by Coxsackievirus B (CVB) infection is a severe inflammatory disease of the myocardium, which may develop to cardiomyopathy and heart failure. No effective specific treatment is available presently. Our previous study demonstrated that suppression of proinflammatory caspase-1 activation effectively inhibited CVB replication. N-acetyl cysteine (NAC) is a widely used antioxidant. In this study, we found that NAC significantly alleviated the myocardial injury caused by CVB type 3 (CVB3) under in vivo condition. Importantly, NAC treatment simultaneously suppressed viral replication and inflammatory response in both myocardium and cell culture. The antiviral and anti-inflammation mechanism of NAC, while independent of its antioxidant property, relies on its inhibition on caspase-1 activation. Moreover, NAC promotes procaspase-1 degradation via ubiquitin proteasome system, which further contributes to caspase-1 down-regulation. NAC also inhibits the activity of viral proteases. Taken together, this study shows that NAC exerts potent anti-CVB and anti-inflammation effect through targeting caspase-1. Given that NAC is a clinically approved medicine, we recommend NAC as a valuable therapeutic agent for viral myocarditis caused by CVB.

https://www.ncbi.nlm.nih.gov/pubmed/31883926

Phytomedicine. 2015 Sep;22(10):911-20.
Antiviral activity of an aqueous extract derived from Aloe arborescens Mill. against a broad panel of viruses causing infections of the upper respiratory tract.
Glatthaar-Saalmüller B, Fal AM, Schönknecht K, Conrad F, Sievers H, Saalmüller A.

BACKGROUND: A number of antiviral therapies have evolved that may be effectively administered to treat respiratory viral diseases. But these therapies are very often of limited efficacy or have severe side effects. Therefore there is great interest in developing new efficacious and safe antiviral compounds e.g. based on the identification of compounds of herbal origin.

HYPOTHESIS: Since an aqueous extract of Aloe arborescens Mill. shows antiviral activity against viruses causing infections of the upper respiratory tract in vitro we hypothesised that a product containing it such as Biaron C(®) could have an antiviral activity too.

STUDY DESIGN: Antiviral activity of Bioaron C(®), an herbal medicinal product consisting of an aqueous extract of Aloe arborescens Mill., Vitamin C, and Aronia melanocarpa Elliot. succus, added as an excipient, was tested in vitro against a broad panel of viruses involved in upper respiratory tract infections.

METHODS: These studies included human adenovirus and several RNA viruses and were performed either with plaque reduction assays or with tests for the detection of a virus-caused cytopathic effect.

RESULTS: Our studies demonstrated an impressive activity of Bioaron C(®) against members of the orthomyxoviridae – influenza A and influenza B viruses. Replication of both analysed influenza A virus strains – H1N1 and H3N2 – as well as replication of two analysed influenza B viruses – strains Yamagatal and Beiying – was significantly reduced after addition of Bioaron C(®) to the infected cell cultures. In contrast antiviral activity of Bioaron C(®) against other RNA viruses showed a heterogeneous pattern. Bioaron C(®) inhibited the replication of human rhinovirus and coxsackievirus, both viruses belonging to the family of picornaviridae and both representing non-enveloped RNA viruses. In vitro infections with respiratory syncytial virus and parainfluenza virus, both belonging to the paramyxoviridae, were only poorly blocked by the test substance. No antiviral activity of Bioaron C(®) was detected against adenovirus – a non-enveloped DNA virus.

CONCLUSIONS: These results represent the first proof of a selective antiviral activity of Bioaron C(®) against influenza viruses and create basis for further analyses of type and molecular mechanisms of the antiviral activity of this herbal medicine.

https://www.ncbi.nlm.nih.gov/pubmed/26321740

J Complement Integr Med. 2020 Jan. pii: /j/jcim.ahead-of-print/jcim-2019-0071/jcim-2019-0071.xml.
Immune stimulatory and anti-HIV-1 potential of extracts derived from marine brown algae Padina tetrastromatica.
Subramaniam D, Hanna LE, Maheshkumar K, Ponmurugan K, Al-Dhabi NA, Murugan P.

Background Marine brown algae are biologically diverse and their medicinal value has been explored limited. We assessed whether Padina tetrastromatica Hauck will possess the immune stimulatory and human immunodeficiency virus (HIV-1) inhibitory activity. Materials and Methods Aqueous and methanolic extracts were tested for the Th1/Th2 cytokines using PBMC. Subsequently, leukotriene B4 (LTB4), nitric oxide (NO) and anti-oxidant effect were analyzed using RAW264.7 cells. In addition, Padina extracts were tested for the HIV-1 clade C & A by measuring the levels of viral p24 antigen in infected peripheral blood mononuclear cells (PBMCs) and against reverse transcriptase (RT). Results At 100 μg/mL, aqueous and methanolic extracts produced a significant amount of IL-10 and IFN-γ at 24 h and 72 h post-stimulation by PBMCs. It also produced a significant amount of LTB4, NO and had an antioxidant effect on RAW264.7 cell, suggesting the immune stimulating potential of P. tetrastromatica. Upon infection of PBMCs with 100 TCID50, aqueous and methanolic extracts of P. tetrastromatica inhibited HIV-1 C (>90%) and HIV-1 A (>50%) showed a significant reduction in HIV-1 p24 levels and HIV-1 RT inhibition (>50%). GC-MS study revealed a relative abundance of tetradecanoic and oleic acid in the methanolic extract of P. tetrastromatica, which might be responsible for immune stimulation and anti-HIV-1 activity. Conclusion At lower concentrations (100 mg/mL), the aqueous and methanolic extracts of P. tetrastromatica showed the strong immune stimulation and greatest anti-HIV-1 potential in vitro. This study demonstrates the therapeutic potential of these brown algae P. tetrastromatica for the benefit of mankind.

https://www.ncbi.nlm.nih.gov/pubmed/31990663

Am J Chin Med. 2019;47(6):1307-1324.
Aloe vera and its Components Inhibit Influenza A Virus-Induced Autophagy and Replication.
Choi JG, Lee H, Kim YS, Hwang YH, Oh YC, Lee B, Moon KM, Cho WK, Ma JY.

Aloe vera ethanol extract (AVE) reportedly has significant anti-influenza virus activity, but its underlying mechanisms of action and constituents have not yet been completely elucidated. Previously, we have confirmed that AVE treatment significantly reduces the viral replication of green fluorescent protein-labeled influenza A virus in Madin-Darby canine kidney (MDCK) cells. In addition, post-treatment with AVE inhibited viral matrix protein 1 (M1), matrix protein 2 (M2), and hemagglutinin (HA) mRNA synthesis and viral protein (M1, M2, and HA) expressions. In this study, we demonstrated that AVE inhibited autophagy induced by influenza A virus in MDCK cells and also identified quercetin, catechin hydrate, and kaempferol as the active antiviral components of AVE. We also found that post-treatment with quercetin, catechin hydrate, and kaempferol markedly inhibited M2 viral mRNA synthesis and M2 protein expression. A docking simulation suggested that the binding affinity of quercetin, catechin hydrate, and kaempferol for the M2 protein may be higher than that of known M2 protein inhibitors. Thus, the inhibition of autophagy induced by influenza virus may explain the antiviral activity of AVE against H1N1 or H3N2. Aloe vera extract and its constituents may, therefore, be potentially useful for the development of anti-influenza agents.

https://www.ncbi.nlm.nih.gov/pubmed/31505936

J Ethnopharmacol. 2016 Jul;188:144-52.
Antiviral activity of hydroalcoholic extract from Eupatorium perfoliatum L. against the attachment of influenza A virus.
Derksen A, Kühn J, Hafezi W, Sendker J, Ehrhardt C, Ludwig S, Hensel A.

ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Eupatorium perfoliatum have been traditionally used by American natives as a treatment for fever and infections. Also modern phytotherapy in Europe documents the use of hydroalcoholic extracts of this herbal material for the treatment of infections of the upper respiratory tract.

AIM OF THE STUDY: The aim of the present study was to characterize the anti-influenza A virus (IAV) potential of extracts derived from the aerial parts of E. perfoliatum and to identify their antiviral mode of action and potential active fraction’s compounds of the extract.

MATERIALS AND METHODS: The inhibitory effects of extracts obtained by different organic solvents with different polarities on the cytopathic effect induced by IAV replication was determined in a Madin-Darby Canine Kidney Epithelial (MDCK II) cell-based assay measuring cell viability by MTT stain (MTTIAV assay). Plaque reduction assays were used for investigation of antiviral activity. The mode of action was investigated by different incubation and treatment cycles as well as hemagglutination inhibition assays. Influence of the test extract on tumor necrosis factor (TNF-α) and epidermal growth factor (EGF)-induced cell signaling was analyzed in human lung epithelial (A549) cells. Analytical characterization of extract and fractions obtained from the extract was performed by UHPLC-MS.

RESULTS: Hydroalcoholic extracts from the aerial parts of E. perfoliatum were shown to inhibit growth of a clinical isolate of IAV(H1N1)pdm09 I1 and the influenza virus A/Puerto Rico/8/34 (PR8; H1N1) with a half-maximal inhibitory concentration (IC50) of 7µg/mL and 14µg/mL, and a selectivity index (SI) (half-maximal cytotoxic concentration (CC50)/IC50)) of 52 and 26, respectively. Extracts prepared with dichloromethane and methanol were inactive. At concentrations >1-10µg/mL of the hydroalcoholic extract plaque formation of IAV(H1N1)pdm09 was abrogated. The extract was also active against an oseltamivir-resistant isolate of IAV(H1N1)pdm09. The extract blocked attachment of IAV and interfered with virus-induced hemagglutination. TNF-α-induced signal transduction in A549 cells was not affected, while the EGF-induced signaling to phosphorylated ERK was slightly upregulated by the extract. Bioassay-guided fractionation and subsequent LC-MS analysis indicated that the antiviral activity might be due to polyphenolic compounds with higher molecular weights, which strongly interact with stationary phases of different chromatographic systems. These still unknown compounds with probably high molecular weight could not be isolated in the present study. A variety of different flavonoid glycosides and caffeoyl quinic acids obtained from E. perfoliatum did definitely not contribute to the antiviral effect of the extract and its respective fractions.

CONCLUSION: Hydroalcoholic extracts from the aerial parts of E. perfoliatum and its main active polyphenolic constituents protect cells from IAV infection by inhibiting viral attachment to the host cells. The extract appears to be a promising expansion of the currently available anti-influenza agents.

https://www.ncbi.nlm.nih.gov/pubmed/27178637

PLoS One. 2014 Oct;9(10):e110089.
3-O-galloylated procyanidins from Rumex acetosa L. inhibit the attachment of influenza A virus.
Derksen A, Hensel A, Hafezi W, Herrmann F, Schmidt TJ, Ehrhardt C, Ludwig S, Kühn J.

Infections by influenza A viruses (IAV) are a major health burden to mankind. The current antiviral arsenal against IAV is limited and novel drugs are urgently required. Medicinal plants are known as an abundant source for bioactive compounds, including antiviral agents. The aim of the present study was to characterize the anti-IAV potential of a proanthocyanidin-enriched extract derived from the aerial parts of Rumex acetosa (RA), and to identify active compounds of RA, their mode of action, and structural features conferring anti-IAV activity. In a modified MTT (MTTIAV) assay, RA was shown to inhibit growth of the IAV strain PR8 (H1N1) and a clinical isolate of IAV(H1N1)pdm09 with a half-maximal inhibitory concentration (IC50) of 2.5 µg/mL and 2.2 µg/mL, and a selectivity index (SI) (half-maximal cytotoxic concentration (CC50)/IC50)) of 32 and 36, respectively. At RA concentrations>1 µg/mL plaque formation of IAV(H1N1)pdm09 was abrogated. RA was also active against an oseltamivir-resistant isolate of IAV(H1N1)pdm09. TNF-α and EGF-induced signal transduction in A549 cells was not affected by RA. The dimeric proanthocyanidin epicatechin-3-O-gallate-(4β→8)-epicatechin-3′-O-gallate (procyanidin B2-di-gallate) was identified as the main active principle of RA (IC50 approx. 15 µM, SI≥13). RA and procyanidin B2-di-gallate blocked attachment of IAV and interfered with viral penetration at higher concentrations. Galloylation of the procyanidin core structure was shown to be a prerequisite for anti-IAV activity; o-trihydroxylation in the B-ring increased the anti-IAV activity. In silico docking studies indicated that procyanidin B2-di-gallate is able to interact with the receptor binding site of IAV(H1N1)pdm09 hemagglutinin (HA). In conclusion, the proanthocyanidin-enriched extract RA and its main active constituent procyanidin B2-di-gallate protect cells from IAV infection by inhibiting viral entry into the host cell. RA and procyanidin B2-di-gallate appear to be a promising expansion of the currently available anti-influenza agents.

https://www.ncbi.nlm.nih.gov/pubmed/25303676

J Gerontol A Biol Sci Med Sci. 2000 Oct;55(10):B496-503.
Effect of Long-Term Dietary Antioxidant Supplementation on Influenza Virus Infection.
Han SN, Meydani M, Wu D, Bender BS, Smith DE, Viña J, Cao G, Prior RL, Meydani SN.

This study compared the effect of vitamin E on the course of influenza infection with that of other antioxidants. (In a previous study we showed that short-term vitamin E supplementation significantly decreased pulmonary viral titer in influenza-infected old mice). Eighteen-month-old C57BL/6NCrlBR mice were fed one of the following semisynthetic diets for 6 months: control, vitamin E supplemented, glutathione supplemented, vitamin E and glutathione supplemented, melatonin supplemented, or strawberry extract supplemented. After influenza virus challenge, mice fed vitamin E-supplemented diet had significantly lower pulmonary viral titers compared to those fed the control diet (10(2.6) vs 10(4.0), p < .05) and were able to maintain their body weight after infection (1.8+/-0.9 g weight loss/5 days postinfection in vitamin E group vs 6.8+/-1.4 g weight loss/5 days postinfection in control group, p < .05). Other antioxidants did not have a significant effect on viral titer or weight loss. There was a significant inverse correlation of weight loss with food intake (r = -.96, p < .01), indicating that the observed weight changes were mainly due to decreased food intake. Pulmonary interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha levels increased significantly postinfection. The vitamin E group had lower lung IL-6 and TNF-alpha levels following infection compared to the control group. In addition, there was a significant positive correlation between weight loss and lung IL-6 (r = .77, p < .01) and TNF-alpha (r = .68, p < .01) levels. Because IL-6 and TNF-alpha have been shown to contribute to the anorexic effect of infectious agents, the prevention of weight loss by vitamin E might be due to its reduced production of IL-6 and TNF-alpha following infection. Thus, among the antioxidants tested, only vitamin E was effective in reducing pulmonary viral titers and preventing an influenza-mediated decrease in food intake and weight loss. Other dietary antioxidant supplementations that reduced one or more measures of oxidative stress (4-hydroxynonenal, malondialdehyde, and hydrogen peroxide) did not have an effect on viral titer, which suggests that, in addition to its antioxidant activity, other mechanisms might be involved in vitamin E’s beneficial effect on lowering viral titer and preventing weight loss.

https://pubmed.ncbi.nlm.nih.gov/11034223/

Am J Respir Cell Mol Biol. 2020 Apr. doi: 10.1165/rcmb.2019-0185OC. [Epub ahead of print]
Alpha-tocopherol Attenuates the Severity of Pseudomonas aeruginosa-induced Pneumonia.
Wagener BM, Anjum N, Evans C, Brandon A, Honavar J, Creighton J, Traber MG, Stuart RL, Stevens T, Pittet JF.

Pseudomonas aeruginosa is a lethal pathogen that causes high mortality and morbidity in immunocompromised and critically ill patients. The Type III secretion system (T3SS) of P. aeruginosa mediates many of the adverse effects of infection with this pathogen including increased lung permeability in a toll-like receptor 4/Rho A/plasminogen activator inhibitor (PAI)-1-dependent manner. Alpha-tocopherol has anti-inflammatory properties that may make it a useful adjunct in treatment of this moribund infection. We measured transendothelial and transepithelial resistance, Rho A and PAI-1 activation, stress fiber formation, P. aeruginosa T3SS exoenzyme (Exo Y) intoxication into host cells, and survival in a murine model of pneumonia in the presence of P. aeruginosa and pretreatment with α-tocopherol. We found that α-tocopherol alleviated P. aeruginosa-mediated alveolar endothelial and epithelial paracellular permeability by inhibiting RhoA, in part, via PAI-1 activation and increased survival in a mouse model of P. aeruginosa pneumonia. Furthermore, we found that α-tocopherol decreased the activation of RhoA and PAI-1 by blocking the injection of T3SS exoenzymes into alveolar epithelial cells. P. aeruginosa is becoming increasingly antibiotic-resistant. We provide evidence that α-tocopherol could be a useful therapeutic agent for individuals that are susceptible to infection with P. aeruginosa such as those who are immunocompromised or critically ill.

https://www.ncbi.nlm.nih.gov/pubmed/32243761

Int J Mol Sci. 2020 Feb;21(3). pii: E1003.
Exploration of Binding Mechanism of a Potential Streptococcus pneumoniae Neuraminidase Inhibitor from Herbaceous Plants by Molecular Simulation.
Guan S, Zhu K, Dong Y, Li H, Yang S, Wang S, Shan Y.

Streptococcus pneumoniae can cause diseases such as pneumonia. Broad-spectrum antibiotic therapy for Streptococcus pneumoniae is increasingly limited due to the emergence of drug-resistant strains. The development of novel drugs is still currently of focus. Abundant polyphenols have been demonstrated to have antivirus and antibacterial ability. Chlorogenic acid is one of the representatives that has been proven to have the potential to inhibit both the influenza virus and Streptococcus pneumoniae. However, for such a potential neuraminidase inhibitor, the interaction mechanism studies between chlorogenic acid and Streptococcus pneumoniae neuraminidase are rare. In the current study, the binding mechanism of chlorogenic acid and Streptococcus pneumoniae neuraminidase were investigated by molecular simulation. The results indicated that chlorogenic acid might establish the interaction with Streptococcus pneumoniae neuraminidase via hydrogen bonds, salt bridge, and cation-π. The vital residues involved Arg347, Ile348, Lys440, Asp372, Asp417, and Glu768. The side chain of Arg347 might form a cap-like structure to lock the chlorogenic acid to the active site. The results from binding energy calculation indicated that chlorogenic acid had strong binding potential with neuraminidase. The results predicted a detailed binding mechanism of a potential Streptococcus pneumoniae neuraminidase inhibitor, which will be provide a theoretical basis for the mechanism of new inhibitors.

https://www.ncbi.nlm.nih.gov/pubmed/32028720

Ann Transl Med. 2020 Feb;8(4):120.
Vitamin A deficiency is associated with severe Mycoplasma pneumoniae pneumonia in children.
Xing Y, Sheng K, Xiao X, Li J, Wei H, Liu L, Zhou W, Tong X.

Background: Children with vitamin A, D, and E deficiency are susceptible to respiratory infections. However, the correlations between the levels with Mycoplasma pneumoniae pneumonia (MPP) and patient MPP occurrence is still unclear. This study aims to measure and compare the serum levels in severe (sMPP) and non-severe MPP (nsMPP) and to investigate the correlations between their levels and the occurrence of MPP.

Methods: A total of 122 children were enrolled, including 52 sMPP and 70 nsMPP aged 0-15 years old in 2015-2018. The serum levels of vitamins A, D, and E were measured and compared, and two-category logistic regression was used for correlation analysis of vitamins A, D, and E levels with nsMPP and sMPP.

Results: The age was older (7.12 vs. 4.01 y, P=0.002) in the sMPP samples than that in the nsMPP samples. Vitamin A deficiency was present in both the nsMPP and sMPP samples; its level was significantly lower (0.15±0.06 vs. 0.19±0.07, P=0.0193) in the sMPP serum than that in the nsMPP serum. Vitamins E and D in the sMPP samples were significantly lower (vitamin E 7.43±1.55 vs. 8.22±2.22, P=0.0104; vitamin D 23.08±11.0 vs. 32.07±19.2, P=0.0007) than that in the nsMPP group; both sMPP and nsMPP did not show a deficiency of vitamins E and D. Logistic regression analysis revealed that vitamin A deficiency was significantly (OR 0.001, 95% CI: 0.001-0.334, P=0.009) associated with sMPP, and vitamin A supplementation could reduce the incidence of sMPP. In ≥6 y sMPP, the incidence of vitamin A deficiency was 62.5%, while <6 y, 85%, showing a significant difference. Vitamin A level in <6 y sMPP was significantly lower than that in ≥6 y sMPP.

Conclusions: Vitamin A deficiency is associated with sMPP and more likely present in the younger sMPP samples. Therefore, it is important to watch and supplement vitamin A in M. pneumoniae infection patients.

https://www.ncbi.nlm.nih.gov/pubmed/32175413

Medicine (Baltimore). 2020 Jan;99(2):e18338.
Effectiveness of vitamin D for adult patients with gingivitis.
Feng Y, Yang DS, Tang HB, Ding YS, Li XG.

Erratum in
Study protocol titles: Erratum. [Medicine (Baltimore). 2020]

BACKGROUND: This study aims to explore the effectiveness of vitamin D for the management of adult patients with gingivitis.

METHODS: We will perform a comprehensive search from the following electronic databases: Cochrane Library, PUBMED, EMBASE, AMED, CINAHL, WANGFANG, VIP, CBM, and China National Knowledge Infrastructure. All databases will be searched from their inceptions to the present without language limitation. We will also search for unpublished data to avoid missing more potential studies. Two authors will carry out study selection, data extraction, and methodological quality evaluation, respectively. RevMan 5.3 software will be utilized for statistical analysis.

RESULTS: This study will summarize the up-to-date evidence about the anti-inflammatory effect of vitamin D for the management of adult patients with gingivitis through assessing modified gingival, gingival bleeding indices, inflammatory factors, plaque, quality of life, and any adverse events.

CONCLUSION: This study may provide helpful evidence of vitamin D for the management of adult patients with gingivitis for clinical practice.

https://www.ncbi.nlm.nih.gov/pubmed/31914014

Bratisl Lek Listy. 2020;121(2):154-158.
Coenzyme Q10 improves the survival and reduces inflammatory markers in septic patients.
Soltani R, Alikiaie B, Shafiee F, Amiri H, Mousavi S.

OBJECTIVE: This study aimed to evaluate the effect of Coenzyme Q10 (CoQ10) administration to patients in the early phase of sepsis to determine its effect on the markers of inflammation and the clinical outcomes of septic patients.

BACKGROUND: Previous studies showed that CoQ10 levels were decreased in septic patients and worsening of mitochondrial dysfunction was observed.

METHODS: In this randomized controlled trial septic patients (n=40) received 100 mg CoQ10 twice a day for seven days added to standard treatment of sepsis. As a primary endpoint levels of Interleukin 6 (IL-6), Tumor Necrosis Factor-α (TNF-α), Glutathione peroxidase and malondialdehyde (MDA) were assessed at baseline, third and 7th day after the intervention. Secondary endpoints included assessment of clinical scores and in-hospital mortality.

RESULTS: There was no difference in baseline inflammatory and oxidative injury markers between the groups. TNF-α and MDA levels decreased significantly in the CoQ10 group on the 7th day of the study (P:0.003 for both). There was a significant difference in the in-hospital mortality in the CoQ10 group compared to the control group (P:0.01).

CONCLUSION: These findings suggest that CoQ10 has a positive effect on clinical parameters as well as mitochondrial dysfunction when administered in the early phase of sepsis (Tab. 2, Fig. 1, Ref. 38).

https://www.ncbi.nlm.nih.gov/pubmed/32115970

Indian J Pediatr. 2019 Dec;86(12):1105-1111.
Effect of Vitamin D Supplementation in the Prevention of Recurrent Pneumonia in Under-Five Children.
Singh N, Kamble D, Mahantshetti NS.

OBJECTIVE: To assess the effect of vitamin D supplementation in the prevention of recurrent pneumonia in under-five children.

METHODS: The present one year 8 months longitudinal, community-based randomized controlled study included a total of 100 under-five children with pneumonia. Children were divided into two groups: intervention group (Group I: standard treatment with vitamin D 300,000 IU; n = 50) and control group (Group C: standard treatment only; n = 50). As nine samples were hemolyzed, groups I and C comprised of 46 and 45 children, respectively. The children were followed up for 1 y and signs of upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), vitamin D deficiency, and vitamin D toxicity were recorded.

RESULTS: The male to female ratio in group C and I was 1.27:1 and 1.5:1, respectively (P = 0.420). Age, gender, birth, anthropometric and clinical characteristics, and feeding habits were not statistically significant (P > 0.05) between both the cohorts (Group C and I). Children with reduced vitamin D levels were high in group C (25) when compared to the group I (15). During all the follow-ups, the URTI and LRTI episodes, severity of pneumonia, number of hospital admissions, complications, mean episodes of LRTI, and mean duration of LRTI were comparable between group I and group C (P > 0.05).

CONCLUSIONS: Overall, the present study highlights that oral vitamin D (300,000 IU bolus dose quarterly) has some beneficial effect in the prevention of recurrent pneumonia in under-five children, although, not to a significant degree. Hence, it is recommended that further studies are required to demonstrate a significant effect of vitamin D in the prevention of pneumonia.

https://www.ncbi.nlm.nih.gov/pubmed/31346969

Int Immunopharmacol. 2019 Nov;76:105882.
Modulation of anti-malaria immunity by vitamin A in C57BL/6J mice infected with heterogenic plasmodium.
Chen G, Du YT, Liu JH, Li Y, Zheng L, Qin XS, Cao YM.

Vitamin A (VA) is an anti-inflammatory agent that is important in modulating and balancing the immune system. The present study aimed to investigate the immunoregulatory effects of vitamin A supplement (VAS) in C57BL/6J mice infected with Plasmodium yoelii 17XL (P.y17XL) or Plasmodium berghei ANKA (P.bANKA). Following VA treatment, parasitaemia decreased, but survival rate did not significantly change during P.y17XL infection. However, in P.bANKA infected C57BL/6J mice, VA pretreatment decreased parasitaemia, and a lag in cerebral malaria (CM) was observed during the early stages of infection. Furthermore, VA pretreatment was also demonstrated to upregulate MHCII expression in dendritic cells (DCs), downregulate Th1 and Tregs, and downregulate TNF-α and IFN-γ production. The results of the current study indicated that VAS downregulated the inflammation response in CM, but did not exhibit an immunoregulatory effect against P.y17XL infection. VAS protected the onset of CM by reducing inflammation, and was also correlated with the downregulation of Th1 by modifying the function of DCs and Tregs. However, no significant effect was observed during P.y17XL infection.

https://www.ncbi.nlm.nih.gov/pubmed/31520991

Nutrients. 2019 Oct;11(10). pii: E2452.
A Review of the Potential Benefits of Increasing Vitamin D Status in Mongolian Adults through Food Fortification and Vitamin D Supplementation.
Grant WB, Boucher BJ.

Serum 25-hydroxyvitamin D (25(OH)D) concentrations are low in Mongolia, averaging 22 ng/mL in summer and only 8 ng/mL in winter. Mongolians have high incidence and/or prevalence of several diseases linked to low 25(OH)D concentrations, including ischemic heart disease, malignant neoplasms, cirrhosis of the liver, ischemic stroke, lower respiratory tract infections, preterm birth complications, and diabetes mellitus. Fortifying regularly consumed foods such as flour, milk, and edible oils with vitamin D₃ could raise 25(OH)D concentrations by about 10 ng/mL. However, to achieve 25(OH)D concentrations of 30-40 ng/mL in adults, vitamin D intakes of 1000 to 4000 IU/day would be required, making personal supplement use necessary. On the basis of prospective observational studies and clinical trials of disease incidence or known mortality rates and adverse pregnancy and birth outcomes, raising mean serum 25(OH)D concentrations to 40 ng/mL would likely reduce incidence and mortality rates for those and other diseases, reduce the rate of adverse pregnancy and birth outcomes, and increase mean life expectancy by one year or more.

https://www.ncbi.nlm.nih.gov/pubmed/31615079

Nutrients. 2019 Sep;11(9).
Vitamin D Modulates the Response of Bronchial Epithelial Cells Exposed to Cigarette Smoke Extract.
Mathyssen C, Serré J, Sacreas A, Everaerts S, Maes K, Verleden S, Verlinden L, Verstuyf A, Pilette C, Gayan-Ramirez G, Vanaudenaerde B, Janssens W.

In chronic obstructive pulmonary disease (COPD), the bronchial epithelium is the first immune barrier that is triggered by cigarette smoke. Although vitamin D (vitD) has proven anti-inflammatory and antimicrobial effects in alveolar macrophages, little is known about the direct role of vitD on cigarette smoke-exposed bronchial epithelial cells. We examined the effects of vitD on a human bronchial epithelial cell line (16HBE) and on air-liquid culture of primary bronchial epithelial cells (PBEC) of COPD patients and controls exposed for 24 h to cigarette smoke extract (CSE). VitD decreased CSE-induced IL-8 secretion by 16HBE cells, but not by PBEC. VitD significantly increased the expression of the antimicrobial peptide cathelicidin in 16HBE and PBEC of both COPD subjects and controls. VitD did not affect epithelial to mesenchymal transition or epithelial MMP-9 expression and was not able to restore impaired wound healing by CSE in 16HBE cells. VitD increased the expression of its own catabolic enzyme CYP24A1 thereby maintaining its negative feedback. In conclusion, vitD supplementation may potentially reduce infectious exacerbations in COPD by the upregulation of cathelicidin in the bronchial epithelium.

https://www.ncbi.nlm.nih.gov/pubmed/31500220

BMJ. 2019 Sep;366:l5016.
Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: follow-up of a randomized intervention trial.
Li WQ, Zhang JY, Ma JL, Li ZX, Zhang L, Zhang Y, Guo Y, Zhou T, Li JY, Shen L, Liu WD, Han ZX, Blot WJ, Gail MH, Pan KF, You WC.

OBJECTIVE: To assess the effects of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation in the prevention of gastric cancer.

DESIGN: Blinded randomized placebo controlled trial.

SETTING: Linqu County, Shandong province, China.

PARTICIPANTS: 3365 residents of a high risk region for gastric cancer. 2258 participants seropositive for antibodies to H pylori were randomly assigned to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2×2×2 factorial design, and 1107 H pylori seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2×2 factorial design.

INTERVENTIONS: H pylori treatment with amoxicillin and omeprazole for two weeks; vitamin (C, E, and selenium) and garlic (extract and oil) supplementation for 7.3 years (1995-2003).

MAIN OUTCOME MEASURES: Primary outcomes were cumulative incidence of gastric cancer identified through scheduled gastroscopies and active clinical follow-up through 2017, and deaths due to gastric cancer ascertained from death certificates and hospital records. Secondary outcomes were associations with other cause specific deaths, including cancers or cardiovascular disease.

RESULTS: 151 incident cases of gastric cancer and 94 deaths from gastric cancer were identified during 1995-2017. A protective effect of H pylori treatment on gastric cancer incidence persisted 22 years post-intervention (odds ratio 0.48, 95% confidence interval 0.32 to 0.71). Incidence decreased significantly with vitamin supplementation but not with garlic supplementation (0.64, 0.46 to 0.91 and 0.81, 0.57 to 1.13, respectively). All three interventions showed significant reductions in gastric cancer mortality: fully adjusted hazard ratio for H pylori treatment was 0.62 (95% confidence interval 0.39 to 0.99), for vitamin supplementation was 0.48 (0.31 to 0.75), and for garlic supplementation was 0.66 (0.43 to 1.00). Effects of H pylori treatment on both gastric cancer incidence and mortality and of vitamin supplementation on gastric cancer mortality appeared early, but the effects of vitamin supplementation on gastric cancer incidence and of garlic supplementation only appeared later. No statistically significant associations were found between interventions and other cancers or cardiovascular disease.

CONCLUSIONS: H pylori treatment for two weeks and vitamin or garlic supplementation for seven years were associated with a statistically significant reduced risk of death due to gastric cancer for more than 22 years. H pylori treatment and vitamin supplementation were also associated with a statistically significantly reduced incidence of gastric cancer.

https://www.ncbi.nlm.nih.gov/pubmed/31511230

Pediatr Crit Care Med. 2019 Sep;20(9):e452-e456.
Matched Retrospective Cohort Study of Thiamine to Treat Persistent Hyperlactatemia in Pediatric Septic Shock.
Weiss SL, Blowey B, Keele L, Ganetzky R, Murali CN, Fitzgerald JC, Sutton RM, Berg RA.

OBJECTIVES: Thiamine deficiency may propagate lactate production by limiting pyruvate dehydrogenase activity, and studies suggest benefit for thiamine administration in septic adults. We studied the effect of thiamine on physiologic and clinical outcomes for children with septic shock and hyperlactatemia.

DESIGN: Retrospective matched cohort study.

SETTING: Single academic PICU.

PATIENTS: Six thiamine-treated cases and nine matched controls.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: The primary outcome was change in blood lactate from prethiamine (T0, cases) or maximum (T0, controls) lactate through 24 hours later (T24). Secondary outcomes were change in lactate over 48 hours (T48) and 72 hours (T72), time to lactate normalization, changes in vasoactive-inotrope score, organ dysfunction severity (daily Pediatric Logistic Organ Dysfunction 2 score), and creatinine, PICU length of stay, and hospital mortality. Lactate was greater than 5 mmol/L for a median of 39 hours (range, 16.1-64.3 hr) prior to thiamine administration for cases compared with 3.4 hours (range, 0-22.9 hr) prior to maximum lactate for controls (p = 0.002). There was no difference in median (interquartile range) change in lactate from T0 to T24 between thiamine-treated cases and controls (-9.0, -17.0 to -5.0 vs -7.2, -9.0 to -5.3 mmol/L, p = 0.78), with both groups exhibiting a rapid decrease in lactate. There were also no differences in secondary outcomes between groups.

CONCLUSIONS: Treatment of pediatric septic shock with thiamine was followed by rapid improvement in physiologic and clinical outcomes after prolonged hyperlactatemia. Although we are not able to infer that thiamine provided benefit over usual care, the rapid decline in lactate after thiamine despite a prolonged period of hyperlactatemia raises the possibility that thiamine helped to reverse lactate production.

https://www.ncbi.nlm.nih.gov/pubmed/31274776

Int J Mol Med. 2019 Sep;44(3):1151-1160.
Biologically active 1,25-dihydroxyvitamin D3 protects against experimental sepsis by negatively regulating the Toll-like receptor 4/myeloid differentiation primary response gene 88/Toll-IL-1 resistance-domain-containing adapter-inducing interferon-β signaling pathway.
Zheng G, Wen N, Pan M, Huang Y, Li Z.

The hormonally active form of vitamin D (VD), 1,25‑dihydroxyvitamin D3, has been reported to be a key immunoregulator in the reduction of inflammation. In this study, we investigated the effects of VD in an experimental sepsis cell model, and the underlying mechanisms. The sepsis cell model was first established in monocytes, isolated from newborns and healthy adults, which were stimulation with lipopolysaccharide (LPS). We observed that cell viability was significantly impaired in the monocytes after LPS stimulation, using a Cell Counting Kit‑8 and trypan blue assays. Additionally, ELISA revealed that LPS stimulation significantly elevated the expression of interleukin 6 (IL‑6), IL‑10 and tumor necrosis factor‑α (TNF‑α). The expression levels of Toll‑like receptor (TLR4), myeloid differentiation primary response gene 88 (MyD88), and Toll‑IL‑1 resistance‑domain‑containing adapter‑inducing interferon‑β (TRIF) mRNA were also significantly elevated under LPS stimulation using reverse transcription‑quantitative PCR and western blot analysis. VD treatment could significantly suppress the effects of LPS simulation on monocytes by negatively regulating inflammatory cytokines and TLR4/MyD88/TRIF signaling. Furthermore, a regulatory feedback mechanism was proposed to involve TLR4, MyD88 and TRIF in the sepsis cell model. In conclusion, VD may effectively decrease the release of inflammatory cytokines by inhibiting the TLR4/MyD88/TRIF signaling pathway, could be considered as a potential therapeutic agent for the treatment of sepsis.

https://www.ncbi.nlm.nih.gov/pubmed/31524226

Eur J Microbiol Immunol (Bp). 2019 Aug;9(3):80-87.
Antimicrobial and Immune-Modulatory Effects of Vitamin D Provide Promising Antibiotics-Independent Approaches to Tackle Bacterial Infections – Lessons Learnt from a Literature Survey.
Golpour A, Bereswill S, Heimesaat MM.

Antimicrobial multidrug-resistance (MDR) constitutes an emerging threat to global health and makes the effective prevention and treatment of many, particularly severe infections challenging, if not impossible. Many antibiotic classes have lost antimicrobial efficacy against a plethora of infectious agents including bacterial species due to microbial acquisition of distinct resistance genes. Hence, the development of novel anti-infectious intervention strategies including antibiotic-independent approaches is urgently needed. Vitamins such as vitamin D and vitamin D derivates might be such promising molecular candidates to combat infections caused by bacteria including MDR strains. Using the Pubmed database, we therefore performed an in-depth literature survey, searching for publications on the antimicrobial effect of vitamin D directed against bacteria including MDR strains. In vitro and clinical studies between 2009 and 2019 revealed that vitamin D does, in fact, possess antimicrobial properties against both Gram-positive and Gram-negative bacterial species, whereas conflicting results could be obtained from in vivo studies. Taken together, the potential anti-infectious effects for the antibiotic-independent application of vitamin D and/or an adjunct therapy in combination with antibiotic compounds directed against infectious diseases such as tuberculosis, H. pylori infections, or skin diseases, for instance, should be considered and further investigated in more detail.

https://www.ncbi.nlm.nih.gov/pubmed/31662886

Health Technol Assess. 2019 Jan;23(2):1-44.
Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.
Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Janssens W, Jensen ME, Kerley CP, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S, Stelmach I, Trilok Kumar G, Urashima M, Camargo CA, Griffiths CJ, Hooper RL.

BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.
OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.
DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.
STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.
STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.
RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.
LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.
CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.

https://www.ncbi.nlm.nih.gov/pubmed/30675873

Mol Neurobiol. 2018 Jun;55(6):5255-5268.
Vitamin B₆ Reduces Neurochemical and Long-Term Cognitive Alterations After Polymicrobial Sepsis: Involvement of the Kynurenine Pathway Modulation.
Danielski LG, Giustina AD, Goldim MP, Florentino D, Mathias K, Garbossa L, de Bona Schraiber R, Laurentino AOM, Goulart M, Michels M, de Queiroz KB, Kohlhof M, Rezin GT, Fortunato JJ, Quevedo J, Barichello T, Dal-Pizzol F, Coimbra RS, Petronilho F.

Neurological dysfunction as a result of neuroinflammation has been reported in sepsis and cause high mortality. High levels of cytokines stimulate the formation of neurotoxic metabolites by kynurenine (KYN) pathway. Vitamin B₆ (vit B₆) has anti-inflammatory and antioxidant properties and also acts as a cofactor for enzymes of the KYN pathway. Thus, by using a relevant animal model of polymicrobial sepsis, we studied the effect of vit B₆ on the KYN pathway, acute neurochemical and neuroinflammatory parameters, and cognitive dysfunction in rats. Male Wistar rats (250-300 g) were submitted to cecal ligation and perforation (CLP) and divided into sham + saline, sham + vit B₆, CLP + saline, and CLP + vit B₆ (600 mg/kg, s.c.) groups. Twenty-four hours later, the prefrontal cortex and hippocampus were removed for neurochemical and neuroinflammatory analyses. Animals were followed for 10 days to determine survival rate, when cognitive function was assessed by behavioral tests. Vitamin B₆ interfered in the activation of kynurenine pathway, which led to an improvement in neurochemical and neuroinflammatory parameters and, consequently, in the cognitive functions of septic animals. Thus, the results indicate that vit B₆ exerts neuroprotective effects in acute and late consequences after sepsis.

https://www.ncbi.nlm.nih.gov/pubmed/28879460

Nutrients. 2017 Mar;9(4).
Vitamin C and Infections.
Hemilä H.

In the early literature, vitamin C deficiency was associated with pneumonia. After its identification, a number of studies investigated the effects of vitamin C on diverse infections. A total of 148 animal studies indicated that vitamin C may alleviate or prevent infections caused by bacteria, viruses, and protozoa. The most extensively studied human infection is the common cold. Vitamin C administration does not decrease the average incidence of colds in the general population, yet it halved the number of colds in physically active people. Regularly administered vitamin C has shortened the duration of colds, indicating a biological effect. However, the role of vitamin C in common cold treatment is unclear. Two controlled trials found a statistically significant dose-response, for the duration of common cold symptoms, with up to 6-8 g/day of vitamin C. Thus, the negative findings of some therapeutic common cold studies might be explained by the low doses of 3-4 g/day of vitamin C. Three controlled trials found that vitamin C prevented pneumonia. Two controlled trials found a treatment benefit of vitamin C for pneumonia patients. One controlled trial reported treatment benefits for tetanus patients. The effects of vitamin C against infections should be investigated further.

https://www.ncbi.nlm.nih.gov/pubmed/28353648

BMC Res Notes. 2015 Sep;8:498.
Vitamin D supplementation improves well-being in patients with frequent respiratory tract infections: a post hoc analysis of a randomized, placebo-controlled trial.
Bergman P, Norlin AC, Hansen S, Björkhem-Bergman L.

BACKGROUND: The aim of this study was to test the hypothesis that vitamin D supplementation improves well-being in patients with frequent respiratory tract infections (RTIs). We performed a post hoc analysis of a randomized, placebo-controlled and double-blind study in which patients with frequent RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124). At the last visit of the study, patients were asked to perform a general assessment of their well-being during the study.
RESULTS: The majority of patients, both placebo- and vitamin D treated, stated that they had felt ‘better’ during the study; 52% in the placebo group and 70% in the vitamin D group, relative risk 1.3 (95% CI 1.0-1.8; p = 0.06, Fisher’s exact test). Statement of better well-being was associated with an increase in 25-hydroxyvitamin D (25-OHD) levels (p < 0.001). In contrast, worse well-being was associated with unchanged 25-OHD levels. Notably, a 25-OHD level above 100 nmol/L at the study end was associated with a higher chance of having a better well-being (p < 0.01). Four patients on anti-depressive treatment could terminate their antidepressant medication during the study. These patients had a significant increase in 25-OHD levels from low levels at study-start.
CONCLUSION: Vitamin D supplementation to patients with frequent RTIs might be beneficial, not only for infections, but also for their general well-being. However, given the post hoc design of this study, these findings need to be confirmed in additional clinical trials before firm conclusions can be drawn.

https://www.ncbi.nlm.nih.gov/pubmed/26419363

BMC Res Notes. 2015 Aug;8:391.
Vitamin D supplementation to patients with frequent respiratory tract infections: a post hoc analysis of a randomized and placebo-controlled trial.
Bergman P, Norlin AC, Hansen S, Björkhem-Bergman L.

BACKGROUND: Vitamin D is considered to be important for a healthy immune system. The aim of this study was to test the hypothesis that vitamin D supplementation reduces number of respiratory tract infections (RTIs) and prolong the time to the first RTI in adult patients with frequent RTIs.
METHODS: We performed a post hoc analysis of a randomized, placebo-controlled and double-blinded study, where adult patients with a high burden of RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124 in the per protocol cohort presented here).
RESULTS: Vitamin D supplementation increased the probability to stay free of RTI during the study year (RR 0.64, 95% CI 0.43-0.94). Further, the total number of RTIs was also reduced in the vitamin D-group (86 RTIs) versus placebo (120 RTIs; p = 0.05). Finally, the time to the first RTI was significantly extended in the vitamin D-group (HR 1.68, 95% CI 1.03-2.68, p = 0.0376).
CONCLUSION: Vitamin D supplementation was found to significantly increase the probability of staying infection free during the study period. This finding further supports the notion that vitamin D-status should be monitored in adult patients with frequent RTIs and suggests that selected patients with vitamin D deficiency are supplemented. This could be a safe and cheap way to reduce RTIs and improve health in this vulnerable patient population. The original trial was registered at http://www.clinicaltrials.gov (NCT01131858).

https://www.ncbi.nlm.nih.gov/pubmed/26319134

Lancet Respir Med. 2015 Feb;3(2):120-130.
Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial.
Martineau AR, James WY, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, Islam K, McLaughlin D, Bhowmik A, Timms PM, Rajakulasingam RK, Rowe M, Venton TR, Choudhury AB, Simcock DE, Wilks M, Degun A, Sadique Z, Monteiro WR, Corrigan CJ, Hawrylowicz CM, Griffiths CJ.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have vitamin D deficiency, which is associated with increased susceptibility to upper respiratory infection-a major precipitant of exacerbation. Multicentre trials of vitamin D supplementation for prevention of exacerbation and upper respiratory infection in patients with COPD are lacking. We therefore investigated whether vitamin D3 (colecalciferol) supplementation would reduce the incidence of moderate or severe COPD exacerbations and upper respiratory infections.
METHODS: We did a randomised, double-blind, placebo-controlled trial of vitamin D3 supplementation in adults with COPD in 60 general practices and four Acute National Health Service Trust clinics in London, UK. Patients were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 or placebo over 1 year in a 1:1 ratio using computer-generated permuted block randomisation. Participants and study staff were masked to treatment assignment. Coprimary outcomes were time to first moderate or severe exacerbation and first upper respiratory infection. Analysis was by intention to treat. A prespecified subgroup analysis was done to assess whether effects of the intervention on the coprimary outcomes were modified by baseline vitamin D status. This trial is registered with ClinicalTrials.gov, number NCT00977873.
FINDINGS: 240 patients were randomly allocated to the vitamin D3 group (n=122) and placebo group (n=118). Vitamin D3 compared with placebo did not affect time to first moderate or severe exacerbation (adjusted hazard ratio 0·86, 95% CI 0·60-1·24, p=0·42) or time to first upper respiratory infection (0·95, 0·69-1·31, p=0·75). Prespecified subgroup analysis showed that vitamin D3 was protective against moderate or severe exacerbation in participants with baseline serum 25-hydroxyvitamin D concentrations of less than 50 nmol/L (0·57, 0·35-0·92, p=0·021), but not in those with baseline 25-hydroxyvitamin D levels of at least 50 nmol/L (1·45, 0·81-2·62, p=0·21; p=0·021 for interaction between allocation and baseline serum 25-hydroxyvitamin D status). Baseline vitamin D status did not modify the effect of the intervention on risk of upper respiratory infection (pinteraction=0·41).
INTERPRETATION: Vitamin D3 supplementation protected against moderate or severe exacerbation, but not upper respiratory infection, in patients with COPD with baseline 25-hydroxyvitamin D levels of less than 50 nmol/L. Our findings suggest that correction of vitamin D deficiency in patients with COPD reduces the risk of moderate or severe exacerbation.

https://www.ncbi.nlm.nih.gov/pubmed/25476069

J Immunol. 2014 Aug;193(3):1314-23.
Vitamin D inhibits the occurrence of experimental cerebral malaria in mice by suppressing the host inflammatory response.
He X, Yan J, Zhu X, Wang Q, Pang W, Qi Z, Wang M, Luo E, Parker DM, Cantorna MT, Cui L, Cao Y.

In animal models of experimental cerebral malaria (ECM), neuropathology is associated with an overwhelming inflammatory response and sequestration of leukocytes and parasite-infected RBCs in the brain. In this study, we explored the effect of vitamin D (VD; cholecalciferol) treatment on host immunity and outcome of ECM in C57BL/6 mice during Plasmodium berghei ANKA (PbA) infection. We observed that oral administration of VD both before and after PbA infection completely protected mice from ECM. VD administration significantly dampened the inducible systemic inflammatory responses with reduced circulating cytokines IFN-γ and TNF and decreased expression of these cytokines by the spleen cells. Meanwhile, VD also resulted in decreased expression of the chemokines CXCL9 and CXCL10 and cytoadhesion molecules (ICAM-1, VCAM-1, and CD36) in the brain, leading to reduced accumulation of pathogenic T cells in the brain and ultimately substantial improvement of the blood-brain barriers of PbA-infected mice. In addition, VD inhibited the differentiation, activation, and maturation of splenic dendritic cells. Meanwhile, regulatory T cells and IL-10 expression levels were upregulated upon VD treatment. These data collectively demonstrated the suppressive function of VD on host inflammatory responses, which provides significant survival benefits in the murine ECM model.

https://www.ncbi.nlm.nih.gov/pubmed/24965778

Nutrients. 2014 Jul;6(7):2572-83.
Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: a randomized controlled trial.
Johnston CS, Barkyoumb GM, Schumacher SS.

The early indications of vitamin C deficiency are unremarkable (fatigue, malaise, depression) and may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This study examined the impact of vitamin C on physical activity and respiratory tract infections during the peak of the cold season. Healthy non-smoking adult men (18-35 years; BMI < 34 kg/m2; plasma vitamin C < 45 µmol/L) received either 1000 mg of vitamin C daily (n = 15) or placebo (n = 13) in a randomized, double-blind, eight-week trial. All participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. In the final two weeks of the trial, the physical activity score rose modestly for the vitamin C group vs. placebo after adjusting for baseline values: +39.6% (95% CI [-4.5,83.7]; p = 0.10). The number of participants reporting cold episodes was 7 and 11 for the vitamin C and placebo groups respectively during the eight-week trial (RR = 0.55; 95% CI [0.33,0.94]; p = 0.04) and cold duration was reduced 59% in the vitamin C versus placebo groups (-3.2 days; 95% CI [-7.0,0.6]; p = 0.06). These data suggest measurable health advantages associated with vitamin C supplementation in a population with adequate-to-low vitamin C status.

https://www.ncbi.nlm.nih.gov/pubmed/25010554

PLoS One. 2013 Jun;8(6):e65835.
Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD.

BACKGROUND: Low levels of 25-OH vitamin D are associated with respiratory tract infection (RTI). However, results from randomized controlled trials are inconclusive. Therefore, we performed a systematic review and meta-analysis to assess the preventive effect of vitamin D supplementation on RTI.
METHODS: Randomized, controlled trials of vitamin D for prevention of RTI were used for the analysis. The risks of within-trial and publication bias were assessed. Odds ratios of RTI were pooled using a random-effects model. Heterogeneity was assessed using Cochran’s Q and I(2). Meta-regressions and subgroup analyses were used to assess the influence of various factors on trial outcome. The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews, registration number CRD42013003530.
FINDINGS: Of 1137 citations retrieved, 11 placebo-controlled studies of 5660 patients were included in the meta-analysis. Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). There was significant heterogeneity among studies (Cohran’s Q p<0.0001, I(2) = 72%). The protective effect was larger in studies using once-daily dosing compared to bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01). There was some evidence that results may have been influenced by publication bias.
INTERPRETATION: Results indicate that vitamin D has a protective effect against RTI, and dosing once-daily seems most effective. Due to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution.

https://www.ncbi.nlm.nih.gov/pubmed/23840373

BMJ Open. 2012 Dec 13;2(6). pii: e001663.
Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.
Bergman P, Norlin AC, Hansen S, Rekha RS, Agerberth B, Björkhem-Bergman L, Ekström L, Lindh JD, Andersson J.

BACKGROUND: Low serum levels of 25-hydroxyvitamin D(3) are associated with an increased risk of respiratory tract infections (RTIs). Clinical trials with vitamin D(3) against various infections have been carried out but data are so far not conclusive. Thus, there is a need for additional randomised controlled trials of effects of vitamin D(3) on infections.
OBJECTIVE: To investigate if supplementation with vitamin D(3) could reduce infectious symptoms and antibiotic consumption among patients with antibody deficiency or frequent RTIs.
DESIGN: A double-blind randomised controlled trial.
SETTING: Karolinska University Hospital, Huddinge.
PARTICIPANTS: 140 patients with antibody deficiency (selective IgA subclass deficiency, IgG subclass deficiency, common variable immune disorder) and patients with increased susceptibility to RTIs (>4 bacterial RTIs/year) but without immunological diagnosis.
INTERVENTION: Vitamin D(3) (4000 IU) or placebo was given daily for 1 year.
PRIMARY AND SECONDARY OUTCOME MEASURES:
The primary endpoint was an infectious score based on five parameters: symptoms from respiratory tract, ears and sinuses, malaise and antibiotic consumption. Secondary endpoints were serum levels of 25-hydroxyvitamin D(3), microbiological findings and levels of antimicrobial peptides (LL-37, HNP1-3) in nasal fluid.
RESULTS: The overall infectious score was significantly reduced for patients allocated to the vitamin D group (202 points) compared with the placebo group (249 points; adjusted relative score 0.771, 95% CI 0.604 to 0.985, p=0.04).
LIMITATIONS: A single study centre, small sample size and a selected group of patients. The sample size calculation was performed using p=0.02 as the significance level whereas the primary and secondary endpoints were analysed using the conventional p=0.05 as the significance level.
CONCLUSIONS: Supplementation with vitamin D(3) may reduce disease burden in patients with frequent RTIs.

https://www.ncbi.nlm.nih.gov/pubmed/23242238

J Pharmacol Pharmacother. 2012 Oct;3(4):300-3.
Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis.
Charan J, Goyal JP, Saxena D, Yadav P.

OBJECTIVES: To explore the effect of vitamin D supplementation in prevention of respiratory tract infections on the basis of published clinical trials.
MATERIALS AND METHODS: Clinical trials were searched from various electronic databases. Five clinical trials were suitable for inclusion. Outcome was events of respiratory tract infections in vitamin D group and placebo group. Data was reported as odds ratio with 95% confidence interval. Both random and fixed model was used for analysis. Analysis was done with the help of Comprehensive meta-analysis software 2.
RESULTS: Events of respiratory tract infections were significantly lower in vitamin D group as compared to control group [Odds ratio = 0.582 (0.417 – 0.812) P = 0.001] according to random model. Results were similar in fixed model. On separate analysis of clinical trials dealing with groups of children and adults, beneficial effect of vitamin D was observed in both, according to fixed model [Odds ratio = 0.579 (0.416 – 0.805), P = 0.001 and Odd ratio = 0.653 (0.472 – 0.9040, P = 0.010 respectively]. On using random model beneficial effect persisted in children’s group but became nonsignificant in adults group [Odds ratio = 0.579 (0.416 – 0.805), P = 0.001 and Odd ratio = 0.544 (0.278 – 1.063) P = 0.075 respectively].
CONCLUSION: Vitamin D supplementation decreases the events related to respiratory tract infections. There is need of more well conducted clinical trials to reach to a certain conclusion.

https://www.ncbi.nlm.nih.gov/pubmed/23326099

Pediatrics. 2012 Sep;130(3):e561-7.
Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, Sumberzul N, Rich-Edwards JW.

OBJECTIVE: Observational studies suggest that serum levels of 25-hydroxyvitamin D (25[OH]D) are inversely associated with acute respiratory infections (ARIs). We hypothesized that vitamin D supplementation of children with vitamin D deficiency would lower the risk of ARIs.

METHODS: By using cluster randomization, classrooms of 744 Mongolian schoolchildren were randomly assigned to different treatments in winter (January-March). This analysis focused on a subset of 247 children who were assigned to daily ingestion of unfortified regular milk (control; n = 104) or milk fortified with 300 IU of vitamin D(3) (n = 143). This comparison was double-blinded. The primary outcome was the number of parent-reported ARIs over the past 3 months.

RESULTS: At baseline, the median serum 25(OH)D level was 7 ng/mL (interquartile range: 5-10 ng/mL). At the end of the trial, follow-up was 99% (n = 244), and the median 25(OH)D levels of children in the control versus vitamin D groups was significantly different (7 vs 19 ng/mL; P < .001). Compared with controls, children receiving vitamin D reported significantly fewer ARIs during the study period (mean: 0.80 vs 0.45; P = .047), with a rate ratio of 0.52 (95% confidence interval: 0.31-0.89). Adjusting for age, gender, and history of wheezing, vitamin D continued to halve the risk of ARI (rate ratio: 0.50 [95% confidence interval: 0.28-0.88]). Similar results were found among children either below or above the median 25(OH)D level at baseline (rate ratio: 0.41 vs 0.57; P(interaction) = .27).

CONCLUSIONS: Vitamin D supplementation significantly reduced the risk of ARIs in winter among Mongolian children with vitamin D deficiency.

https://www.ncbi.nlm.nih.gov/pubmed/22908115

Cytokine. 2011 Aug;55(2):294-300.
Vitamin D(3) down-regulates proinflammatory cytokine response to Mycobacterium tuberculosis through pattern recognition receptors while inducing protective cathelicidin production.
Khoo AL, Chai LY, Koenen HJ, Oosting M, Steinmeyer A, Zuegel U, Joosten I, Netea MG, van der Ven AJ.

A well-known association between vitamin D(3) and infection with Mycobacterium tuberculosis has previously been reported, but little is known regarding the underlying mechanisms. We have investigated how 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] affects the proinflammatory cytokine production induced by M. tuberculosis. Furthermore, we explored whether 1,25(OH)(2)D(3) influence the production of the protective antimycobacterial peptide cathelicidin. Upon in vitro stimulation with M. tuberculosis, 1,25(OH)(2)D(3) induced a dose-dependent down-regulation of IL-6, TNFα and IFNγ, while increasing the production of IL-10 in culture supernatant as well as cathelicidin mRNA expression. This effect on cytokine response was not due to modulation of T-helper cell differentiation, as T-bet, GATA3, Foxp3 and ROR-γt mRNA expression remained unaffected. Similarly, 1,25(OH)(2)D(3) did not affect suppressor of cytokine signaling (SOCS)1 and SOCS3 mRNA expression. The mechanism whereby 1,25(OH)(2)D(3) inhibited the proinflammatory cytokine response was through reduced expression of the pattern recognition receptors (PRR) – TLR2, TLR4, Dectin-1 and mannose receptor, whose mRNA and protein expression were both reduced. The suppression of PRRs could be restored by a VDR antagonist. Upon M. tuberculosis stimulation, 1,25(OH)(2)D(3) modulates the balance in cytokine production towards an anti-inflammatory profile by repression of TLR2, TLR4, Dectin-1 and mannose receptor expression, while increasing cathelicidin production. These two effects may have beneficial consequences, by reducing the collateral tissue damage induced by proinflammatory cytokines, while the antibacterial effects of cathelicidin are enhanced.

https://www.ncbi.nlm.nih.gov/pubmed/21592820

J Infect Dis. 2011 Jan;203(1):122-30.
1,25-dihydroxyvitamin D3 modulates cytokine production induced by Candida albicans: impact of seasonal variation of immune responses.
Khoo AL, Chai LY, Koenen HJ, Kullberg BJ, Joosten I, van der Ven AJ, Netea MG.

BACKGROUND: Our interest in immunological effects produced by vitamin D(3) (1,25(OH)(2)D(3)) and its therapeutic potential prompted us to examine the role of 1,25(OH)(2)D(3) on cytokine production by Candida albicans.
METHODS: Peripheral blood mononuclear cells (PBMC) with stimulated C. albicans and 1,25(OH)(2)D(3), cytokine concentrations were measured in supernatant. Quantitative polymerase chain reaction (qPCR) was performed for T cell transcription factors, SOCS1 and 3. TLR2/4, Dectin-1, and mannose receptor expression was studied using flow cytometry and qPCR. An ex-vivo stimulation study was carried out in healthy volunteers to investigate the seasonality of immune response to C. albicans.
RESULTS: Upon in vitro C. albicans stimulation, 1,25(OH)(2)D(3) induced a dose-dependent, down-regulation of IL-6, TNFα, IL-17, and IFNγ. It also increased IL-10 production. The shift in cytokine profile was not due to 1,25(OH)(2)D(3) augmenting expression of either Thelper differentiation factors or SOCS1 and SOCS3 mRNA. 1,25(OH)(2)D(3) inhibited TLR2, TLR4, Dectin-1, and MR mRNA and protein expression. In our seasonality study, both IL-17 and IFNγ levels were suppressed in summer when 25(OH)D(3) levels were elevated.
CONCLUSION: Vitamin D(3) skews cytokine responses toward an antiinflammatory profile, mediated by suppression of TLR2, TLR4, Dectin-1, and MR transcription, leading to reduced surface expression. The biological relevance of these effects has been confirmed by the seasonality of cytokine responses.

https://www.ncbi.nlm.nih.gov/pubmed/21148505

Trop Med Int Health. 2010 Oct;15(10):1148-55.
Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G.

OBJECTIVES: To determine whether (i) supplementation of oral 100,000 iu of vitamin D(3) (cholecalciferol) along with antibiotics will reduce the duration of illness in children with pneumonia; (ii) supplementation will reduce the risk of repeat episodes.
METHODS: Double-blind individually randomised placebo-controlled trial in an inner-city hospital in Kabul, of 453 children aged 1-36 months, diagnosed with non-severe or severe pneumonia at the outpatient clinic. Children with rickets, other concurrent severe diseases, very severe pneumonia or wheeze, were excluded. Children were given vitamin D(3) or placebo drops additional to routine pneumonia treatment.
RESULTS: Two hundred and twenty-four children received vitamin D(3;) and 229 received placebo. There was no significant difference in the mean number of days to recovery between the vitamin D(3) (4.74 days; SD 2.22) and placebo arms (4.98 days; SD 2.89; P = 0.17). The risk of a repeat episode of pneumonia within 90 days of supplementation was lower in the intervention (92/204; 45%) than the placebo group [122/211; (58%; relative risk 0.78; 95% CI 0.64, 0.94; P = 0.01]. Children in the vitamin D(3) group survived longer without experiencing a repeat episode (72 days vs. 59 days; HR 0.71; 95% CI 0.53-0.95; P = 0.02).
CONCLUSION: A single high-dose oral vitamin D(3) supplementation to young children along with antibiotic treatment for pneumonia could reduce the occurrence of repeat episodes of pneumonia.

https://www.ncbi.nlm.nih.gov/pubmed/20723187

Int J Tuberc Lung Dis. 2004 Feb;8(2):263-6.
Ascorbic acid in blood serum of patients with pulmonary tuberculosis and pneumonia.
Bakaev VV, Duntau AP.

Ascorbic acid plays a major role in pulmonary antioxidant defense. Sufficient amounts of ascorbic acid are necessary to maintain normal metabolic processes in the lung. We measured the levels of ascorbic, dehydroascorbic and diketogulonic acids in blood serum of patients with pulmonary tuberculosis (PTB) and pneumonia. The serum levels of ascorbic acid were decreased in PTB and pneumonia, and those of dehydroascorbic acid were decreased in PTB, but not in pneumonia. The serum diketogulonic acid levels were not significantly changed in either PTB or pneumonia. The ratio of ascorbic to dehydroascorbic acid levels in serum were increased in PTB, but in pneumonia we observed a significant decrease in this index. The ratio of dehydroascorbic to diketogulonic acid in PTB was decreased, but in pneumonia this index did not significantly differ from the control value. Thus, in PTB the rate of ascorbic acid oxidation is decreased and the rate of dehydroascorbic acid oxidation is increased. By contrast, in pneumonia the rate of ascorbic acid oxidation is increased, but the rate of dehydroascorbic acid oxidation did not differ from control values.

https://www.ncbi.nlm.nih.gov/pubmed/15139458

Cochrane Database Syst Rev. 2013 Aug;(8):CD005532.
Vitamin C for preventing and treating pneumonia.
Hemilä H, Louhiala P.

Background: Pneumonia is one of the most common serious infections, causing two million deaths annually among young children in low-income countries. In high-income countries pneumonia is most significantly a problem of the elderly.
Objectives: To assess the prophylactic and therapeutic effects of vitamin C on pneumonia.
Search Methods: We searched CENTRAL 2013, Issue 3, MEDLINE (1950 to March week 4, 2013), EMBASE (1974 to April 2013) and Web of Science (1955 to April 2013).
Selection Criteria: To assess the therapeutic effects of vitamin C, we selected placebo-controlled trials. To assess prophylactic effects, we selected controlled trials with or without a placebo.
Data Collection and Analysis: Two review authors independently read the trial reports and extracted data.
Main Results: We identified three prophylactic trials which recorded 37 cases of community-acquired pneumonia in 2335 people. Only one was satisfactorily randomised, double-blind and placebo-controlled. Two trials examined military recruits and the third studied boys from “lower wage-earning classes” attending a boarding school in the UK during World War II. Each of these three trials found a statistically significant (80% or greater) reduction in pneumonia incidence in the vitamin C group. We identified two therapeutic trials involving 197 community-acquired pneumonia patients. Only one was satisfactorily randomised, double-blind and placebo-controlled. That trial studied elderly patients in the UK and found lower mortality and reduced severity in the vitamin C group; however, the benefit was restricted to the most ill patients. The other therapeutic trial studied adults with a wide age range in the former Soviet Union and found a dose-dependent reduction in the duration of pneumonia with two vitamin C doses. We identified one prophylactic trial recording 13 cases of hospital-acquired pneumonia in 37 severely burned patients; one-day administration of vitamin C had no effect on pneumonia incidence. The identified studies are clinically heterogeneous which limits their comparability. The included studies did not find adverse effects of vitamin C.
Authors’ Conclusions: The prophylactic use of vitamin C to prevent pneumonia should be further investigated in populations who have a high incidence of pneumonia, especially if dietary vitamin C intake is low. Similarly, the therapeutic effects of vitamin C should be studied, especially in patients with low plasma vitamin C levels. The current evidence is too weak to advocate prophylactic use of vitamin C to prevent pneumonia in the general population. Nevertheless, therapeutic vitamin C supplementation may be reasonable for pneumonia patients who have low vitamin C plasma levels because its cost and risks are low.

https://www.ncbi.nlm.nih.gov/pubmed/23925826

J Food Sci Technol. 2020 Apr;57(4):1205-1215.
Grape seed extract: having a potential health benefits.
Gupta M, Dey S, Marbaniang D, Pal P, Ray S, Mazumder B.

Grapes are one of the most highly consumed fruits across the world. In ancient Europe the leaves and the sap of grape plants has been used in traditional treatment for ages. Besides being a wellspring for vitamins and fibre, the skin and seeds of grapes are highly rich in Polyphenols specifically proanthocyanidins, which can be used as a functional ingredient to address various health issues by boosting the natural bio-processes of the body. Since, grape seeds are by product of wine making companies therefore can be easily procured. The present review article briefly describes the various pharmacological activities of grape seed extract and different experimental studies were done which supports the beneficial health qualities of the extract. Through different and various studies, it was proved that the proanthocyanidin rich grape seed extract provides benefits against many diseases i.e. inflammation, cardiovascular disease, hypertension, diabetes, cancer, peptic ulcer, microbial infections, etc. Therefore, beside from using it as a nutraceutical or cosmeceutical, as a result they may have a potential to substitute or complement in currently used drugs in the treatment of diseases by developing it into other successful pharmaceutical formulations for better future prospective.

https://www.ncbi.nlm.nih.gov/pubmed/32180617

J Anim Sci. 2020 Jan. pii: skaa030.
Dietary phytonutrients and animal health: regulation of immune function during gastrointestinal infections.
Williams AR, Andersen-Civil AIS, Zhu L, Blanchard A.

The composition of dietary macronutrients (proteins, carbohydrates and fibres) and micronutrients (vitamins, phytochemicals) can markedly influence the development of immune responses to enteric infection. This has important implications for livestock production, where a significant challenge exists to ensure healthy and productive animals in an era of increasing drug resistance and concerns about the sector’s environmental footprint. Nutritional intervention may ultimately be a sustainable method to prevent disease and improve efficiency of livestock enterprises, and it is now well-established that certain phytonutrients can significantly improve animal performance during challenge with infectious pathogens. However, many questions remain unanswered concerning the complex interplay between diet, immunity and infection. In this review, we examine the role of phytonutrients in regulating immune and inflammatory responses during enteric bacterial and parasitic infections in livestock, with a specific focus on some increasingly well-studied phytochemical classes – polyphenols (especially proanthocyanidins), essential oil components (cinnamaldehyde, eugenol and carvacrol), and curcumin. Despite the contrasting chemical structures of these molecules, they appear to induce a number of similar immunological responses. These include promotion of mucosal antibody and anti-microbial peptide production, coupled with a strong suppression of inflammatory cytokines and reactive oxygen species. Whilst there have been some recent advances in our understanding of the mechanisms underlying their bioactivity, how these phytonutrients modulate immune responses in the intestine remains mostly unknown. We discuss the complex inter-relationships between metabolism of dietary phytonutrients, the gut microbiota and the mucosal immune system, and propose that an increased understanding of the basic immunological mechanisms involved will allow the rational development of novel dietary additives to promote intestinal health in farmed animals.

https://www.ncbi.nlm.nih.gov/pubmed/31999321

Nutrients. 2019 Dec;12(1):4.
Prevention of Acute Upper Respiratory Infections by Consumption of Catechins in Healthcare Workers: A Randomized, Placebo-Controlled Trial.
Furushima D, Nishimura T, Takuma N, Iketani R, Mizuno T, Matsui Y, Yamaguchi T, Nakashima Y, Yamamoto S, Hibi M, Yamada H.

Catechins, phytochemicals contained mainly in green tea, exhibit antiviral activity against various acute infectious diseases experimentally. Clinical evidence supporting these effects, however, is not conclusive. We performed a placebo-controlled, single-blind, randomized control trial to evaluate the clinical effectiveness of consumption of catechins-containing beverage for preventing acute upper respiratory tract infections (URTIs). Two hundred and seventy healthcare workers were randomly allocated to high-catechin (three daily doses of 57 mg catechins and 100 mg xanthan gum), low-catechin (one daily dose of 57 mg catechins and 100 mg xanthan gum), or placebo (0 mg catechins and 100 mg xanthan gum) group. Subjects consumed a beverage with or without catechins for 12 weeks from December 2017 through February 2018. The primary endpoint was incidence of URTIs compared among groups using a time-to-event analysis. A total of 255 subjects were analyzed (placebo group n = 86, low-catechin group n = 85, high catechin group n = 84). The URTI incidence rate was 26.7% in the placebo group, 28.2% in the low-catechin group, and 13.1% in the high-catechin group (log rank test, p = 0.042). The hazard ratio (95% confidence interval (CI)) with reference to the placebo group was 1.09 (0.61-1.92) in the low-catechin group and 0.46 (0.23-0.95) in the high-catechin group. These findings suggest that catechins combined with xanthan gum protect against URTIs.

https://pubmed.ncbi.nlm.nih.gov/31861349/

Pharmaceutics. 2019 Dec;12(1). pii: E9.
Utilizing Liposomal Quercetin and Gallic Acid in Localized Treatment of Vaginal Candida Infections.
Giordani B, Basnet P, Mishchenko E, Luppi B, Škalko-Basnet N.

Vulvovaginal candidiasis (VVC) is a widely spread fungal infection that causes itching, pain and inflammation at the vaginal site. Although common, currently available treatment suffers from limited efficacy and high recurrence. In addition, the growing problem of resistance to azole drugs used in current treatments emphasizes the need for superior treatment options. Antimicrobial polyphenols are an attractive approach offering multitargeting therapy. We aimed to develop novel liposomes for simultaneous delivery of two polyphenols (quercetin, Q, and gallic acid, GA) that, when released within the vaginal cavity, act in synergy to eradicate infection while alleviating the symptoms of VVC. Q was selected for its anti-itching and anti-inflammatory properties, while GA for its reported activity against Candida. Novel liposomes containing only Q (LP-Q), only GA (LP-GA) or both polyphenols (LP-Q+GA) were in the size range around 200 nm. Q was efficiently entrapped in both LP-Q and in LP-Q+GA (85%) while the entrapment of GA was higher in LP-Q+GA (30%) than in LP-GA (25%). Liposomes, especially LP-Q+GA, promoted sustained release of both polyphenols. Q and GA acted in synergy, increasing the antioxidant activities of a single polyphenol. Polyphenol-liposomes were not cytotoxic and displayed stronger anti-inflammatory effects than free polyphenols. Finally, LP-GA and LP-Q+GA considerably reduced C. albicans growth.

https://www.ncbi.nlm.nih.gov/pubmed/31861805

Phytother Res. 2019 Dec. doi: 10.1002/ptr.6574. [Epub ahead of print]
Tart cherry (Prunus cerasus L.) fractions inhibit biofilm formation and adherence properties of oral pathogens and enhance oral epithelial barrier function.
Ben Lagha A, LeBel G, Grenier D.

Dental caries, candidiasis, and periodontal disease are the most common oral infections affecting a wide range of the population worldwide. The present study investigated the effects of two tart cherry (Prunus cerasus L.) fractions on important oral pathogens, including Candida albicans, Streptococcus mutans, and Fusobacterium nucleatum, as well as on the barrier function of oral epithelial cells. Procyanidins and quercetin and its derivatives were the most important constituents found in the tart cherry fractions. Although the fractions showed poor antimicrobial activity, they inhibited biofilm formation by the three oral pathogens in a dose-dependent manner. The tart cherry fractions also attenuated the adherence of C. albicans and S. mutans to a hydroxylapatite surface as well as the adherence of F. nucleatum to oral epithelial cells. Treating oral epithelial cells with the tart cherry fractions significantly enhanced the barrier function as determined by monitoring the transepithelial electrical resistance. In conclusion, this study showed that the tart cherry fractions and their bioactive constituents could be promising antiplaque compounds by targeting biofilm formation and adherence properties of oral pathogens. Furthermore, its property of increasing the epithelial barrier function may protect against microbial invasion of the underlying connective tissue

https://www.ncbi.nlm.nih.gov/pubmed/31846135

J Ethnopharmacol. 2019 Jul;239:111930.
Antibacterial effects of extracts obtained from plants of Argentina: Bioguided isolation of compounds from the anti-infectious medicinal plant Lepechinia meyenii.
Chabán MF, Karagianni C, Joray MB, Toumpa D, Sola C, Crespo MI, Palacios SM, Athanassopoulos CM, Carpinella MC.

ETHNOPHARMACOLOGICAL RELEVANCE: The mostly native species from Argentina are used in traditional medicine generally for the treatment of pain and inflammation, respiratory, gastro-intestinal and urinary disorders and as antiseptics.
AIM OF THE STUDY: Since these ailments may be associated with bacterial infections and that it is necessary to discover alternative compounds with antibacterial activity, 69 extracts from these plants were screened for their activity against pathogenic bacteria. The most effective extract was then submitted to bioguided isolation to obtain the compounds responsible for this activity.
MATERIALS AND METHODS: Extracts and fractions were screened using agar dilution, and compounds using microbroth dilution methods. A large panel of pathogenic bacteria was used, especially methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Bioguided fractionation was performed using successive chromatographic techniques, while the chemical structures of the isolated compounds were determined by nuclear magnetic resonance (NMR). Additionally, a series of derivatives of the most active compound were prepared in order to study the chemical features required for achieving the antibacterial effect.
RESULTS: Lepechinia meyenii (Walp.) Epling (Lamiaceae) extract showed itself the most effective, with minimum inhibitory concentration (MIC) against Gram positive and negative bacteria ranging from 62.5 to 500 μg/mL, and showing better activity on MRSA than on MSSA. Activity-guided fractionation yielded the abietanes carnosol (1), rosmanol (2) and carnosic acid (3) as active principles, with MICs ranging from 15.6-31.2, 15.6-62.5 and 7.8-15.6 μg/mL, respectively against 15 MRSA strains, and 15.6-31.2, 31.2-62.5 and 7.8-15.6 μg/mL, respectively against 11 MSSA strains, maintaining higher activity against the resistant bacteria, as does the extract. In addition, Enterococcus faecalis was sensitive to 1-3 with MICs of 15.6-62.5 μg/mL. The structure activity analysis showed that 12-OH is necessary for remarkable activity, but methylation in C-20 significantly increased this, as observed with 20-methyl carnosate (5) displaying the greatest effect, even more so than 3, with MICs of 3.9 μg/mL against all the tested MRSA and 3.9-7.8 μg/mL against the MSSA.
CONCLUSIONS: The results of this study contribute to validate the traditional antibacterial use of species native to Argentina, particularly of L. meyenii. The chemical structures of the compounds obtained may aid the design of antibacterial agents, especially those effective against MRSA.

https://www.ncbi.nlm.nih.gov/pubmed/31059749

Infect Immun. 2018 Aug;86(9). pii: e00356-18.
Reduction of Articular and Systemic Inflammation by Kava-241 in a Porphyromonas gingivalis-Induced Arthritis Murine Model.
Huck O, You J, Han X, Cai B, Panek J, Amar S.

Rheumatoid arthritis (RA) is an inflammatory disease that has been linked to several risk factors, including periodontitis. Identification of new anti-inflammatory compounds to treat arthritis is needed. We had previously demonstrated the beneficial effect of Kava-241, a kavain-derived compound, in the management of Porphyromonas gingivalis-induced periodontitis. The present study evaluated systemic and articular effects of Kava-241 in an infective arthritis murine model triggered by P. gingivalis bacterial inoculation and primed with a collagen antibody cocktail (CIA) to induce joint inflammation and tissular destruction. Clinical inflammation score and radiological analyses of the paws were performed continuously, while histological assessment was obtained at sacrifice. Mice exposed to P. gingivalis and a CIA cocktail and treated concomitantly with Kava-241 exhibited a reduced clinical inflammatory score and a decreased number of inflammatory cells and osteoclasts within joint. Kava-241 treatment also decreased significantly tumor necrosis factor alpha (TNF-α) in serum from mice injected with a Toll-like receptor 2 or 4 (TLR-2/4) ligand, P. gingivalis-lipopolysaccharide (LPS). Finally, bone marrow-derived macrophages infected with P. gingivalis and exposed to Kava-241 displayed reduced TLR-2/4, reduced mitogen-activated protein kinase (MAPK)-related signal elements, and reduced LPS-induced TNF-α factor (LITAF), all explaining the observed reduction of TNF-α secretion. Taken together, these results emphasized the novel properties of Kava-241 in the management of inflammatory conditions, especially TNF-α-related diseases such as infective RA.

https://www.ncbi.nlm.nih.gov/pubmed/29914930

Biomed Res Int. 2018 Jul;2018:9105261.
Green Tea Catechins: Their Use in Treating and Preventing Infectious Diseases.
Reygaert WC.

Green tea is one of the most popular drinks consumed worldwide. Produced mainly in Asian countries from the leaves of the Camellia sinensis plant, the potential health benefits have been widely studied. Recently, researchers have studied the ability of green tea to eradicate infectious agents and the ability to actually prevent infections. The important components in green tea that show antimicrobial properties are the catechins. The four main catechins that occur in green tea are (-)-epicatechin (EC), (-)-epicatechin-3-gallate (ECG), (-)-epigallocatechin (EGC), and (-)-epigallocatechin-3-gallate (EGCG). Of these catechins, EGCG and EGC are found in the highest amounts in green tea and have been the subject of most of the studies. These catechins have been shown to demonstrate a variety of antimicrobial properties, both to organisms affected and in mechanisms used. Consumption of green tea has been shown to distribute these compounds and/or their metabolites throughout the body, which allows for not only the possibility of treatment of infections but also the prevention of infections.

https://pubmed.ncbi.nlm.nih.gov/30105263/

Phytomedicine. 2018 Jan;39:93-99.
Synergism of prenylflavonoids from Morus alba root bark against clinical MRSA isolates.
Zuo GY, Yang CX, Han J, Li YQ, Wang GC.

BACKGROUND: Clinical methicillin-resistant Staphylococcus aureus (MRSA) is a thorny problem in current anti-infective therapeutics and a challenge of new drug development. Plant prenylflavonoids possess anti-MRSA activity, but few of the prenylflavonoids have been reported the synergistic anti-MRSA effect when they are used in combination with conventional antibacterial agents.
PURPOSE: This study deals with anti-MRSA activity of four prenylflavonoids from the root bark of Morus alba and their synergism with 11 conventional antibacterial agents.
METHODS: Chromatographic methods and spectral analysis were used to isolate and identify the prenylflavonoids. The antibacterial activity and synergism were assessed by the broth microdilution method, checkerboard dilution test, and time-kill curve assay, respectively.
RESULTS: Four prenylflavonoids, i.e., cyclocommunol (Cy, 1), morusinol (Ml, 2), morusin (Mi, 3) and kuwanon E (Ku, 4), were isolated from Morus alba bark ethanol extract. Compounds 1, 3 and 4 showed high antimicrobial activity on both methicillin-susceptible S. aureus (MSSA) and MRSA strains with MICs/MBCs at 4-16/32-64 and 4-32/16-128 µg/ml, respectively. Ml (2) was not active. Compound 2 showed synergy with amikacin (AK) and streptomycin (SM) against all the ten MRSA isolates. Ml (2) and Ku (4) also showed synergy with ciprofloxacin (CI), etimicin (EM) and vancomycin (VA) against 7-9 isolates. The fractional inhibitory concentration indices (FICIs) ranged 0.09-1.00 and the dose reduction indices (DRIs) of these antibacterial agents ranged 2-128. Cy (1) and Mi (3) showed synergy with the tested antibacterial agents against only 1-3 MRSA isolates except VA. Furthermore, the MRSA resistance could be reversed in the combinations of AK with Cy, Ml, Mi and Ku; EM with Mi and Ku; and SM with Ml by the criteria of MIC interpretive standards for Staphylococcus spp. of CLSI. All the combinations showed only indifference in the 1 × MIC time-killing experiments. The prenylated substitutions play an important role in the activity of the compounds used alone and combined with the tested antibacterials.
CONCLUSIONS: The study revealed for the first time the anti-MRSA synergism of prenylflavonoids 1-4 with eleven antibacterial agents and the reversal of MRSA resistance to aminoglycosides, especially amikacin. The results might be valuable for the development of new antibacterial drugs and synergists against MRSA infection.

https://www.ncbi.nlm.nih.gov/pubmed/29433688

Molecules. 2017 Sep;22(9). pii: E1529.
The Effects of Resveratrol on Inflammation and Oxidative Stress in a Rat Model of Chronic Obstructive Pulmonary Disease.
Wang XL, Li T, Li JH, Miao SY, Xiao XZ.

Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans-3,5,4′-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.

https://www.ncbi.nlm.nih.gov/pubmed/28895883

J Biomed Mater Res A. 2017 Sep;105(9):2510-2521.
Anti-inflammatory, anti-osteoclastic, and antioxidant activities of genistein protect against alveolar bone loss and periodontal tissue degradation in a mouse model of periodontitis.
Bhattarai G, Poudel SB, Kook SH, Lee JC.

Genistein, a dietary polyphenol primarily found in soy products, has beneficial effects on bone. However, the effect of genistein on inflammatory periodontal destruction has not been investigated in detail. We explored whether genistein protects against lipopolysaccharide (LPS)/ligature-induced periodontitis in mice. We also examined the effect of genistein on LPS-stimulated inflammatory and oxidative stress using RAW 264.7 macrophages and human gingival fibroblasts (hGFs). The results from μCT and histological analyses revealed that intraperitoneal injection of genistein (20 mg/kg body weight) daily for three weeks inhibited LPS-mediated alveolar bone loss and periodontal tissue degradation. The administration of genistein also inhibited osteoclast formation and the expression of inflammation-related molecules in the inflamed region of mice with periodontitis. Treatment with 30-70 μM genistein significantly prevented osteoclast differentiation in receptor activator of nuclear factor κB ligand- or LPS-stimulated macrophages by suppressing the expression of osteoclast-specific molecules. The addition of genistein led to a dose-dependent inhibition of the expression of inflammation-related molecules both in LPS-stimulated macrophages and hGFs. In addition, genistein at 50 μM protected hGFs from LPS-mediated stresses such as mitochondrial impairment and cellular ROS accumulation. However, such protection was significantly diminished by combined treatment with 25 nM bafilomycin A1, a chemical autophagy inhibitor. Collectively, our results indicate that genistein protects against inflammatory periodontal damage by regulating autophagy induction and inhibiting osteoclast activation, the production of inflammation mediators, and mitochondrial oxidative damage.

https://www.ncbi.nlm.nih.gov/pubmed/28509410

Eur J Microbiol Immunol (Bp). 2017 Mar;7(1):92-98.
Finding Novel Antibiotic Substances from Medicinal Plants – Antimicrobial Properties of Nigella Sativa Directed against Multidrug-resistant Bacteria.
Bakal SN, Bereswill S, Heimesaat MM.

The progressive rise in multidrug-resistant (MDR) bacterial strains poses serious problems in the treatment of infectious diseases. While the number of newly developed antimicrobial compounds has greatly fallen, the resistance of pathogens against commonly prescribed drugs is further increasing. This rise in resistance illustrates the need for developing novel therapeutic and preventive antimicrobial options. The medicinal herb Nigella sativa and its derivatives constitute promising candidates. In a comprehensive literature survey (using the PubMed data base), we searched for publications on the antimicrobial effects of N. sativa particularly directed against MDR bacterial strains. In vitro studies published between 2000 and 2015 revealed that N. sativa exerted potent antibacterial effects against both Gram-positive and Gram-negative species including resistant strains. For instance, N. sativa inhibited the growth of bacteria causing significant gastrointestinal morbidity such as Salmonella, Helicobacter pylori, and Escherichia coli. However, Listeria monocytogenes and Pseudomonas aeruginosa displayed resistance against black cumin seed extracts. In conclusion, our literature survey revealed potent antimicrobial properties of N. sativa against MDR strains in vitro that should be further investigated in order to develop novel therapeutic perspectives for combating infectious diseases particularly caused by MDR strains.

https://www.ncbi.nlm.nih.gov/pubmed/28386474

Phytomedicine. 2016 Dec;23(14):1814-1820.
Synergism of coumarins from the Chinese drug Zanthoxylum nitidum with antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA).
Zuo GY, Wang CJ, Han J, Li YQ, Wang GC.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious therapeutic challenge in current clinic and new drug development. Natural coumarins have diverse bioactivities and the potential of resistance modifying effects.
PURPOSE: This study is to present in-depth evaluations of in vitro antimicrobial activities of four natural coumarins 5-geranyloxy-7-methoxycoumarin (Gm, 1), (5,7-dimethoxy-8-prenyloxycoumarin (artanin, Ar, 2)), isopimpinellin (Is, 3) and phellopterin (Ph, 4) from Zanthoxylum nitidum (Roxb.) DC. (Rutaceae) extracts, focusing on their potential restoration the activity of conventional antibacterial agents against clinical MRSA strains.
METHODS: Bioactivity-guided fractionation and spectral analyses were used to isolate the coumarins and identify the structures, respectively. The double broth microdilution method was used to assay the coumarins’ alone activity. The classic checkerboard microdilution and dynamic time-killing methods were used to evaluate combinatory effects.
RESULTS: The four plant coumarins Gm (1), Ar (2), Is (3) and Ph (4) were isolated and identified from Z. nitidum extracts. Coumarins 1-4 displayed promising inhibition against both MSSA and MRSA with minimal inhibitory concentrations (MICs) of 8-64µg/ml, but very weak against Gram-negative pathogen and yeast with MICs of 256 to ≥1024µg/ml. The geranyloxy and prenyloxy substitutions showed to be more active than the methoxy substitution on the coumarin skeletons. 1-4 also showing different extent of synergism with a total of eight conventional antibacterial agents, i.e. chloramphenicol (CL), gentamicin (CN), fosfomycin (FF), levofloxacin (LE), minocycline (MI), piperacillin/tazobactam (P/T), teicoplanin (TE) and vancomycin (VA) against ten clinical MRSA strains. Four to ten of the tested MRSA strains showed bacteriostatic synergy in the eleven combinations. The anti-MRSA modifying effects were related to different arrangement in the combinations with fractional inhibitory concentration indices (FICIs) from 0.187 to 1.125 and the three combinations CN (Is), CL (Ph) and MI (Gm) were the best ones. The enhancement of activity was also shown by 2-64 of dose reduction indices (DRIs) of the combined MICs, with VA (Ph) combination resulted the biggest DRI. The resistance of MRSA to antibacterial agents could be reversed in the combinations of CL (Gm or Ph), LE (Ph) and MI (Is) following the Clinical and Laboratory Standards Institute (CLSI) criteria. Six combinations P/T (Gm), TE (Ar), CN (Is), VA (Ph) and CL (Gm or Ph) also showed bactericidal synergy with Δlog10CFU/ml >2 at 24h incubation.
CONCLUSIONS: The coumarins showed high potentiating effects of the antibacterial agents against multi-drug resistant SA. The resistance reversal effect of CL, LE and MI warrants further pharmacological investigation on combinatory therapy for the sake of fighting against MRSA infections.

https://www.ncbi.nlm.nih.gov/pubmed/27912884

BMC Complement Altern Med. 2016 Mar;16:105.
Biocidal effects of stem bark extract of Chrysophyllum albidium G. Don on vancomycin-resistant Staphylococcus aureus.
Akinpelu DA, Odewade JO, Aiyegoro OA, Ashafa AO, Akinpelu OF, Agunbiade MO.

BACKGROUND: Staphylococcus aureus causes variety of infections in humans and animals worldwide and predominates in surgical wound infections. This study assessed the antimicrobial potential of the stem bark extract of Chrysophyllum albidum against an array of vancomycin resistant Staphylococcus aureus (VRSA) isolated from clinical samples.
METHODS: The methanolic crude extract of the plant was preliminary screened for the presence of phytochemicals; after then, the extract was partitioned into n-hexane, chloroform, ethyl acetate and butanol fractions. A range of concentrations of the plant extract fractions was prepared to assess its antimicrobial potency; the minimum inhibitory concentrations (MICs); the minimum bactericidal concentrations (MBCs); the rate of killing; the potassium ion leakage potential and nucleotides leakage ability against the VRSAs.
RESULTS: The phytochemical screening revealed the presence of tannins, alkaloids, flavonoids, saponins, steroids, reducing sugars and terpenoids as major phytoconstituents resident in the crude plant extract. The two active fractions (n-hexane and butanol) at a concentration of 10 mg/ml exhibited antibacterial activities with the MIC and MBC values for the fractions ranged between 0.63-10 mg/ml and 1.25-10 mg/ml respectively. The time kill assay revealed that the antibacterial action of the two fractions are time and concentration dependent; the n-hexane and butanol fractions achieved 100 % kill on the test isolates at a concentration of 3 × MIC and 2 × MIC respectively after 120 min of reaction time. Varying amount of potassium ions as well as nucleotides were leaked from the test cells by n-hexane and butanol fractions.
CONCLUSIONS: This study has established the possibility of developing antimicrobial agents of natural origin to manage possible infection from vancomycin resistant Staphylococcus aureus that are now developing multi-resistance against many antibiotics.

https://www.ncbi.nlm.nih.gov/pubmed/27004526

Food Chem. 2016 Mar;194:1048-55.
Phenolic profile, antibacterial and cytotoxic properties of second grade date extract from Tunisian cultivars (Phoenix dactylifera L.).
Kchaou W, Abbès F, Mansour RB, Blecker C, Attia H, Besbes S.

The present study aimed to investigate the phenolic profile of second grade date extracts and evaluate their antimicrobial and cytotoxic activities with regard to some pathogenic microorganisms. Phenolic content was analyzed by HPLC. Antimicrobial activity was evaluated by the agar disk diffusion method, and in vitro cytotoxic activity was examined by cell proliferation assay. The results revealed that second grade dates presented three benzoic acids, five cinnamic acids and two flavonoids, with the predominance of ρ-coumaric acid (1998.80μg/100g). The antimicrobial activities showed that the date extracts were active against Gram (+) and Gram (-) bacteria, showing marked activity against Escherichia coli with an inhibition zone of 25mm. Cytotoxicity assays showed that the date extracts were able to inhibit the proliferation of HeLa cell lines. The results confirmed that the date extracts were rich in biologically active compounds that are highly valued in the functional food and nutraceutical industries.

https://www.ncbi.nlm.nih.gov/pubmed/26471652

Arch Oral Biol. 2016 Feb;62:70-9.
Genistein suppresses Prevotella intermedia lipopolysaccharide-induced inflammatory response in macrophages and attenuates alveolar bone loss in ligature-induced periodontitis.
Choi EY, Bae SH, Ha MH, Choe SH, Hyeon JY, Choi JI, Choi IS, Kim SJ.

OBJECTIVE: Genistein is a major isoflavone subclass of flavonoids found in soybean and a potent tyrosine kinase inhibitor. The present study aimed to assess the effect of genistein on the production of proinflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) isolated from Prevotella intermedia, a pathogen associated with different forms of periodontal disease, and to evaluate its possible influence on alveolar bone loss in ligature-induced periodontitis using micro-computed tomography (micro-CT) analysis as well.

DESIGN: LPS was isolated from P. intermedia ATCC 25611 by using the standard hot phenol-water method. Culture supernatants were analyzed for nitric oxide (NO) and interleukin-6 (IL-6). Inducible NO synthase (iNOS) protein expression was evaluated by immunoblot analysis. Real-time PCR was carried out to measure iNOS and IL-6 mRNA expression. In addition, effect of genistein on alveolar bone loss was evaluated in a rat model of experimental periodontitis using micro-CT analysis.

RESULTS: Genistein significantly attenuated P. intermedia LPS-induced production of iNOS-derived NO and IL-6 with attendant decrease in their mRNA expression in RAW264.7 cells. In addition, when genistein was administered to rats, decreases in alveolar bone height and bone volume fraction induced by ligature placement were significantly inhibited. Genistein administration also prevented ligature-induced alterations in the microstructural parameters of trabecular bone, including trabecular thickness, trabecular separation, bone mineral density and structure model index.

CONCLUSIONS: While additional studies are required, we suggest that genistein could be utilized for the therapy of human periodontitis in the future.

https://www.ncbi.nlm.nih.gov/pubmed/26655950

J Ethnopharmacol. 2016 Feb;178:180-7.
Cleistochlamys kirkii chemical constituents: Antibacterial activity and synergistic effects against resistant Staphylococcus aureus strains.
Pereira F, Madureira AM, Sancha S, Mulhovo S, Luo X, Duarte A, Ferreira MJ.

ETHNOPHARMACOLOGICAL RELEVANCE: Cleistochlamys kirkii (Benth) Oliv., (Annonaceae) is a medicinal plant traditionally used in Mozambique to treat infectious diseases.
AIMS OF THE STUDY: To find antibacterial lead compounds from C. kirkii and provide scientific validation for its use in traditional medicine.
MATERIALS AND METHODS: Through bioassay-guided fractionation, nine compounds (1-9), with different scaffolds, were isolated from the methanol extract of C. kirkii whose structures were identified by spectroscopic methods. Compounds 1-9 were evaluated for their in vitro antibacterial activity against a panel of eight Gram-positive, including five drug-resistant strains of Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and two Gram-negative bacteria strains. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined. A chemosensitization assay, using the checkerboard method, was also performed in order to evaluate the type of interaction of compounds with antibiotics/compounds against two S. aureus resistant strains (ATCC 9144 and CIP 106760) and a susceptible strain (ATCC 6538).
RESULTS: Dichamanetin (3), a rare C-benzylated flavanone, was very active against all the Gram-positive strains tested, displaying MIC values in the range of 1-7.5 μg/mL. The C-benzylated flavanones chamanetin (1), isochamanetin (2), and the α,β-unsaturated lactone (-)-cleistenolide (6) also showed relevant antibacterial activity against some of the Gram-positive strains assayed. Compounds 4, 5, and 7-9 have shown no significant activity at the concentration ranges tested. In the combination with antibiotics, polycarpol (8) (MIC 125 μg/mL) showed a strong synergistic effect against the methicillin-resistant S. aureus ATCC 9144. When combined with oxacillin (MIC 125 μg/mL), compound 8 reduced the MIC to 1.5 μg/mL (FICI=0.11). Similarly, it reduced the MIC of amoxicillin (MIC 250 μg/mL) to 7.5 μg/mL (FICI=0.18). Synergy was also obtained when this compound was combined with both β-lactam antibiotics (FICI=0.30) and with vancomycin (FICI=0.24) against vancomycin-intermediate S. aureus (VISA) CIP 106760. Remarkable, compound 8 was also able to reduce synergistically the MIC value of dichamanetin (3) (FICI=0.18) against this strain.
CONCLUSIONS: These results suggested that C. kirkii constituents may be valuable as a leads for restoring antibiotic activity against resistant S. aureus strains.

https://www.ncbi.nlm.nih.gov/pubmed/26674158

J Ethnopharmacol. 2016 Feb;179:76-82.
Antibacterial effects of Alchornea cordifolia (Schumach. and Thonn.) Müll. Arg extracts and compounds on gastrointestinal, skin, respiratory and urinary tract pathogens.
Noundou XS, Krause RW, van Vuuren SF, Ndinteh DT, Olivier DK.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves, stems and roots of Alchornea cordifolia (Schumach. and Thonn.) Müll. Arg. are used as traditional medicine in many African countries for the management of gastrointestinal, respiratory and urinary tract infections as well as for the treatment of wounds.
AIM OF THE STUDY: To determine the in vitro antibacterial activity of the crude extracts of leaves and stems of A. cordifolia on gastrointestinal, skin, respiratory and urinary tract pathogens and to identify the compounds in the extracts that may be responsible for this activity.
MATERIALS AND METHODS: The antibacterial activities of crude extracts [hexane, chloroform (CHCl3), ethyl acetate (EtOAc), ethanol (EtOH), methanol (MeOH) and water (H2O)] as well as pure compounds isolated from these extracts were evaluated by means of the micro-dilution assay against four Gram-positive bacteria, i.e. Bacillus cereus ATCC 11778, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923 and S. saprophyticus ATCC 15305, as well as four Gram-negative bacterial strains, i.e. Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 13883, Moraxella catarrhalis ATCC 23246 and Proteus mirabilis ATCC 43071. The isolation of the active constituents was undertaken by bio-autographic assays in conjunction with chromatographic techniques. The identification and characterisation of the isolated compounds were done using mass spectrometry (MS) and Fourier transformed infrared spectrometry (FTIR) as well as 1D- and 2D- nuclear magnetic resonance (NMR) analyses.
RESULTS: The leaves and stems of A. cordifolia exhibited varied antibacterial activity against all eight pathogens. Most of the MIC values ranged between 63 and 2000µg/ml. The highest activities for the crude extracts (63µg/ml) were observed against S. saprophyticus [stem (EtOAc, CHCl3 and hexane), leaves (MeOH, EtOH, EtOAc and CHCl3)], E. coli [stem (MeOH and EtOH), leaves (MeOH, EtOH, EtOAc and CHCl3)], M. catarrhalis [leaves (EtOAc and CHCl3)], K. pneumoniae [stem (CHCl3), leaves (CHCl3)] and S. aureus [leaves (CHCl3)]. Seven constituents [stigmasterol (1), stigmasta-4,22-dien-3-one (2), friedelin (3), friedelane-3-one-28-al (4), 3-O-acetyl-aleuritolic acid (5), 3-O-acetyl-erythrodiol (6) and methyl-3,4,5-trihydroxybenzoate (methyl gallate) (7)] were isolated from the stem MeOH extract. All these compounds displayed some antibacterial activity against the eight pathogens with highest activity against S. saprophyticus (2µg/ml). Furthermore, this is the first report of compounds 1, 2, 3, 4, 6 and 7 isolated from A. cordifolia and where a complete set of 2D-NMR data for fridelane-3-one-28-al (4) is presented.
CONCLUSION: The study demonstrated that the antibacterial activities of A. cordifolia extracts may be due to the presence of the seven isolated compounds, where compounds 3-6 showed the best activity. The observed activity against gastrointestinal, skin, respiratory and urinary tract pathogens supports the traditional use for the treatment of such ailments.

https://www.ncbi.nlm.nih.gov/pubmed/26724423

Acta Biomater. 2016 Jan;29:398-408.
Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis.
Bhattarai G, Poudel SB, Kook SH, Lee JC.

Resveratrol is an antioxidant and anti-inflammatory polyphenol. Periodontitis is induced by oral pathogens, where a systemic inflammatory response accompanied by oxidative stress is the major event initiating disease. We investigated how resveratrol modulates cellular responses and the mechanisms related to this modulation in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (hGFs). We also explored whether resveratrol protects rats against alveolar bone loss in an experimental periodontitis model. Periodontitis was induced around the first upper molar of the rats by applying ligature infused with LPS. Stimulating hGFs with 5μg/ml LPS augmented the expression of cyclooxygenase-2, matrix metalloproteinase (MMP)-2, MMP-9, and Toll-like receptor-4. LPS treatment also stimulated the production of reactive oxygen species (ROS) and the phosphorylation of several protein kinases in the cells. However, the expression of heme oxygenase-1 (HO-1) and nuclear factor-E2 related factor 2 (Nrf2) was inhibited by the addition of LPS. Resveratrol treatment almost completely inhibited all of these changes in LPS-stimulated cells. Specifically, resveratrol alone augmented HO-1 induction via Nrf2-mediated signaling. Histological and micro-CT analyses revealed that administration of resveratrol (5mg/kg body weight) improved ligature/LPS-mediated alveolar bone loss in rats. Resveratrol also attenuated the production of inflammation-related proteins, the formation of osteoclasts, and the production of circulating ROS in periodontitis rats. Furthermore, resveratrol suppressed LPS-mediated decreases in HO-1 and Nrf2 levels in the inflamed periodontal tissues. Collectively, our findings suggest that resveratrol protects rats from periodontitic tissue damage by inhibiting inflammatory responses and by stimulating antioxidant defense systems.

https://www.ncbi.nlm.nih.gov/pubmed/26497626

BMC Complement Altern Med. 2015 Dec;15:425.
In vitro synergism of magnolol and honokiol in combination with antibacterial agents against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA).
Zuo GY, Zhang XJ, Han J, Li YQ, Wang GC.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen posing a serious therapeutic challenge in the clinic. It is often multidrug-resistant (MDR) to conventional classes of antibacterial agents and there is an urgent need to develop new agents or strategies for treatment. Magnolol (ML) and honokiol (HL) are two naturally occurring diallylbiphenols which have been reported to show inhibition of MRSA. In this study their synergistic effects with antibacterial agents were further evaluated via checkerboard and time-kill assays.
METHODS: The susceptibility spectrum of clinical MRSA strains was tested by the disk diffusion method. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ML and HL were assayed by broth microdilution. The synergy was evaluated through checkerboard microdilution and time-killing experiments.
RESULTS: ML and HL showed similar activity against both MSSA and MRSA with MIC/MBC at 16 ~ 64 mg/L, with potency similar to amikacin (AMK) and gentamicin (GEN). When they were used in combination with conventional antibacterial agents, they showed bacteriostatic synergy with FICIs between 0.25 ~ 0.5, leading to the combined MICs decreasing to as low as 1 ~ 2 and 1 ~ 16 mg/L for ML (HL) and the agents, respectively. MIC50 of the combinations decreased from 16 mg/L to 1 ~ 4 mg/L for ML (HL) and 8 ~ 128 mg/L to 2 ~ 64 mg/L for the antibacterial agents, which exhibited a broad spectrum of synergistic action with aminoglycosides (AMK, etilmicin (ETM) and GEN), floroquinolones (levofloxacin (LEV), ciprofloxacin and norfloxacin), fosfomycin (FOS) and piperacillin. The times of dilution (TOD, the extent of decreasing in MIC value) were determined up to 16 for the combined MIC. A more significant synergy after combining was determined as ML (HL) with AMK, ETM, GEN and FOS. ML (HL) combined with antibacterial agents did not show antagonistic effects on any of the ten MRSA strains. Reversal effects of MRSA resistance to AMK and GEN by ML and HL were also observed, respectively. All the combinations also showed better dynamic bactericidal activity against MRSA than any of single ML (HL) or the agents at 24 h incubation. The more significant synergy of combinations were determined as HL (ML) + ETM, HL + LEV and HL + AMK (GEN or FOS), with △LC24 of 2.02 ~ 2.25.
CONCLUSION: ML and HL showed synergistic potentiation of antibacterial agents against clinical isolates of MRSA and warrant further pharmacological investigation.

https://www.ncbi.nlm.nih.gov/pubmed/26627468

Arch Med Sci. 2015 Aug;11(4):863-8.
In vitro antibacterial activity of seven Indian spices against high level gentamicin resistant strains of enterococci.
Revati S, Bipin C, Chitra PB, Minakshi B.

INTRODUCTION: The aim of the study was to explore the in vitro antibacterial activity of seven ethanolic extracts of spices against high level gentamicin resistant (HLGR) enterococci isolated from human clinical samples.
MATERIAL AND METHODS: Two hundred and fifteen enterococcal strains were isolated from clinical samples. High level gentamicin resistance in ethanolic extracts of cumin (Cuminum cyminum), cinnamon (Cinnamomum zeylanicum), ginger (Zingiber officinale), fenugreek (Trigonella foenum-graecum), cloves (Syzygium aromaticum), cardamom (Elettaria cardamomum Maton) and black pepper (Piper nigrum) were prepared using Soxhlet apparatus. The antibacterial effect of the extracts was studied using the well diffusion method. Statistical analysis was carried out by χ(2) test using SPSS 17 software.
RESULTS: Only cinnamon and ginger were found to have activity against all the isolates, whereas cumin and cloves had a variable effect on the strains. Fenugreek, black pepper and cardamom did not show any effect on the isolates. The zone diameter of inhibition obtained for cinnamon, ginger, cloves and cumin was in the range 31-34 mm, 27-30 mm, 25-26 mm and 19-20 mm respectively.
CONCLUSIONS: Cinnamomum zeylanicum and Z. officinale showed the maximum antibacterial activity against the enterococcal isolates followed by S. aromaticum and C. cyminum. The findings of the study show that spices used in the study can contribute to the development of potential antimicrobial agents for inclusion in the anti-enterococcal treatment regimen.

https://www.ncbi.nlm.nih.gov/pubmed/26322099

Sci Rep. 2015 Mar;5:9253.
Phytonutrient diet supplementation promotes beneficial Clostridia species and intestinal mucus secretion resulting in protection against enteric infection.
Wlodarska M, Willing BP, Bravo DM, Finlay BB.

Plant extracts, or phytonutrients, are used in traditional medicine practices as supplements to enhance the immune system and gain resistance to various infectious diseases and are used in animal production as health promoting feed additives. To date, there are no studies that have assessed their mechanism of action and ability to alter mucosal immune responses in the intestine. We characterized the immunomodulatory function of six phytonutrients: anethol, carvacrol, cinnamaldehyde, eugenol, capsicum oleoresin and garlic extract. Mice were treated with each phytonutrient to assess changes to colonic gene expression and mucus production. All six phytonutrients showed variable changes in expression of innate immune genes in the colon. However only eugenol stimulated production of the inner mucus layer, a key mucosal barrier to microbes. The mechanism by which eugenol causes mucus layer thickening likely involves microbial stimulation as analysis of the intestinal microbiota composition showed eugenol treatment led to an increase in abundance of specific families within the Clostridiales order. Further, eugenol treatment confers colonization resistance to the enteric pathogen Citrobacter rodentium. These results suggest that eugenol acts to strengthen the mucosal barrier by increasing the thickness of the inner mucus layer, which protects against invading pathogens and disease.

https://www.ncbi.nlm.nih.gov/pubmed/25787310

Free Radic Biol Med. 2014 Oct;75:222-9.
Resveratrol improves oxidative stress and prevents the progression of periodontitis via the activation of the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in a rat periodontitis model.
Tamaki N, Cristina Orihuela-Campos R, Inagaki Y, Fukui M, Nagata T, Ito HO.

Oxidative stress is a key factor regulating the systemic pathophysiological effects associated with periodontitis. Resveratrol is a phytochemical with antioxidant and anti-inflammatory properties that can reduce oxidative stress and inflammation. We hypothesized that resveratrol may prevent the progression of periodontitis and reduce systemic oxidative stress through the activation of the sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) and the nuclear factor E2-related factor 2 (Nrf2)/antioxidant defense pathways. Three groups of male Wistar rats (periodontitis treated with melinjo resveratrol, periodontitis without resveratrol, and control rats with no periodontitis or resveratrol treatment) were examined. A ligature was placed around the maxillary molars for 3 weeks to induce periodontitis, and the rats were then given drinking water with or without melinjo resveratrol. In rats with periodontitis, ligature placement induced alveolar bone resorption, quantified using three-dimensional images taken by micro-CT, and increased proinflammatory cytokine levels in gingival tissue. Melinjo resveratrol intake relieved alveolar bone resorption and activated the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in inflamed gingival tissues. Further, melinjo resveratrol improved the systemic levels of 8-hydroxydeoxyguanosine, dityrosine, nitric oxide metabolism, nitrotyrosine, and proinflammatory cytokines. We conclude that oral administration of melinjo resveratrol may prevent the progression of ligature-induced periodontitis and improve systemic oxidative and nitrosative stress.

https://www.ncbi.nlm.nih.gov/pubmed/25091897

Integr Med Res. 2014 Sep;3(3):133-141.
Monitoring in vitro antibacterial efficacy of 26 Indian spices against multidrug resistant urinary tract infecting bacteria.
Rath S, Padhy RN.

BACKGROUND: To screen methanolic extracts of 26 commonly used Indian spices against nine species of uropathogenic bacteria (Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa), isolated from clinical samples of a tertiary care hospital for antibacterial activity.

METHODS: Bacterial strains were subjected to antibiotic sensitivity testing by Kirby-Bauer’s disc diffusion method. Monitoring antibacterial potentiality of spice extracts was done by the agar-well diffusion method with multidrug resistant (MDR) strains of nine uropathogens.

RESULTS: The Gram-positive (GP) bacteria E. faecalis and S. aureus were resistant to 16 of the 21 antibiotics used. Among the Gram-negative (GN) bacteria, resistant patterns were A. baumannii and E. aerogenes to 12, C. freundii to 14, E. coli to 12, K. pneumoniae to 10, P. mirabilis to 11, and P. aeruginosa to 15 antibiotics of the 18 antibiotics used. The most effective 15 spices, having at least 25-29 mm as the size of the zone of inhibition, were Allium cepa, Brassica juncea, Cinnamomum tamala, Cinnamomum zeylanicum, Coriandrum sativum, Cuminum cyminum, Curcuma longa, Mentha spicata, Murraya koenigii, Nigella sativa, Papaver somniferum, Piper nigrum, S. aromaticum, Trachyspermum ammi, and Trigonella foenum for at least one of the GP or GN MDR bacterial strains used. Moderate control capacity was registered by nine spices, Curcuma amada, Foeniculum vulgare, Illicium verum, Mentha spicata, Papaver somniferum, Syzygium aromaticum, Trachyspermum ammi, Trigonella foenum, and Zingiber officinale. However, the best two spices for controlling all the pathogens used were C. zeylanicum and C. longa, with the highest value of 29 mm as the inhibition zone size.

CONCLUSION: The most effective and unique 16 spice plants recorded for the in vitro control of MDR uropathogens could further be pursued for the development of complementary and supplementary medicine against MDR bacteria.

https://www.ncbi.nlm.nih.gov/pubmed/28664089

J Ethnopharmacol. 2014 May;153(3):587-95.
In vitro antibacterial effects of Cinnamomum extracts on common bacteria found in wound infections with emphasis on methicillin-resistant Staphylococcus aureus.
Buru AS, Pichika MR, Neela V, Mohandas K.

ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum species have been widely used in many traditional systems of medicine around the world. In the Malaysian traditional system of medicine, the leaves, stem bark and stem wood of Cinnamomum iners, Cinnamomum porrectum, Cinnamomum altissimum and Cinnamomum impressicostatum have been used to treat wound infections. To study the antibacterial effects of Cinnamomum iners, Cinnamomum porrectum, Cinnamomum altissimum and Cinnamomum impressicostatum against common bacteria found in wound infections with primary focus on methicillin-resistant Staphylococcus aureus (MRSA).
MATERIALS AND METHODS: The crude extracts from the leaves, stem-bark and stem-wood of Cinnamomum iners, Cinnamomum porrectum, Cinnamomum altissimum and Cinnamomum impressicostatum were obtained using sequential extraction with hexane, ethylacetate, methanol and water. The volatile oils were obtained by hydro-distillation. The antibacterial activities of extracts were investigated using disk diffusion assays and broth microdilution assays.
RESULTS: The volatile oils obtained from the stem-bark of Cinnamomum altissimum, Cinnamomum porrectum and Cinnamomum impressicostatum have shown significant antibacterial activity against a wide range of Gram positive and Gram negative bacteria including MRSA. A few test extracts have shown better activity against MRSA as compared to methicillin sensitive Staphylococcus aureus (MSSA). Amongst all the test extracts, Cinnamomum impressicostatum stem-bark water extract produced the largest inhibition zone of 21.0mm against MRSA while its inhibition zone against MSSA was only 8.5mm. The minimum inhibitory concentration (MIC) of this extract against MRSA was 19.5 μg mL(-1) and the corresponding minimum bactericidal concentration (MBC) was 39.0 μg mL(-1).
CONCLUSIONS: This study has scientifically validated the traditional use of Cinnamomum species in treating wound infections. Of high scientific interest was the observation that the antibacterial effect of Cinnamomum impressicostatum stem-bark crude water extract against MRSA was significantly higher than its effect against MSSA, suggesting that the extract contains a compound(s) with higher specific neutralising activity against the drug resistance markers of MRSA.

https://www.ncbi.nlm.nih.gov/pubmed/24613273

J Ethnopharmacol. 2014 Feb;151(2):1023-7.
Antibacterial activity of the roots, stems and leaves of Alchornea floribunda.
Siwe Noundou X, Krause RW, van Vuuren SF, Tantoh Ndinteh D, Olivier DK.

ETHNOPHARMACOLOGICAL RELEVANCE: Alchornea floribunda Müll. Arg. is used in traditional medicine across Africa for the treatment of bacterial, fungal, parasitic and inflammatory disorders.
AIM OF THE STUDY: To evaluate the antibacterial activity of the crude extracts of different plant parts in order to provide a scientific rationale for the proposed broad efficacy of Alchornea floribunda in the treatment of bacterial infections.
MATERIALS AND METHODS: Extracts of roots, stems and leaves were prepared using solvents of various polarities in order to extract a wide range of phytochemicals. The antibacterial activity of these crude extracts was evaluated by micro-dilution assay, against Gram-positive (i.e. Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus and Staphylococcus saprophyticus) as well as Gram-negative (i.e. Escherichia coli, Klebsiella pneumoniae, Moraxella catarrhalis and Proteus mirabilis) bacteria.
RESULTS: Generally, the ethanol (EtOH), methanol (MeOH), ethyl acetate (EtOAc) and chloroform (CHCl3) extracts demonstrated the best activities, with the leaves exhibiting the highest average activity for six of the eight pathogens. Of these, the ethanolic leaf extract was the most active against Staphylococcus aureus with an MIC value of 50µg/mL. Some other notable activity was observed for the ethyl acetate and chloroform root extracts against Staphylococcus aureus (50µg/mL), and for selected stem extracts against Staphylococcus aureus (50µg/mL), Klebsiella pneumoniae (63µg/mL) and Staphylococcus saprophyticus (63µg/mL).
CONCLUSION: This study demonstrates the promising antibacterial activity of Alchornea floribunda against both Gram-positive and Gram-negative bacteria responsible for gastrointestinal, skin, respiratory and urinary ailments, and validates its use in the ethnopharmacology of the region.

https://www.ncbi.nlm.nih.gov/pubmed/24333961

Osong Public Health Res Perspect. 2013 Dec;4(6):347-57.
In Vitro antibacterial efficacy of 21 Indian timber-yielding plants against multidrug-resistant bacteria causing urinary tract infection.
Mishra MP, Padhy RN.

OBJECTIVES: To screen methanolic leaf extracts of 21 timber-yielding plants for antibacterial activity against nine species of uropathogenic bacteria isolated from clinical samples of a hospital (Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa).

METHODS: Bacterial strains were subjected to antibiotic sensitivity tests by the Kirby-Bauer’s disc diffusion method. The antibacterial potentiality of leaf extracts was monitored by the agar-well diffusion method with multidrug-resistant (MDR) strains of nine uropathogens.

RESULTS: Two Gram-positive isolates, E. faecalis and S. aureus, were resistant to 14 of the 18 antibiotics used. Gram-negative isolates A. baumannii, C. freundii, E. aerogenes, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa were resistant to 10, 12, 9, 11, 11, 10, and 11 antibiotics, respectively, of the 14 antibiotics used. Methanolic leaf extracts of Anogeissus acuminata had the maximum zone of inhibition size-29 mm against S. aureus and 28 mm against E. faecalis and P. aeruginosa. Cassia tora had 29 mm as the zone of inhibition size for E. faecalis, E. aerogenes, and P. aeruginosa. Based on the minimum inhibitory concentration and minimum bactericidal concentration values, the most effective 10 plants against uropathogens could be arranged in decreasing order as follows: C. tora > A. acuminata > Schleichera oleosa > Pterocarpus santalinus > Eugenia jambolana > Bridelia retusa > Mimusops elengi > Stereospermum kunthianum > Tectona grandis > Anthocephalus cadamba. The following eight plants had moderate control capacity: Artocarpus heterophyllus, Azadirachta indica, Dalbergia latifolia, Eucalyptus citriodora, Gmelina arborea, Pongamia pinnata, Pterocarpus marsupium, and Shorea robusta. E. coli, followed by A. baumannii, C. freundii, E. aerogenes, P. mirabilis, and P. aeruginosa were controlled by higher amounts/levels of leaf extracts. Phytochemicals of all plants were qualitatively estimated.

CONCLUSIONS: A majority of timber-yielding plants studied had in vitro control capacity against MDR uropathogenic bacteria.

https://www.ncbi.nlm.nih.gov/pubmed/24524024

Oman Med J. 2011 Sep;26(5):319-23.
In Vitro Antibacterial Activity of three Indian Spices Against Methicillin-Resistant Staphylococcus aureus. Mandal S; Manisha DebMandal, Saha K, Pal NK.

OBJECTIVE: To explore the in vitro antibacterial activity of ethanolic extracts of cinnamon (Cinnamomum zeylanicum; CIN), clove (Syzygium aromaticum, CLV) and cumin (Cuminum cyminum, CMN) against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA), from Kolkata, India.
METHODS: The CIN, CLV and CMN were tested for their antibacterial activity against MRSA by in vitro methods. Minimum inhibitory concentration (MIC) values of the three extracts were determined, and time-kill studies were performed in order to investigate the bactericidal activity of the extracts (at the MIC level) for the isolates. The killing efficacy of the extracts was determined at various concentrations.
RESULTS: The zone diameter of inhibition (ZDI) obtained due to CIN, CLV and CMN ranged between 22-27 mm, 19-23 mm and 9-15 mm, respectively; while the MICs, for the isolates, were in the range of 64-256, 64-512 and 128-512 µg/ml, respectively. When tested for their MIC levels; the CIN and CLV were found to be bactericidal after 6 hrs of incubation, while CMN showed bactericidal activity after 24 hrs. However, when tested at various concentrations; CIN, CLV and CMN displayed bactericidal activity against S. aureus, after 24 hrs of incubation, at 200, 200 and 300 µg/ml, respectively.
CONCLUSION: The C. zeylanicum and S. aromaticum showed the strongest in vitro antibacterial activity followed by C. cyminum against MRSA, and such findings could be considered a valuable support in the treatment of infection and may contribute to the development of potential antimicrobial agents for inclusion in anti- S. aureus regimens.

https://www.ncbi.nlm.nih.gov/pubmed/22125725

Adv Clin Exp Med. 2020 Feb;29(2):215-224.
Microbiological, antioxidant and lipoxygenase-1 inhibitory activities of fruit extracts of chosen Rosaceae family species.
Hendrich AB, Strugała P, Dudra A, Kucharska AZ, Sokół-Łętowska A, Wojnicz D, Cisowska A, Sroka Z Gabrielska J.

BACKGROUND: Extracts from the Rosaceae family fruits are rich in natural, biologically active polyphenols, but their antibacterial properties are still poorly understood. Therefore, we focused our research on their activity against uropathogenic Escherichia coli strains. This research also concerned the proof of their ability to reduce oxidative stress and modulate the activity of lipoxygenase-1 (LOX-1). It is well-known that plants represent a source of bioactive compounds whose antioxidant activity may be useful in protecting against oxidative damage in cells, which have been linked to the pathogenesis of many oxidative diseases.

OBJECTIVES: The study determined the biological activity of methanol (ME) and water (WE) extracts rich in polyphenols from the hawthorn (Crataegus monogyna Jacq.), dog rose (Rosa canina L.), quince (Cydonia oblonga Mill.), and Japanese quince (Chaenomeles speciosa (Sweet) Nakai).

MATERIAL AND METHODS: The antioxidant capacity was evaluated using 1,1diphenyl-2-picrylhydrazyl (DPPH▪) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS+▪) radical scavenging methods. The inhibition of liposome membrane oxidation was studied using the thiobarbituric acid reactive substances assay. Lipoxygenase-1 inhibitory activity was measured using the spectrophotometric method. Bacterial growth was determined by evaluating the number of colony forming units per milliliter (CFU/mL). Hydrophobicity was established with salt aggregation hydrophobicity test (SAT). Swimming and swarming motilities were evaluated using soft-agar plates. Production of curli fimbriae was estimated on CFA agar. The P fimbriae were detected using the hemagglutination of erythrocytes. Adhesion of bacteria to human uroepithelial cells was assessed. The amount of biofilm was determined spectrophotometrically.

RESULTS: We showed that most of these extracts are effective antioxidants and free radical scavengers, possess reasonable potential anti-inflammatory activity, reduce the adhesion of E. coli to uroepithelial cells, and reduce the ability of these bacteria to form biofilm.

CONCLUSIONS: The extracts examined, showing very promising biological properties, seem to be able to join the list of substances that can be used as dietary supplements aimed at preventing, for example, urinary tract infections, or as support of drug treatment in many diseases.

https://www.ncbi.nlm.nih.gov/pubmed/32073762

J Tradit Chin Med. 2019 Dec;39(6):764-771.
Phytochemical screening, antioxidant and antibacterial properties of daphne mucronata.
Ghosia L, Asma S, Kafeel A, Jamila H.

OBJECTIVE: To aim at preliminary phytochemical screening of Daphne mucronata and evaluate its antioxidant and antibacterial activities.
METHODS: Preliminary phytochemical screening was conducted for the crude extracts using standard methods. Antioxidant properties of crude methanolic extracts, n-hexane, chloroform, ethyl acetate and aqueous fractions of leaves, roots and bark were evaluated following standard procedures. The antibacterial activities were checked against Acinetobacter baumannii (A. baumannii), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Morganella morganii (M. morganii) and vancomycin resistant S. aureus (VRSA).
RESULTS: Carbohydrates, saponins, steroids, phenols/ tannins, flavonoids and glycosides were present in different parts of Daphne mucronata. The extracts showed good antioxidant activity with EC50 values of 157.82-361.61 μg/mL. Methanolic extracts of roots showed good activity against A. baumannii (86.95%), E. coli (85.18%) and S. aureus (84.61%). Methanolic extracts of bark were active against A. bumanni (65.21%), M. morganii (65.21%) and E. coli (62.96%). Methanolic extracts of leaves showed good activity against A. bumanni (78.26%), E. coli (77.78%), P. aeruginosa (74.07%), S. aureus (73.07%), M. morganii (69.56%), VRSA (68%) and Proteus vulgaris (60%). The n-hexane fraction of roots was effective against A. bumanni (78.26%). Chlorofom fraction of roots showed moderate activity against A. bumanni (60.86%) and S. aureus (61.53%). Ethyl acetate fraction of roots showed moderate activity against A. bumanii (69.56%), E. coli (62.96%) and S. aureus (69.23%).
CONCLUSION: This study illustrates that Daphne mucronata possesses good antioxidant and antibacterial properties. The plant could be further exploited as potential natural antioxidant and as a new source of antimicrobials for treatment of various infections.

https://www.ncbi.nlm.nih.gov/pubmed/32186146

An Acad Bras Cienc. 2019 Dec;91(4):e20190434.
Vitamin B6 reduces oxidative stress in lungs and liver in experimental sepsis.
Giustina AD, Danielski LG, Novochadlo MM, Goldim MPS, Joaquim L, Metzker KLL, Carli RJ, Denicol T, Cidreira T, Vieira T, Petronilho F.

Sepsis is a life-threatening organ dysfunction induced by a disrupted host response to infecting pathogens. Inflammation and oxidative stress are intrinsically related to sepsis progression and organ failure. Vitamin B6 is an important cellular cofactor for metabolic processes and has anti-inflammatory and antioxidant properties. We aimed at evaluating the effect of vit B6 on inflammation and oxidative stress markers in the liver and lung of rats subjected to a relevant animal model of polymicrobial sepsis. Adult male Wistar rats were submitted to cecal ligation and perforation model and immediately after sepsis induction, vit B6 was administered as a single dose (600 mg/kg, subcutaneous). Twenty-four hours later, the lung and liver were harvest for neutrophil infiltration, oxidative markers to lipids and protein and antioxidant activity of endogenous enzyme. Vitamin B6 diminished neutrophil infiltration in both organs, oxidative markers in the liver and restored catalase activity levels in the lung of septic animals. Vitamin B6 exerts anti-inflammatory and antioxidant effects in peripheral organs after polymicrobial sepsis.

https://www.ncbi.nlm.nih.gov/pubmed/31800708

Parasitol Int. 2019 Aug;71:106-120.
Oral administration of Coenzyme Q10 protects mice against oxidative stress and neuro-inflammation during experimental cerebral malaria.
Nyariki JN, Ochola LA, Jillani NE, Nyamweya NO, Amwayi PE, Yole DS, Azonvide L, Isaac AO.

In animal model of experimental cerebral malaria (ECM), the genesis of neuropathology is associated with oxidative stress and inflammatory mediators. There is limited progress in the development of new approaches to the treatment of cerebral malaria. Here, we tested whether oral supplementation of Coenzyme Q10 (CoQ10) would offer protection against oxidative stress and brain associated inflammation following Plasmodium berghei ANKA (PbA) infection in C57BL/6 J mouse model. For this purpose, one group of C57BL/6 mice was used as control; second group of mice were orally supplemented with 200 mg/kg CoQ10 and then infected with PbA and the third group was PbA infected alone. Clinical, biochemical, immunoblot and immunological features of ECM was monitored. We observed that oral administration of CoQ10 for 1 month and after PbA infection was able to improve survival, significantly reduced oedema, TNF-α and MIP-1β gene expression in brain samples in PbA infected mice. The result also shows the ability of CoQ10 to reduce cholesterol and triglycerides lipids, levels of matrix metalloproteinases-9, angiopoietin-2 and angiopoietin-1 in the brain. In addition, CoQ10 was very effective in decreasing NF-κB phosphorylation. Furthermore, CoQ10 supplementation abrogated Malondialdehyde, and 8-OHDG and restored cellular glutathione. These results constitute the first demonstration that oral supplementation of CoQ10 can protect mice against PbA induced oxidative stress and neuro-inflammation usually observed in ECM. Thus, the need to study CoQ10 as a candidate of antioxidant and immunomodulatory molecule in ECM and testing it in clinical studies either alone or in combination with antimalaria regimens to provide insight into a potential translatable therapy.

https://www.ncbi.nlm.nih.gov/pubmed/30981893

Medicina (Kaunas). 2019 Jun;55(6). pii: E289.
In Vitro Antioxidant and Bactericidal Efficacy of 15 Common Spices: Novel Therapeutics for Urinary Tract Infections?
Mickymaray S, Al Aboody MS.

Background and Objectives: Bacterial urinary tract infection (UTI) is the most common ailment affecting all age groups in males and females. The commercial antibiotics usage augments antibiotics resistance and creates higher recurrence rates of such communal infections. Hence, this study is aimed at investigating the antibacterial and antioxidant potentials of 15 common spices against 11 UTI-causing bacterial pathogens. Materials and Methods: The antioxidant potential of the methanolic extracts was analyzed as contents of total phenols and flavonoids; radical scavenging, total reducing power, the ferric reducing power assay. Urinary pathogens were subjected to spice extracts to investigate antibacterial assays. Results: Preliminary phytochemical study of spices was performed to find those containing alkaloids, flavonoids, phenolic compounds, and steroids that can be recognized for their noteworthy bactericidal effects. The outcome of the antioxidative potential from the four methods demonstrated the sequence of potent antioxidant activity: Acorus calamus > Alpinia galanga > Armoracia rusticana > Capparis spinosa > Aframomum melegueta. The total polyphenols and flavonoids in the studied species positively correlated with their antioxidant properties. The four most effective spices (A. calamus, A. galanga, A. rusticana, and C. spinosa) had a zone of inhibition of at least 22 mm. A. calamus, A. melegueta, and C. spinosa had the lowest minimum inhibitory concentration (MIC) value against Enterobacter aerogenes, Staphylococcus aureus and Proteus mirabilis. All 15 spices had the lowest minimum bactericidal concentration (MBC) value against most of the pathogenic bacteria. Conclusion: The four highly potent and unique spices noted for the in vitro control of UTI-causing pathogens could be pursued further in the development of complementary and alternative medicine against UTI-causing pathogens.

https://www.ncbi.nlm.nih.gov/pubmed/31248181

J Integr Med. 2018 Jul;16(4):255-262.
In vitro antioxidant, antilipoxygenase and antimicrobial activities of extracts from seven climbing plants belonging to the Bignoniaceae.
Torres CA, Pérez Zamora CM, Nuñez MB, Gonzalez AM.

OBJECTIVES: This study aimed to evaluate the in vitro antioxidant capacity, to determine the anti-inflammatory effect due to lipoxygenase inhibition and to test the antimicrobial activity of ethanolic extracts from leaves of seven climbing species belonging to the Bignoniaceae family. These species are Adenocalymma marginatum (Cham.) DC., Amphilophium vauthieri DC., Cuspidaria convoluta (Vell.) A. H. Gentry, Dolichandra dentata (K. Schum.) L. G. Lohmann, Fridericia caudigera (S. Moore) L. G. Lohmann, Fridericia chica (Bonpl.) L. G. Lohmann and Tanaecium selloi (Spreng.) L. G. Lohmann.

METHODS: The antioxidant activity was evaluated using three methods, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power. Lipoxygenase-inhibiting activity was assayed spectrophotometrically; the result was expressed as percent inhibition. The antimicrobial activity was assessed using the agar disk diffusion method. Minimal inhibitory concentration (MIC) and minimal bactericidal/fungicidal concentration were also determined for each extract against 12 pathogenic bacterial strains of Staphylococcus aureus and seven fungal strains of the Candida genus. The identification of the major compounds present in the most promising extract was established by high-performance liquid chromatography-tandem mass spectrometry.

RESULTS: convoluta, F. caudigera, and F. chica exhibited the best antioxidant activity by scavenging DPPH and ABTS⁺ radicals and reducing Fe³⁺ ion. These extracts showed a notable inhibition of lipoxygenase. F. caudigera was found to have the lower MIC value against S. aureus strains and six Candida species. The extracts of F. caudigera and C. convoluta were active even against methicillin-resistant S. aureus. C. convoluta had higher total phenol content, better antioxidant activity and superior anti-inflammatory and antimicrobial activity. The main phenolic compounds found in this extract were coumaric and hydroxybenzoic acid derivatives and glycosylated and nonglycosylated flavones.

CONCLUSION: Most of the extracts exhibited antioxidant activity as well as in vitro inhibition of lipoxygenase. The excellent antimicrobial activity of T. selloi and F. chica supports their use in traditional medicine as antiseptic agents. The extracts of F. caudigera and C. convoluta, both with notable biological activities in this study, could be used as herbal remedies for skin care. In addition, this study provides, for the first time, information about phenolic compounds present in C. convoluta.

https://www.ncbi.nlm.nih.gov/pubmed/29759936

Food Res Int. 2017 Dec;102:119-128.
Chilean berry Ugni molinae Turcz. fruit and leaves extracts with interesting antioxidant, antimicrobial and tyrosinase inhibitory properties.
López de Dicastillo C, Bustos F, Valenzuela X, López-Carballo G, Vilariño JM, Galotto MJ.

The knowledge of the biological properties of fruits and leaves of murta (Ugni molinae Turcz.) has been owned by native Chilean culture. The present study investigated the phenolic content, the antioxidant, antimicrobial and anti-tyrosinase activities of different murta fruit and leaves extracts to approach their uses on future food, pharmaceutical and cosmetic applications. Extractions of murta fruit and leaves were carried out under water, ethanol and ethanol 50%. Phenolic content of these extracts was measured through Folin Ciocalteu test and the antioxidant power by four different antioxidant systems (ORAC, FRAP, DPPH and TEAC assays) owing to elucidate the main mechanism of antioxidant. Some flavonoids, such as rutin, isoquercitrin and quercitrin hydrate were identified and quantified through HPLC analysis. Antimicrobial activity was determined measuring minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) values against Escherichia coli and Listeria monocytogenes, and the effect of these extracts on L. monocytogenes was confirmed by flow cytometry. Highest contents of polyphenol compounds were obtained in hydroalcoholic extracts (28±1mggallicacid/g dry fruit, and 128±6mggallicacid/g dry leaves). The same trend was found for the values of biological properties: hydroalcoholic extracts showed the strongest activities. Leaves presented higher antioxidant, antimicrobial and anti-tyrosinase properties than murta fruit. Highest antioxidant activity values according to ORAC, FRAP, TEAC and DPPH were 80±8mgTrolox/g, 70±2mgTrolox/g, 87±8mgTrolox/g and 110±12mgTrolox/g, respectively, for murta fruit samples, and 280±10mgTrolox/g, 192±4mgTrolox/g, 286±13mgTrolox/g and 361±13mgTrolox/g, respectively, for murta leaves. These activities were confirmed by HPLC analysis that revealed highest presence of analyzed compounds on leaves hydroalcoholic extract. Regarding to antimicrobial analysis, hydroalcoholic leaves extract presented the highest activity presenting the lowest MIC value for L. monocytogenes (0.07mg/mL). This extract also performed the highest anti-tyrosinase activity (CE₅₀ values of 1.6±0.3 (g/L) and 8.9±1.2 (g/L) for leaves and fruit, respectively).

https://www.ncbi.nlm.nih.gov/pubmed/29195930

Eur J Med Chem. 2017 Nov;140:604-614.
4-Alkyliden-azetidinones modified with plant derived polyphenols: Antibacterial and antioxidant properties.
Giacomini D, Musumeci R, Galletti P, Martelli G, Assennato L, Sacchetti G, Guerrini A, Calaresu E, Martinelli M, Cocuzza C.

Antimicrobial resistance is one of the major and growing concerns in hospital- and community acquired infections, and new antimicrobial agents are therefore urgently required. It was reported that oxidative stress could contribute to the selection of resistant bacterial strains, since reactive oxygen species (ROS) revealed to be an essential driving force. In the present work 4-alkylidene-azetidinones, a new class of antibacterial agents, were functionalized with phytochemical polyphenolic acids such as protocatechuic, piperonyl, caffeic, ferulic, or sinapic acids and investigated as dual target antibacterial-antioxidant compounds. The best candidates showed good activities against multidrug resistant clinical isolates of MRSA (MICs 2-8 μg/mL). Among the new compounds, two revealed the best antioxidant capacity with TEAC-DPPH and TEAC-ABTS being significantly more active than Trolox®.

https://www.ncbi.nlm.nih.gov/pubmed/28992569

Pharmacogn Mag. 2017 Oct;13(Suppl 3):S392-S400.
Bioactive Constituents, Radical Scavenging, and Antibacterial Properties of the Leaves and Stem Essential Oils from Peperomia pellucida (L.) Kunth.
Okoh SO, Iweriebor BC, Okoh OO, Okoh AI.

Background: Peperomia pellucida is an annual herbaceous ethnomedicinal plant used in the treatment of a variety of communicable and noncommunicable diseases in the Amazon region.

Objective: The study aimed at profiling the bioactive constituents of the leaves and stem essential oils (LEO and SEO) of P. pellucida, their in vitro antibacterial and radical scavenging properties as probable lead constituents in the management of oxidative stress and infectious diseases. Materials and.

Methods: The EOs were obtained from the leaves and stem P. pellucida using modified Clevenger apparatus and characterized by a high-resolution gas chromatography-mass spectrometry, while the radicals scavenging and antibacterial effects on four oxidants and six reference bacteria strains were examined by spectrophotometric and agar diffusion techniques, respectively.

Results: The EOs exhibited strong antibacterial activities against six bacteria (Escherichia coli [180], Enterobacter cloacae, Mycobacterium smegmatis, Listeria ivanovii, Staphylococcus aureus, Streptococcus uberis, and Vibrio paraheamolyticus) strains. The SEO antibacterial activities were not significantly different (P < 0.05) from the LEO against most of the test bacteria with minimum inhibitory concentration ranging between 0.15 and 0.20 mg/mL for both EOs. The two oils were bactericidal at 0.20 mg/mL against S. aureus while the minimum bactericidal concentration (0.15 mg/mL) of LEO against L. ivanovii was lower than of SEO (0.20 mg/mL) after 24 h. The LEO IC₅₀ value (1.67 mg/mL) revealed more radical scavenging activity than the SEO (2.83 mg/mL) and reference compounds against 2,2-diphenyl-1-picrylhydrazyl radical. The EOs also scavenged three other different radicals (2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical, lipid peroxyl radical, and nitric oxide radical) in concentration-dependent manner.

Conclusion: Our results suggest that apart from the indigenous uses of the plant extracts, the EO contains strong bioactive compounds with antibacterial and radicals scavenging properties and may be good alternative candidates in the search for novel potent antibiotics in this present era of increasing multidrug-resistant bacterial strains as well as effective antioxidants agents.

https://www.ncbi.nlm.nih.gov/pubmed/29142389

Microb Pathog. 2017 Oct;111:41-49.
Chemical composition of Mentha pulegium and Rosmarinus officinalis essential oils and their antileishmanial, antibacterial and antioxidant activities.
Bouyahya A, Et-Touys A, Bakri Y, Talbaui A, Fellah H, Abrini J, Dakka N.

The aim of the study was the determination of the chemical composition of Mentha pulegium L. and Rosmarinus officinalis L. essential oils and the evaluation of their antileishmanial, antibacterial and antioxidant activities. Essential oils (EOs) were isolated using steam distillation and the chemical composition was determined using GC-MS analysis. The antibacterial activity was tested against ten pathogenic strains using the diffusion method, the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) by microtitration assay. The antioxidant activity was estimated by DPPH free radical scavenging ability and ferric-reducing power. The antileishmanial activity was tested against Leishmania major, Leishmania tropica and Leishmania infantum using MTT (3-(4.5-dimethylthiazol-2yl)-2.5-diphenyltetrazolium bromide) assay. The yield of essential oils (v/w %) M. puleguim and R. officinalis based on dry weight were 5.4 and 2.7% respectively. GC/MS analysis of R. officinalis essential oil (ROEO) revealed the presence of 29 components, mainly represented by oxygenated monoterpenes (63.743%) and hydrocarbons monoterpenes (21.231%). Mentha pulegium essential oil (MPEO) revealed 21 components, mainly represented by oxygenated monoterpenes (83.865%). The major components of ROEO were α-pinene (14.076), 1,8-Cineole (23.673) and camphor (18.743), while menthone (21.164) and pulegone (40.98) were the main major components of MPEO. M. pulegium and R. officinalis EOs showed a significant antioxidant activity compared with ascorbic acid and Trolox to the IC50 values of 58.27 ± 2.72 and 85.74 ± 7.57 μg/mL respectively revealed by reducing power assay. As for the antibacterial effect, the highest zone diameters were shown by the MPEO against Bacillus subtilis (30 ± 1.43 mm) and Proteus mirabilis (28 ± 1.32 mm). These values are significantly important compared with those of the commercialized antibiotic (Erythromycin and Chlorophenicol). The lowest MIC and MBC values were obtained with MPEO against S. aureus MBLA (MIC = MBC = 0.25% (v/v)). While, ROEO has exhibited a bactericidal effect against Listeria monocytogenes (MIC = MBC = 0.5% (v/v)), Bacillus subtilis (MIC = MBC = 1% (v/v)) and Escherichia coli (MIC = MBC = 1% (v/v)). For the antileishmanial effect, ROEO is the most active against L. major (IC50 = 1.2 ± 0.36 μg/mL. While, the MPEO has the most leishmanicidal effect against L. major (IC50 = 1.3 ± 0.45 μg/mL). These findings show that the EOs of M. pulegium and R. officinalis are good sources of bioactive molecules that could have potential applications in the food and pharmaceutical industries.

https://www.ncbi.nlm.nih.gov/pubmed/28821401

Neurochem Int. 2017 Sep;108:436-447.
Alpha-lipoic acid attenuates acute neuroinflammation and long-term cognitive impairment after polymicrobial sepsis.
Della Giustina A, Goldim MP, Danielski LG, Florentino D, Mathias K, Garbossa L, Oliveira Junior AN, Fileti ME, Zarbato GF, da Rosa N, Martins Laurentino AO, Fortunato JJ, Mina F, Bellettini-Santos T, Budni J, Barichello T, Dal-Pizzol F, Petronilho F.

Sepsis is a complication of an infection which imbalance the normal regulation of several organ systems, including the central nervous system (CNS). Evidence points towards inflammation and oxidative stress as major steps associated with brain dysfunction in sepsis. Thus, we investigated the α-lipoic acid (ALA) effect as an important antioxidant compound on brain dysfunction in rats. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with ALA (200 mg/kg after CLP) or vehicle. Animals were divided into sham + saline, sham + ALA, CLP + saline and CLP + ALA groups. Twelve, 24 h and 10 days after surgery, the hippocampus, prefrontal cortex and cortex were obtained and assayed for levels of TNF-α and IL-1β, blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, thiobarbituric acid reactive species (TBARS) formation, protein carbonyls, superoxide dismutase (SOD) and catalase (CAT) activity and neurotrophins levels. Behavioral tasks were performed 10 days after surgery. ALA reduced BBB permeability and TNF-α levels in hippocampus in 24 h and IL-1β levels and MPO activity in hippocampus and prefrontal cortex in 24 h. ALA reduced nitrite/nitrate concentration and lipid peroxidation in 24 h in all structures and protein carbonylation in 12 and 24 h in hippocampus and cortex. CAT activity increased in the hippocampus and cortex in all times. ALA enhanced NGF levels in hippocampus and cortex and prevented cognitive impairment. Our data demonstrates that ALA reduces the consequences of polymicrobial sepsis in rats by decreasing inflammatory and oxidative stress parameters in the brain.

https://www.ncbi.nlm.nih.gov/pubmed/28606823

Pharmacol Res. 2017 May;119:303-312.
Anti-inflammatory and antioxidant effects of polyphenols extracted from Antirhea borbonica medicinal plant on adipocytes exposed to Porphyromonas gingivalis and Escherichia coli lipopolysaccharides.
Le Sage F, Meilhac O, Gonthier MP.

In obesity, gut microbiota LPS may translocate into the blood stream and then contribute to adipose tissue inflammation and oxidative stress, leading to insulin resistance. A causal link between periodontal infection, obesity and type 2 diabetes has also been suggested. We evaluated the ability of polyphenols from Antirhea borbonica medicinal plant to improve the inflammatory and redox status of 3T3-L1 adipocytes exposed to LPS of Porphyromonas gingivalis periodontopathogen or Escherichia coli enterobacteria. Our results show that LPS enhanced the production of Toll-like receptor-dependent MyD88 and NFκB signaling factors as well as IL-6, MCP-1, PAI-1 and resistin. Plant polyphenols reduced LPS pro-inflammatory action. Concomitantly, polyphenols increased the production of adiponectin and PPARγ, known as key anti-inflammatory and insulin-sensitizing mediators. Moreover, both LPS increased intracellular ROS levels and the expression of genes encoding ROS-producing enzymes including NOX2, NOX4 and iNOS. Plant polyphenols reversed these effects and up-regulated MnSOD and catalase antioxidant enzyme gene expression. Noticeably, preconditioning of cells with caffeic acid, chlorogenic acid or kaempferol identified among A. borbonica major polyphenols, led to similar protective properties. Altogether, these findings demonstrate the anti-inflammatory and antioxidant effects of A. borbonica polyphenols on adipocytes, in response to P. gingivalis or E. coli LPS. It will be of major interest to assess A. borbonica polyphenol benefits against obesity-related metabolic disorders such as insulin resistance in vivo.

https://www.ncbi.nlm.nih.gov/pubmed/28249816

Open Forum Infect Dis. 2017 Apr;4(2):ofx059.
Zinc Acetate Lozenges May Improve the Recovery Rate of Common Cold Patients: An Individual Patient Data Meta-Analysis.
Hemilä H, Fitzgerald JT, Petrus EJ, Prasad A.

BACKGROUND: A previous meta-analysis of 3 zinc acetate lozenge trials estimated that colds were on average 40% shorter for the zinc groups. However, the duration of colds is a time outcome, and survival analysis may be a more informative approach. The objective of this individual patient data (IPD) meta-analysis was to estimate the effect of zinc acetate lozenges on the rate of recovery from colds.
METHODS: We analyzed IPD for 3 randomized placebo-controlled trials in which 80-92 mg/day of elemental zinc were administered as zinc acetate lozenges to 199 common cold patients. We used mixed-effects Cox regression to estimate the effect of zinc.
RESULTS: Patients administered zinc lozenges recovered faster by rate ratio 3.1 (95% confidence interval, 2.1-4.7). The effect was not modified by age, sex, race, allergy, smoking, or baseline common cold severity. On the 5th day, 70% of the zinc patients had recovered compared with 27% of the placebo patients. Accordingly, 2.6 times more patients were cured in the zinc group. The difference also corresponds to the number needed to treat of 2.3 on the 5th day. None of the studies observed serious adverse effects of zinc.
CONCLUSIONS: The 3-fold increase in the rate of recovery from the common cold is a clinically important effect. The optimal formulation of zinc lozenges and an ideal frequency of their administration should be examined. Given the evidence of efficacy, common cold patients may be instructed to try zinc acetate lozenges within 24 hours of onset of symptoms.

https://www.ncbi.nlm.nih.gov/pubmed/28480298

BMC Complement Altern Med. 2017 Feb;17(1):99.
Antibacterial and antioxidant properties of crude extract, fractions and compounds from the stem bark of Polyscias fulva Hiern (Araliaceae).
Njateng GS, Du Z, Gatsing D, Mouokeu RS, Liu Y, Zang HX, Gu J, Luo X, Kuiate JR.

BACKGROUND: In our previous work, the dichloromethane-methanol (1:1 v/v) extract, fractions and isolated compounds from Polyscias fulva stem bark showed interesting antifungal activity. As a continuity of that work, this study aimed to bring out complementary informations about the antimicrobial properties of P. fulva stem bark that may be useful in the standardization of phytomedicine from this plant.
METHODS: The antibacterial activities of the crude extract, fractions (n-hexane, ethyl acetate, n-butanol and residual) and isolated compounds from Polyscias fulva stem bark were assayed by broth microdilution techniques. Their antioxidant activity were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH), pyrogallol (superoxide anion) and β-carotene – linoleic acid assays.
RESULTS: The crude extract presented antibacterial activities against S. typhi (ATCC 6539), E. aerogenes (ATCC 13045), P. aeruginosa (PA01) and E. coli (ATCC 10536) with MIC values of 2000 to 8000 μg/ml. The fractionation led the ethyle acetate and n-butanol fractions relatively more active (MIC = 500 to 1000 μg/ml) as compared to the crude extract. β-sitosterol and 3-O-α-L- arabinopyranosyl-hederagenin were the most active compounds on the tested bacteria with MIC values ranging from 6.25 to 100 μg/ml. The most sensitive was P. aeruginosa (PA01) on which all the tested compounds were active with MICs ranging from 6.25 to 400 μg/ml. Among all the tested substances, the crude extract (RSa50 = 84.86 μg/ml) and the methyl atrarate (RSa50 = 14.77 μg/ml), showed the highest scavenging activities against DPPH free radicals and those arising from the oxidation of the linoleic acid respectively.
CONCLUSION: From this study, the results obtained reveal that the stem bark of P. fulva possesses antibacterial and antioxidant activities. It may then be useful in the development of an antimicrobial phytomedicine with a large spectrum of actvity endowed with antioxidant properties which can be standardised based on the isolated compounds.

https://www.ncbi.nlm.nih.gov/pubmed/28173794

Curr Pharm Biotechnol. 2017;18(4):336-342.
Phytochemical Screening, Alpha-Glucosidase Inhibition, Antibacterial and Antioxidant Potential of Ajuga bracteosa Extracts.
Hafeez K, Andleeb S, Ghousa T, Mustafa RG, Naseer A, Shafique I, Akhter K.

BACKGROUND: Ajuga bracteosa, a medicinal herb, is used by local community to cure a number of diseases such as inflammation, jaundice bronchial asthma, cancer and diabetes.
OBJECTIVES: The aim of present work was to evaluate the antioxidant potential, in vitro antidiabetic and antimicrobial effects of A. bracteosa.
METHODS: n-hexane, ethyl acetate, chloroform, acetone, methanol and aqueous extracts of Ajuga bracteosa roots, were prepared via maceration. Antibacterial activity was carried out by agar well diffusion method. Quantitative and qualitative phytochemical screening was done. The antioxidant activity was determined by iron (II) chelating activity, iron reducing power, DPPH, and ABTS free radical scavenging methods, Antidiabetic activity was evaluated through inhibition of α-glucosidase assay.
RESULTS: Phytochemical analysis showed the presence of phenols, flavonoids, tannins, saponins, quinines, terpenoids, xanthoproteins, glycosides, carbohydrates, steroids, phytosterols and amino acids. DPPH and ABTS potential values were recorded as 61.92% to 88.84% and 0.11% to 38.82%, respectively. Total phenolic and total flavonoid contents were expressed as gallic acid and rutin equivalents. Total iron content was expressed as FeSO4 equivalents. Chloroform and n-hexane extracts showed significant enzyme inhibition potential with IC50 values of 29.92 μg/ml and 131.7 μg/ml respectively. Aqueous extract showed maximum inhibition of E. coli, S. typhimurium, E. amnigenus, S. pyogenes, and S. aureus, (18.0±1.0 mm, 12.5±0.7 mm, 17.0±0.0 mm, 11.0±0.0 mm and 15.3±2.0 mm mm), respectively. Similarly, n-hexane extract showed maximum inhibition of E. coli, E. amnigenus, S. aureus (11.6±1.5 mm; 11.3±1.5 mm; 13.3±0.5 mm). This study also shows that n-hexane, chloroform, ethyl acetate and aqueous extracts of A. bracteosa root possess α-glucosidase inhibitory activities and therefore it may be used as hypoglycemic agents in the management of postprandial hyperglycemia.
CONCLUSION: Ajuga bracteosa root extracts may provide a basis for development of antioxidant, antimicrobial and antidiabetic drugs.

https://www.ncbi.nlm.nih.gov/pubmed/28294059

Afr J Tradit Complement Altern Med. 2016 Aug;13(5):182-189.
ISOLATION AND CHARACTERIZATION OF CHEMICAL CONSTITUENTS FROM CHRYSOPHYLLUM ALBIDUM G. DON-HOLL. STEM-BARK EXTRACTS AND THEIR ANTIOXIDANT AND ANTIBACTERIAL PROPERTIES.
Idowu TO, Ogundaini AO, Adesanya SA, Onawunmi GO, Osungunna MO, Obuotor EM, Abegaz BM.

BACKGROUND: The plant, Chrysophyllum albidum is indigenous to Nigeria and its stem-bark has wide application in traditional medicine for the treatment of infections and oxidative stress related diseases. The aim of the study was to isolate the chemical constituents responsible for the antioxidant and antibacterial activity from the stem-bark of the plant in order to justify some of its ethnomedicinal uses.
MATERIALS AND METHODS: Crude extract of stem-bark of Chrysophyllum albidum obtained from 80% ethanol was successively partitioned with ethyl acetate (EtOAc) and n-butanol. The solvent fractions and isolated compounds were tested for antioxidant property using 2-2-diphenyl-1-picrylhydrazyl. Antibacterial activities were also assessed by means of agar-diffusion and broth micro dilution methods. EtOAc fraction was repeatedly fractionated on column chromatography to afford four compounds and their chemical structures were established using NMR (1D and 2D) and MS.
RESULTS: Chromatographic fractionation of EtOAc fraction with the highest antioxidant and antimicrobial activities afforded stigmasterol (1),: epicatechin (2),: epigallocatechin (3): and procyanidin B5 (4).: Procyanidin B5 isolated for the first time from genus Chrysophyllum demonstrated the highest antioxidant activity with IC50 values of 8.8 μM and 11.20 μM in DPPH and nitric oxide assays respectively and equally demonstrated the highest inhibitory activity against Escherichia coli (MIC 156.25 μg/mL), Staphylococcus aureus (MIC 156.25 μg/mL), Pseudomonas aeruginosa (MIC 625 μg/mL) and Bacillus subtilis (MIC 156.25 μg/mL).
CONCLUSION: The antibacterial and antioxidant activities of epicatechin, epigallocatechin and procyanidin B5 isolated from Chrysophyllum albidum stem-bark validate the folkloric uses.

https://www.ncbi.nlm.nih.gov/pubmed/28487910

BMC Complement Altern Med. 2016 May;16:143.
Effect of drying on the bioactive compounds, antioxidant, antibacterial and antityrosinase activities of pomegranate peel.
Mphahlele RR, Fawole OA, Makunga NP, Opara UL.

BACKGROUND: The use of pomegranate peel is highly associated with its rich phenolic concentration. Series of drying methods are recommended since bioactive compounds are highly sensitive to thermal degradation. The study was conducted to evaluate the effects of drying on the bioactive compounds, antioxidant as well as antibacterial and antityrosinase activities of pomegranate peel.
METHODS: Dried pomegranate peels with the initial moisture content of 70.30 % wet basis were prepared by freeze and oven drying at 40, 50 and 60 °C. Difference in CIE-LAB, chroma (C*) and hue angle (h°) were determined using colorimeter. Individual polyphenol retention was determined using LC-MS and LC-MS(E) while total phenolics concentration (TPC), total flavonoid concentration (TFC), total tannins concentration (TTC) and vitamin C concentration were measured using colorimetric methods. The antioxidant activity was measured by radical scavenging activity (RSA) and ferric reducing antioxidant power (FRAP). Furthermore, the antibacterial activity of methanolic peel extracts were tested on Gram negative (Escherichia coli and Klebsiella pneumonia) and Gram positive bacteria (Staphylococcus aureus and Bacillus subtilis) using the in vitro microdilution assays. Tyrosinase enzyme inhibition was investigated against monophenolase (tyrosine) and diphenolase (DOPA), with arbutin as positive controls.
RESULTS: Oven drying at 60 °C resulted in high punicalin concentration (888.04 ± 141.03 mg CE/kg dried matter) along with poor red coloration (high hue angle). Freeze dried peel contained higher catechin concentration (674.51 mg/kg drying matter) + catechin and -epicatechin (70.56 mg/kg drying matter) compared to oven dried peel. Furthermore, freeze dried peel had the highest total phenolic, tannin and flavonoid concentrations compared to oven dried peel over the temperature range studied. High concentration of vitamin C (31.19 μg AAE/g dried matter) was observed in the oven dried (40 °C) pomegranate peel. Drying at 50 °C showed the highest inhibitory activity with the MIC values of 0.10 mg/ml against Gram positive (Staphylococcus aureus and Bacillus subtili. Likewise, the extracts dried at 50 °C showed potent inhibitory activity concentration (22.95 mg/ml) against monophenolase. Principal component analysis showed that the peel colour characteristics and bioactive compounds isolated the investigated drying method.
CONCLUSIONS: The freeze and oven dried peel extracts exhibited a significant antibacterial and antioxidant activities. The freeze drying method had higher total phenolic, tannin and flavonoid concentration therefore can be explored as a feasible method for processing pomegranate peel to ensure retention of the maximum amount of their naturally occurring bioactive compounds.

https://www.ncbi.nlm.nih.gov/pubmed/27229852

Molecules. 2016 Mar;21(4):419.
Antibacterial Properties and Effects of Fruit Chilling and Extract Storage on Antioxidant Activity, Total Phenolic and Anthocyanin Content of Four Date Palm (Phoenix dactylifera) Cultivars.
Samad MA, Hashim SH, Simarani K, Yaacob JS.

Phoenix dactylifera or date palm fruits are reported to contain natural compounds that exhibit antioxidant and antibacterial properties. This research aimed to study the effect of fruit chilling at 4 °C for 8 weeks, extract storage at -20 °C for 5 weeks, and extraction solvents (methanol or acetone) on total phenolic content (TPC), antioxidant activity and antibacterial properties of Saudi Arabian P. dactylifera cv Mabroom, Safawi and Ajwa, as well as Iranian P. dactylifera cv Mariami. The storage stability of total anthocyanin content (TAC) was also evaluated, before and after storing the extracts at -20 °C and 4 °C respectively, for 5 weeks. Mariami had the highest TAC (3.18 ± 1.40 mg cyd 3-glu/100 g DW) while Mabroom had the lowest TAC (0.54 ± 0.15 mg cyd 3-glu/100 g DW). The TAC of all extracts increased after storage. The chilling of date palm fruits for 8 weeks prior to solvent extraction elevated the TPC of all date fruit extracts, except for methanolic extracts of Mabroom and Mariami. All IC50 values of all cultivars decreased after the fruit chilling treatment. Methanol was a better solvent compared to acetone for the extraction of phenolic compounds in dates. The TPC of all cultivars extracts decreased after 5 weeks of extract storage. IC50 values of all cultivars extracts increased after extract storage except for the methanolic extracts of Safawi and Ajwa. Different cultivars exhibited different antibacterial properties. Only the methanolic extract of Ajwa exhibited antibacterial activity against all four bacteria tested: Staphylococcus aureus, Bacillus cereus, Serratia marcescens and Escherichia coli. These results could be useful to the nutraceutical and pharmaceutical industries in the development of natural compound-based products.

https://www.ncbi.nlm.nih.gov/pubmed/27023514

BMC Complement Altern Med. 2016 Mar;16:104.
Variation in secondary metabolite production as well as antioxidant and antibacterial activities of Zingiber zerumbet (L.) at different stages of growth.
Ghasemzadeh A, Jaafar HZ, Ashkani S, Rahmat A, Juraimi AS, Puteh A, Muda Mohamed MT.

BACKGROUND: Zingiber zerumbet (L.) is a traditional Malaysian folk remedy that contains several interesting bioactive compounds of pharmaceutical quality.
METHODS: Total flavonoids and total phenolics content from the leaf, stem, and rhizome of Z. zerumbet at 3 different growth stages (3, 6, and 9 months) were determined using spectrophotometric methods and individual flavonoid and phenolic compounds were identified using ultra-high performance liquid chromatography method. Chalcone Synthase (CHS) activity was measured using a CHS assay. Antioxidant activities were evaluated by ferric reducing antioxidant potential (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. The antibacterial activity was determined against Gram-positive and Gram-negative bacteria using the disc diffusion method.
RESULTS: Highest content of total flavonoid [29.7 mg quercetin equivalents (QE)/g dry material (DM)] and total phenolic (44.8 mg gallic acid equivalents (GAE)/g DM) were detected in the rhizome extracts of 9-month-old plants. As the plant matured from 3 to 9 months, the total flavonoid content (TFC) and total phenolic content (TPC) decreased in the leaf, but increased significantly in the rhizomes. Among the secondary metabolites identified, the most abundant, based on the concentrations, were as follows: flavonoids, catechin > quercetin > rutin > luteolin > myricetin > kaempferol; phenolic acids, gallic acid > ferulic acid > caffeic acid > cinnamic acid. Rhizome extracts from 9-month-old plants demonstrated the highest CHS activity (7.48 nkat/mg protein), followed by the 6-month-old rhizomes (5.79 nkat/mg protein) and 3-month-old leaf (4.76 nkat/mg protein). Nine-month-old rhizomes exhibited the highest DPPH activity (76.42 %), followed by the 6-month-old rhizomes (59.41 %) and 3-month-old leaves (57.82 %), with half maximal inhibitory concentration (IC50) of 55.8, 86.4, and 98.5 μg/mL, respectively, compared to that of α- tocopherol (84.19 %; 44.8 μg/mL) and butylated hydroxytoluene (BHT) (70.25 %; 58.6 μg/mL). The highest FRAP activity was observed in 9-month-old rhizomes, with IC50 of 62.4 μg/mL. Minimal Inhibitory Concentration (MIC) of Z. zerumbet extracts against Gram-positive and Gram-negative bacteria ranged from 30 to >100 µg/mL. Among the bacterial strains examined, Staphylococcus aureus was sensitive to the leaf extract of Z. zerumbet, with MIC of 30.0 μg/mL and other strains were sensitive to the rhizome extracts.
CONCLUSIONS: Three- and 9-month-old plants are recommended when harvesting the leaf and rhizome of Z. zerumbet, respectively, in order to obtain effective pharmaceutical quality of the desired compounds.

https://www.ncbi.nlm.nih.gov/pubmed/27004511

BMC Complement Altern Med. 2015 Oct;15:385.
Antioxidant, antibacterial activity, and phytochemical characterization of Melaleuca cajuputi extract.
Al-Abd NM, Mohamed Nor Z, Mansor M, Azhar F, Hasan MS, Kassim M.

BACKGROUND: The threat posed by drug-resistant pathogens has resulted in the increasing momentum in research and development for effective alternative medications. The antioxidant and antibacterial properties of phytochemical extracts makes them attractive alternative complementary medicines. Therefore, this study evaluated the phytochemical constituents of Melaleuca cajuputi flower and leaf (GF and GL, respectively) extracts and their antioxidant and antibacterial activities.

METHODS: Radical scavenging capacity of the extracts was estimated using 2,2-diphenyl-2-picrylhydrazyl and Fe(2+)-chelating activity. Total antioxidant activity was determined using ferric reducing antioxidant power assay. Well diffusion, minimum inhibitory concentration, and minimum bactericidal concentration assays were used to determine antibacterial activity against eight pathogens, namely Staphylococcus aureus, Escherichia coli, Bacillus cereus, Staphylococcus epidermidis, Salmonella typhimurium, Klebsiella pneumonia, Streptococcus pneumoniae, and Pasteurella multocida. We identified and quantified the phytochemical constituents in methanol extracts using liquid chromatography/mass spectrometry (LC/MS) and gas chromatography (GC)/MS.

RESULTS: This study reports the antioxidant and radical scavenging activity of M. cajuputi methanolic extracts. The GF extract showed better efficacy than that of the GL extract. The total phenolic contents were higher in the flower extract than they were in the leaf extract (0.55 ± 0.05 and 0.37 ± 0.05 gallic acid equivalent per mg extract dry weight, respectively). As expected, the percentage radical inhibition by GF was higher than that by the GL extract (81 and 75 %, respectively). A similar trend was observed in Fe(2+)-chelating activity and β-carotene bleaching tests. The antibacterial assay of the extracts revealed no inhibition zones with the Gram-negative bacteria tested. However, the extracts demonstrated activity against B. cereus, S. aureus, and S. epidermidis.

CONCLUSIONS: In this study, we found that M. cajuputi extracts possess antioxidant and antibacterial activities. The results revealed that both extracts had significant antioxidant and free radical-scavenging activity. Both extracts had antibacterial activity against S. aureus, S. epidermidis, and B. cereus. The antioxidant and antimicrobial activities could be attributed to high flavonoid and phenolic contents identified using GC/MS and LC/MS. Therefore, M. cajuputi could be an excellent source for natural antioxidant and antibacterial agents for medical and nutraceutical applications.

https://www.ncbi.nlm.nih.gov/pubmed/26497742

BMC Complement Altern Med. 2012 Oct;12:200.
Antibacterial, antioxidant and tyrosinase-inhibition activities of pomegranate fruit peel methanolic extract.
Fawole OA, Makunga NP, Opara UL.

BACKGROUND: This study evaluated, using in vitro assays, the antibacterial, antioxidant, and tyrosinase-inhibition activities of methanolic extracts from peels of seven commercially grown pomegranate cultivars.

METHODS: Antibacterial activity was tested on Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Klebsiella pneumonia) using a microdilution method. Several potential antioxidant activities, including radical-scavenging ability (RSA), ferrous ion chelating (FIC) and ferric ion reducing antioxidant power (FRAP), were evaluated. Tyrosinase enzyme inhibition was investigated against monophenolase (tyrosine) and diphenolase (DOPA), with arbutin and kojic acid as positive controls. Furthermore, phenolic contents including total flavonoid content (TFC), gallotannin content (GTC) and total anthocyanin content (TAC) were determined using colourimetric methods. HPLC-ESI/MSn analysis of phenolic composition of methanolic extracts was also performed.

RESULTS: Methanolic peel extracts showed strong broad-spectrum activity against Gram-positive and Gram-negative bacteria, with the minimum inhibitory concentrations (MIC) ranging from 0.2 to 0.78 mg/ml. At the highest concentration tested (1000 μg/ml), radical scavenging activities were significantly higher in Arakta (83.54%), Ganesh (83.56%), and Ruby (83.34%) cultivars (P< 0.05). Dose dependent FIC and FRAP activities were exhibited by all the peel extracts. All extracts also exhibited high inhibition (>50%) against monophenolase and diphenolase activities at the highest screening concentration. The most active peel extract was the Bhagwa cultivar against monophenolase and the Arakta cultivar against diphenolase with IC50 values of 3.66 μg/ml and 15.88 μg/ml, respectively. High amounts of phenolic compounds were found in peel extracts with the highest and lowest total phenolic contents of 295.5 (Ganesh) and 179.3 mg/g dry extract (Molla de Elche), respectively. Catechin, epicatechin, ellagic acid and gallic acid were found in all cultivars, of which ellagic acid was the most abundant comprising of more than 50% of total phenolic compounds detected in each cultivar.

CONCLUSIONS: The present study showed that the tested pomegranate peels exhibited strong antibacterial, antioxidant and tyrosinase-inhibition activities. These results suggest that pomegranate fruit peel could be exploited as a potential source of natural antimicrobial and antioxidant agents as well as tyrosinase inhibitors.

https://www.ncbi.nlm.nih.gov/pubmed/23110485

J Ethnopharmacol. 2012 Oct;143(3):826-39.
The antimicrobial, antioxidative, anti-inflammatory activity and cytotoxicity of different fractions of four South African Bauhinia species used traditionally to treat diarrhoea.
Ahmed AS, Elgorashi EE, Moodley N, McGaw LJ, Naidoo V, Eloff JN.

ETHNOPHARMACOLOGICAL IMPORTANCE: Many Bauhinia species, including those indigenous to South Africa, are used in traditional medicine across the world for treating ailments such as gastrointestinal tract (GIT) disorders, diabetes, infectious diseases and inflammation.

AIMS: Several relevant aspects of different fractions of leaf extracts of Bauhinia bowkeri (BAB), Bauhinia galpinii (BAG), Bauhinia petersiana (BAP), and Bauhinia variegata (BAV) used in South African traditional medicine to alleviate diarrhoea related symptoms were evaluated.

MATERIALS AND METHODS: The antioxidative activities of the extracts were determined using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH), 2, 2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS(+)) radical scavenging and ferric reducing antioxidant power (FRAP) methods. In vitro antimicrobial activities of the extracts were determined against bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus faecalis) and clinical isolates of the opportunistic fungal strains (Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans) using a serial dilution microplate method. The polyphenolic contents were quantified using standard methods, and anti-inflammatory activities of the crude extracts were determined using the cyclooxygenase and soybean 15-lipoxygenase enzyme inhibitory assays. The safety of the extracts was evaluated by determining the cytotoxicity against Vero cell lines.

RESULTS: The acidified 70% acetone crude extract and their fractions had good antiradical potency against the DPPH and ABTS radicals. The methanol soluble portions of the butanol fractions were more potent (EC(50) ranges from 0.64 ± 0.05 to 1.51 ± 0.07 and 0.88 ± 0.18 to 1.49 ± 0.09 μg/ml against DPPH and ABTS radical respectively) compared to the standard, trolox and ascorbic acid (EC(50) ranges from 1.47 ± 0.24 to 1.70 ± 0.27 μg/ml) for both DPPH and ABTS. The crude extracts contained variable quantities of phenolic content. The crude extracts and their fractions had weak to good antimicrobial activities, inhibiting the growth of the organisms at concentrations ranging from 39 to 2500 μg/ml. The BAG crude extract and its fractions were the most active against the fungi (MICs ranging from 39 to 625 μg/ml) while the BAB extract and its fractions were the least active with the MICs ranging between 39 and 2500 μg/ml. Aspergillus fumigatus was the least susceptible fungus while Cryptococcus neoformans was the most susceptible. The phenolic-rich crude extracts of BAB, BAG, and BAP had moderate to good dose-dependent cyclooxygenase-1 enzyme inhibitory activity with inhibitions between 22.8% and 71.4%. The extracts were however, inactive against cyclooxygenase-2. The extracts had some level of cytotoxicity towards Vero cell lines, reducing cell viability to less than 10% at concentrations more than 50 μg/ml.

CONCLUSION: The biological activities observed in Bauhinia species provide a scientific basis for the use of the plants in traditional medicines to treat diseases with multi-factorial pathogenesis such as diarrhoea, with each aspect of activity contributing to the ultimate therapeutic benefit of the plants. However, the use of the phenolic-rich extracts of these plants to treat diarrhoea or any other ailments in traditional medicine needs to be monitored closely because of potential toxic effects and selective inhibition of COX-1 with the associated GIT injury.

https://www.ncbi.nlm.nih.gov/pubmed/22917809

J Int Med Res. 2012;40(1):28-42.
A combination of high-dose vitamin C plus zinc for the common cold.
Maggini S, Beveridge S, Suter M.

Vitamin C and zinc play important roles in nutrition, immune defence and maintenance of health. Intake of both is often inadequate, even in affluent populations. The common cold continues to place a great burden on society in terms of suffering and economic loss. After an overview of the literature on the effects of the separate administration of either vitamin C or zinc against the common cold, this article presents data from two preliminary, double-blind, randomized, placebo-controlled trials, conducted with a combination of 1000 mg vitamin C plus 10 mg zinc in patients with the common cold. In both studies, a nonsignificant reduction of rhinorrhoea duration (range 9-27%) was seen. In pooled analyses of both studies (n=94), vitamin C plus zinc was significantly more efficient than placebo at reducing rhinorrhoea over 5 days of treatment. Furthermore, symptom relief was quicker and the product was well tolerated. In view of the burden associated with the common cold, supplementation with vitamin C plus zinc may represent an efficacious measure, with a good safety profile, against this infectious viral disease.

https://www.ncbi.nlm.nih.gov/pubmed/22429343

J Ethnopharmacol. 2011 Jul;136(3):496-503.
Anti-inflammatory, antioxidant, anti-tyrosinase and phenolic contents of four Podocarpus species used in traditional medicine in South Africa.
Abdillahi HS, Finnie JF, Van Staden J.

ETHNOPHARMACOLOGICAL RELEVANCE: Species of Podocarpus are used traditionally in their native areas for the treatment of fevers, asthma, coughs, cholera, chest complaints, arthritis, rheumatism, venereal diseases and distemper in dogs.

AIMS OF THE STUDY: To investigate the antioxidant, anti-inflammatory and anti-tyrosinase activities of four Podocarpus species, Podocarpus elongatus, Podocarpus falcatus, Podocarpus henkelii and Podocarpus latifolius, used in traditional medicine in South Africa. Phytochemical analysis to determine the phenolic contents was also carried out.

MATERIALS AND METHODS: DPPH, FRAP and β-carotene-linoleic acid assays were used to determine the antioxidant/radical scavenging activities of these species. Anti-inflammatory activity of these species was assayed against two cyclooxygenase enzymes (COX-1 and COX-2). Tyrosinase inhibition activity was analysed using the modified dopachrome method with l-DOPA as the substrate. Phenolics were quantitatively determined using spectrophotometric methods.

RESULTS: Stems of Podocarpus latifolius exhibited the lowest EC(50) (0.84 μg/ml) inhibition against DPPH. The percentage antioxidant activity based on the bleaching rate of β-carotene ranged from 96% to 99%. High ferric reducing power was observed in all the extracts. For COX-1, the lowest EC(50) value was exhibited by stem extracts of Podocarpus elongatus (5.02 μg/ml) and leaf extract of Podocarpus latifolius showed the lowest EC(50) against COX-2 (5.13 μg/ml). All extracts inhibited tyrosinase activity in a dose-dependent manner with stem extract of Podocarpus elongatus being the most potent with an EC(50) value of 0.14 mg/ml. The total phenolic content ranged from 2.38 to 6.94 mg of GAE/g dry sample.

CONCLUSION: The significant pharmacological activities observed support the use of these species in traditional medicine and may also be candidates in the search for modern pharmaceuticals in medicine, food and cosmetic industries.

https://www.ncbi.nlm.nih.gov/pubmed/20633623

Open Respir Med J. 2011;5:51-8.
Zinc lozenges may shorten the duration of colds: a systematic review.
Hemilä H.

BACKGROUND: A number of controlled trials have examined the effect of zinc lozenges on the common cold but the findings have diverged. The purpose of this study was to examine whether the total daily dose of zinc might explain part of the variation in the results.
METHODS: The Medline, Scopus and Cochrane Central Register of Controlled Trials data bases were searched for placebocontrolled trials examining the effect of zinc lozenges on common cold duration. Two methods were used for analysis: the P-values of the trials were combined by using the Fisher method and the results of the trials were pooled by using the inverse-variance method. Both approaches were used for all the identified trials and separately for the low zinc dose and the high zinc dose trials.
RESULTS: Thirteen placebo-controlled comparisons have examined the therapeutic effect of zinc lozenges on common cold episodes of natural origin. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, the pooled result indicating a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%).
CONCLUSIONS: This study shows strong evidence that the zinc lozenge effect on common cold duration is heterogeneous so that benefit is observed with high doses of zinc but not with low doses. The effects of zinc lozenges should be further studied to determine the optimal lozenge compositions and treatment strategies.

https://www.ncbi.nlm.nih.gov/pubmed/21769305

Endocr Metab Immune Disord Drug Targets. 2020 Apr. doi: 10.2174/1871530320666200402121917. [Epub ahead of print]
Vitamin D levels correlate with Metabolic Syndrome Criteria in Algerian Patients: The Ex-vivo Immuomodulatory Effect of α, 25 Dihydroxyvitamin D3.
Bouchemal M, Hakem D, Azzouz M, Touil-Boukoffa C, Mezioug D.

BACKGROUND: Metabolic syndrome (MetS) is a combination of metabolic disorders with increased risks for several diseases, such as cardiovascular diseases and diabetes. It is associated with the presence of various inflammatory molecules. Vitamin D plays an important role in the regulation of metabolism homeostasis.
OBJECTIVE: The main goal of this work is to investigate vitamin D levels among Algerian MetS patients and its possible outcomes on key molecules of the immune response, as well, the immunemodulatory effects of its active metabolite.
METHODS: In this context, we evaluated the vitamin D status by electrochemiluminescence method, Nitric Oxide (NO) levels by the Griess method and extracellular. Matrix Metalloproteinases (MMPs) activities such as MMP-2 and MMP-9 by zymography in plasma of patients and healthy controls (HC). The immunmodulatory effects of the active metabolite of vitamin D (α-25 (OH)2D3) on the production of NO, IL-6, IL-10, TGF-β and s-CTLA-4 was assessed by Griess method and ELISA, in peripheral blood mononuclear cells (PBMCs) of Algerian MetS patients and HC. MMPs activities were also determinated ex-vivo, while iNOS expression was assessed by immunofluorescence staining.
RESULTS: Severe vitamin D deficiency was registered in Algerian MetS patients, the deficiency was found to be associated with an elevated in vivo NO production and high MMPs activity. Interestingly,on α-25 (OH)2D3 declined the NO/iNOS system and IL-6 production, as well as MMPs activities. However, the ex-vivo production of IL-10, TGF-β increased in response to the treatment. We observed in the same way, the implication of s-CTLA-4 in MetS, which was markedly up regulated with α-25 (OH)2D3.
CONCLUSION: Our report indicated the relationship between MetS factors and Vitamin D deficiency. The ex-vivo findings emphasize its impact on maintaining regulated immune balance.

https://www.ncbi.nlm.nih.gov/pubmed/32238143

Sci Transl Med. 2020 Feb;12(532).
High-dose vitamin C enhances cancer immunotherapy.
Magrì A, Germano G, Lorenzato A, Lamba S, Chilà R, Montone M, Amodio V, Ceruti T, Sassi F, Arena S, Abrignani S, D’Incalci M, Zucchetti M, Di Nicolantonio F, Bardelli A.

Vitamin C (VitC) is known to directly impair cancer cell growth in preclinical models, but there is little clinical evidence on its antitumoral efficacy. In addition, whether and how VitC modulates anticancer immune responses is mostly unknown. Here, we show that a fully competent immune system is required to maximize the antiproliferative effect of VitC in breast, colorectal, melanoma, and pancreatic murine tumors. High-dose VitC modulates infiltration of the tumor microenvironment by cells of the immune system and delays cancer growth in a T cell-dependent manner. VitC not only enhances the cytotoxic activity of adoptively transferred CD8 T cells but also cooperates with immune checkpoint therapy (ICT) in several cancer types. Combination of VitC and ICT can be curative in models of mismatch repair-deficient tumors with high mutational burden. This work provides a rationale for clinical trials combining ICT with high doses of VitC.

https://www.ncbi.nlm.nih.gov/pubmed/32102933

Cell Immunol. 2020 Feb:104082.
Autophagy efficacy and vitamin D status: Population effects.
Abhimanyu, Meyer V, Jones BR, Bornman L.

Toll-like receptor (TLR) 2/1 signalling is linked to autophagy through transcriptional actions of the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-vitamin D receptor (VDR) complex. Population-specific effects have been reported for TLR2/1-VDR signalling. We hypothesized that population effects extend to autophagy and are influenced by vitamin D status. Serum 25(OH)D3 of healthy South Africans (Black individuals n = 10, White individuals n = 10) was quantified by LC-MS/MS. Primary monocytes-macrophages were supplemented in vitro with 1,25(OH)2D3 and stimulated with the lipoprotein Pam3CysSerLys4. TLR2, VDR, hCAP18, Beclin1, LC3-IIB, cytokines and CYP24A1 mRNA were quantified by flow cytometry and RT-qPCR, respectively. Black individuals showed significantly lower overall cumulative LC3-IIB (P < 0.010), but higher Beclin1, VDR, IL6 and TNFA (P < 0.050) than White individuals. 1,25(OH)2D3 enhanced autophagic flux in monocytes-macrophages from Black individuals upon TLR2/1 stimulation and strengthened autophagy in 25(OH)D3 deficient individuals (independent cohort, n = 20). These findings support population-directed vitamin D supplementation.

https://www.ncbi.nlm.nih.gov/pubmed/32241530

Nutrients. 2020 Jan;12(1). pii: E236.
A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection.
Gombart AF, Pierre A, Maggini S.

Immune support by micronutrients is historically based on vitamin C deficiency and supplementation in scurvy in early times. It has since been established that the complex, integrated immune system needs multiple specific micronutrients, including vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium, which play vital, often synergistic roles at every stage of the immune response. Adequate amounts are essential to ensure the proper function of physical barriers and immune cells; however, daily micronutrient intakes necessary to support immune function may be higher than current recommended dietary allowances. Certain populations have inadequate dietary micronutrient intakes, and situations with increased requirements (e.g., infection, stress, and pollution) further decrease stores within the body. Several micronutrients may be deficient, and even marginal deficiency may impair immunity. Although contradictory data exist, available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection. Micronutrients with the strongest evidence for immune support are vitamins C and D and zinc. Better design of human clinical studies addressing dosage and combinations of micronutrients in different populations are required to substantiate the benefits of micronutrient supplementation against infection.

https://www.ncbi.nlm.nih.gov/pubmed/31963293

Nutrients. 2020 Jan;12(1).
A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection.
Gombart AF, Pierre A, Maggini S.

Immune support by micronutrients is historically based on vitamin C deficiency and supplementation in scurvy in early times. It has since been established that the complex, integrated immune system needs multiple specific micronutrients, including vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium, which play vital, often synergistic roles at every stage of the immune response. Adequate amounts are essential to ensure the proper function of physical barriers and immune cells; however, daily micronutrient intakes necessary to support immune function may be higher than current recommended dietary allowances. Certain populations have inadequate dietary micronutrient intakes, and situations with increased requirements (e.g., infection, stress, and pollution) further decrease stores within the body. Several micronutrients may be deficient, and even marginal deficiency may impair immunity. Although contradictory data exist, available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection. Micronutrients with the strongest evidence for immune support are vitamins C and D and zinc. Better design of human clinical studies addressing dosage and combinations of micronutrients in different populations are required to substantiate the benefits of micronutrient supplementation against infection.

https://www.ncbi.nlm.nih.gov/pubmed/31963293

J Therm Biol. 2019 Aug;84:451-459.
Nutraceutical effect of vitamins and minerals on performance and immune and antioxidant systems in dairy calves during the nutritional transition period in summer.
Bordignon R, Volpato A, Glombowsky P, Souza CF, Baldissera MD, Secco R, Pereira WAB, Leal MLR, Vedovatto M, Da Silva AS.

We aimed to determine whether the use of injectable vitamins and minerals improves growth performance and immune and antioxidant responses in dairy calves during pre- and post-weaning period in summer. Twenty dairy calves (45 days of age) were randomized to two groups (10 each): control group (CON) and treated group [TREAT; injection providing 0.20, 0.80, 0.20, 0.10, 35 and 1 mg/kg of copper, zinc, manganese selenium, and vitamins A and E, during two periods (15 days pre- and 15 days post-weaning)]. The animals were weighed and blood samples were collected on days 1, 15, 30 and 45 of the study. Levels of serum copper, selenium, zinc, and manganese were measured on day 1; and the results showed that calves were not deficient in these minerals. The TREAT group had greater BW gain during the final third of the experiment. There was an increase in total leukocyte numbers as a result of elevation in neutrophil counts (day 45) and monocytes (days 30 and 45) in the TREAT group. This group also had lower reactive oxygen species (ROS) content (days 15, 30 and 45) and lipid peroxidation (LPO; days 15 and 45). Furthermore, the TREAT group had greater antioxidant capacity against peroxyl radicals (ACAP; days 15 and 30), activities of the enzymes glutathione peroxidase (GPx; days 15, 30 and 45) and superoxide dismutase (SOD; day 15), concentrations of total serum proteins (day 30), serum globulin (days 15 and 30), ceruloplasmin (day 15), tumor necrosis factor-alpha (TNF-α), interleukin-1, (IL-1; days 30 and 45) and interferon gamma (IFNγ; day 45), compared to CON group. High respiratory rates during hot times of the day in all study calves was suggestive of heat stress. Taken together, the data suggest that mineral and vitamins injections increased the growth performance and boosted the antioxidant and immunological systems of dairy calves during the diet transition period in summer.

https://www.ncbi.nlm.nih.gov/pubmed/31466786

J Clin Gastroenterol. 2018 Nov/Dec;52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017:S86-S88.
Vitamin D: Immunomodulatory Aspects.
Miraglia Del Giudice M, Indolfi C, Strisciuglio C.

Vitamin D is a group of liposoluble prohormones consisting of 5 different vitamins, the most important forms being vitamin D2 and vitamin D3. The ergocalciferol (vitamin D2) is less efficacious and derives from irradiated fungi, while colecalciferol (vitamin D3), derived from cholesterol, is synthesized via ultraviolet B rays in animal organisms. Only the ultraviolet B rays (290 to 315 nm) portion of the solar ray photolyzes 7-dehydrocholesterol in the skin to previtamin D3, which is converted subsequently to vitamin D3. Moreover, the skin makes little vitamin D from the sun at latitudes above 37 degrees north or below 37 degrees south of the equator. Calcidiol [25(OH)D] is the more stable metabolite of vitamin D in serum and the best indicator of the vitamin D status. Optimal values range are >30 ng/mL. Calcitriol [1,25(OH)2D] is the active hormone form of vitamin D. The 1,25(OH)2D binds to its nuclear receptor (vitamin D receptor), expressed in many tissues, regulating the expression of genes involved in calcium metabolism, cell differentiation, apoptosis, and immunity. About immunity, calcitriol stimulates innate immune responses by enhancing the chemotactic and phagocytotic responses of macrophages as well as the production of antimicrobial peptides. 1,25(OH)2D strongly enhances production of interleukine-10 by stimulating T regulatory cells and inhibiting Th1 and Th17 cell differentiation. Furthermore, several studies suggest that lower 25(OH)D serum levels are associated with an increased risk of respiratory infection at all ages in a dose-response manner.

https://www.ncbi.nlm.nih.gov/pubmed/30300262

Cell Prolif. 2018 Oct;51(5):e12461.
1,25(OH)₂ D₃ inhibited Th17 cells differentiation via regulating the NF-κB activity and expression of IL-17.
Sun D, Luo F, Xing JC, Zhang F, Xu JZ, Zhang ZH.

OBJECTIVES: The role of vitamin D (VD) in innate and adaptive immune responses to tuberculosis is still unclear. Our research was aimed to uncover the effect of VD on Th17 cells and elucidate potential molecular mechanism.

MATERIALS AND METHODS: VDR-deficient and wild-type mice were used to obtain CD4 T cells. Th17 cells were induced and activated by Bacillus Calmette Guerin. Flow cytometry was used to analyse the apoptosis rate and degree of differentiation of Th17 cells in the treatment of 1,25(OH)₂ D₃ . The interaction between P65 and Rorc was determined by immunofluorescence assay, luciferase reporter assay, EMSA-Super-shelf assay and ChIP assay. Co-IP assay was carried out to test the interaction between VDR and NF-κB family proteins. qRT-PCR and Western blot were also performed to detect the levels of P65, RORγt and IL-17.

RESULTS: The Th17 cells differentiation was suppressed by 1,25(OH)₂ D₃ in vitro. We confirmed that Rorc was a downstream gene of the transcription factor P65. VDR interacts with P105/P50, P100/P52 and P65 NF-κB family proteins. 1,25(OH)₂ D₃ inhibited the expression of RORγt/IL-17 by suppressing p65 transcription factor translocating to nucleus. In vivo experiments, the expression of IL-17 and RANKL was suppressed by 1,25(OH)₂ D₃ by VD receptor. Moreover, 1,25(OH)₂ D₃ suppressed the inflammatory infiltrates and inhibited the expression of P65, RORγt and IL-17 in the spleen tissues of model mice.

CONCLUSIONS: Together, 1,25(OH)₂ D₃ suppressed the differentiation of Th17 cells via regulating the NF-κB activity.

https://www.ncbi.nlm.nih.gov/pubmed/29687949

PLoS One. 2018 Apr;13(4):e0194867.
Chronic calcitriol supplementation improves the inflammatory profiles of circulating monocytes and the associated intestinal/adipose tissue alteration in a diet-induced steatohepatitis rat model.
Su YB, Li TH, Huang CC, Tsai HC, Huang SF, Hsieh YC, Yang YY, Huang YH, Hou MC, Lin HC.

Vitamin D deficiency and up-regulated TNFα-related signals are reported to be involved in abnormalities including intestinal hyper-permeability, bacterial translocation, systemic/portal endotoxemia, intestinal/adipose tissue/hepatic inflammation, and hepatic steatosis in nonalcoholic steatohepatitis (NASH). This study aims to explore the molecular mechanisms and effects of chronic calcitriol [1,25-(OH)2D3, hormonal form of vitamin D] on gut-adipose tissue-liver axis abnormalities using a high-fat diet (HFD)-fed rat model of NASH. In HFD-fed obese rats on a 10-week calcitriol (0.3 μg/kg/TIW) or vehicle treatment (NASH-vit. D and NASH-V rats) reigme, various in vivo and in vitro experiments were undertaken. Through anti-TNFα-TNFR1-NFκB signaling effects, chronic calcitriol treatment significantly restored plasma calcitriol levels and significantly improved vitamin D receptor (VDR) expression in monocytes and the small intestine of NASH-vit. D rats. Significantly, plasma and portal endotoxin/TNFα levels, bacterial translocation to mesenteric lymph nodes, plasma DX-4000-FITC, fecal albumin-assessed intestinal hyper-permeability, over-expression of TNFα-related immune profiles in monocytes, inflammation of intestinal/mesenteric adipose tissue (MAT)/liver and hepatic steatosis were improved by chronic calcitriol treatment of NASH rats. Additionally, in vitro experiments with acute calcitriol co-incubation reversed NASH-V rat monocyte supernatant/TNFα-induced monolayer barrier dysfunction in caco-2 cells, cytokine release from MAT-derived adipocytes, and triglyceride synthesis by lean-V rat hepatocytes. Using in vivo and in vitro experiments, our study reported calcitriol signaling in the gut as well as in adipose tissue. Meanwhile, our study suggests that restoration of systemic and intestinal vitamin D deficiency using by chronic vitamin D treatment effectively reduces TNFα-mediated immunological abnormalities associated with the gut-adipose tissue-liver axis and hepatic steatosis in NASH rats.

https://www.ncbi.nlm.nih.gov/pubmed/29684027

Mol Immunol. 2017 Nov;91:156-164.
1,25(OH)₂D₃ induces regulatory T cell differentiation by influencing the VDR/PLC-γ1/TGF-β1/pathway.
Zhou Q, Qin S, Zhang J, Zhon L, Pen Z, Xing T

Vitamin D has been recommended as an immune modulator in recent years, in addition to regulating calcium-phosphorous-bone metabolism. Clinical studies on organ transplantation found that vitamin D sufficiency patients were less likely to develop acute cellular rejection within one year after transplantation compared to those with vitamin D deficiency. Thus, a high percentage of regulatory T cells might play a key role in preventing acute cellular rejection (ACR). In this report, we studied the specific effects of 1,25(OH)2D3 on human T cell diff ;erentiation, and determined the potential molecule mechanism behind. Results showed that 1,25(OH)2D3 induced the differentiation of T-regulatory cells (Treg cells), while inhibiting Th17 cell proliferation. In addition, 1,25(OH)2D3 promoted secretion of the anti-inflammatory cytokine, transforming Growth Factor beta1 (TGF-β1) but suppressed pro-inflammatory cytokines such as interleukin-17 (IL-17). Phospholipase C gamma 1 (PLC-γ1) is an indispensable signaling protein downstream of the classical TCR signaling pathway and was shown to play a crucial role in T cell activation, while Naive T cells expressed less PLC-γ1. Here we showed that Vitamin D could significantly upregulate PLC-γ1 expression, which then induced expression of TGF-β1. In summary, 1,25(OH)2D3 indirectly modulates the differentiation of Treg/Th17 cells by aff ;ecting the VDR/PLC-γ1/TGF-β1pathway. These results indicate that administration 1,25(OH)2D3 supplements may be a beneficial treatment for organ transplantation recipients.

https://www.ncbi.nlm.nih.gov/pubmed/28926770

Nutrients. 2017 Nov;9(11). pii: E1211.
Vitamin C and Immune Function.
Carr AC, Maggini S.

Vitamin C is an essential micronutrient for humans, with pleiotropic functions related to its ability to donate electrons. It is a potent antioxidant and a cofactor for a family of biosynthetic and gene regulatory enzymes. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C supports epithelial barrier function against pathogens and promotes the oxidant scavenging activity of the skin, thereby potentially protecting against environmental oxidative stress. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100-200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.

https://www.ncbi.nlm.nih.gov/pubmed/29099763

Physiol Rep. 2017 Aug;5(15).
Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity.
Gorman S, Buckley AG, Ling KM, Berry LJ, Fear VS, Stick SM, Larcombe AN, Kicic A, Hart PH.

In disease settings, vitamin D may be important for maintaining optimal lung epithelial integrity and suppressing inflammation, but less is known of its effects prior to disease onset. Female BALB/c dams were fed a vitamin D3-supplemented (2280 IU/kg, VitD+) or nonsupplemented (0 IU/kg, VitD-) diet from 3 weeks of age, and mated at 8 weeks of age. Male offspring were fed the same diet as their mother. Some offspring initially fed the VitD- diet were switched to a VitD+ diet from 8 weeks of age (VitD-/+). At 12 weeks of age, signs of low-level inflammation were observed in the bronchoalveolar lavage fluid (BALF) of VitD- mice (more macrophages and neutrophils), which were suppressed by subsequent supplementation with vitamin D3 There was no difference in the level of expression of the tight junction proteins occludin or claudin-1 in lung epithelial cells of VitD+ mice compared to VitD- mice; however, claudin-1 levels were reduced when initially vitamin D-deficient mice were fed the vitamin D3-containing diet (VitD-/+). Reduced total IgM levels were detected in BALF and serum of VitD-/+ mice compared to VitD+ mice. Lung mRNA levels of the vitamin D receptor (VDR) were greatest in VitD-/+ mice. Total IgG levels in BALF were greater in mice fed the vitamin D3-containing diet, which may be explained by increased activation of B cells in airway-draining lymph nodes. These findings suggest that supplementation of initially vitamin D-deficient mice with vitamin D3 suppresses signs of lung inflammation but has limited effects on the epithelial integrity of the lungs.

https://www.ncbi.nlm.nih.gov/pubmed/28774952

Clin Immunol. 2016 May;166-167:59-71.
Comparative effect of 25(OH)D3 and 1,25(OH)2D3 on Th17 cell differentiation. Fawaz L, Mrad MF, Kazan JM, Sayegh S, Akika R, Khoury SJ.

Vitamin D is a secosteroid hormone that plays an important regulatory role in calcium homeostasis and bone metabolism. Immune cells can both produce and respond to 1,25(OH)2D3. CD4+ T cells from vitamin D receptor (VDR) KO mice produce higher levels of IFN-γ and IL-17 than their wild type counterparts, and play a crucial role in the pathogenesis of autoimmune diseases (AID). We are particularly interested in studying the effect of vitamin D on pathogenic Th17 cells in humans. We investigated the in vitro effect of 1,25(OH)2D3 and 25(OH)D3 on the differentiation and cytokine production of primary CD4+ T cells from normal donors, and cultured in Th17 polarizing conditions. Both forms of vitamin D reduced the expression of pathogenic Th17 markers and their secretion of pro-inflammatory cytokines (IL-17A, IFN-γ). Furthermore, both vitamin D forms induced an expansion of CD25hi cells and upregulated their expression of CTLA-4 and Foxp3 regulatory markers. https://www.ncbi.nlm.nih.gov/pubmed/27041081

Vitam Miner. 2015 May;3:128.
Multivitamin Supplementation Supports Immune Function and Ameliorates Conditions Triggered By Reduced Air Quality. Haryanto B, Suksmasari T, Wintergerst E, Maggini S.

Our bodies are normally well protected against continual attack from pathogens and noxious insult by a complex and integrated immune system. However, daily bombardment from indoor and outdoor air pollutants can compromise immune function and ultimately lead to infection (e.g. acute respiratory tract infections, diarrhoea) and conditions such as sick building syndrome (with mucosal, skin and general symptoms). All of us may be affected by reduced air quality, although certain factors increase the risk of impaired immunity (e.g. young or advancing age, exposure to tobacco smoke, close proximity to areas of high air pollution, office work, commuting). A major exogenous factor modulating immune function is nutrition; even subclinical deficiencies in various nutrients can have adverse effects on the immune system, which may be exacerbated by environmental threats. In particular, the oxidant-antioxidant balance (vital for communication within the immune system) may be affected. Dietary supplementation can help to restore immune function to the normal range, and an antioxidant-containing multivitamin supplement has been shown to ameliorate the symptoms of sick building syndrome, acute respiratory tract infections and diarrhoea. This review looks at the impact of reduced air quality on the oxidant-antioxidant balance and the role of selected micronutrients (vitamins A, D, E, C, B6, B12, folate and the trace elements copper, iron, selenium and zinc) and multivitamin supplementation.

https://www.omicsonline.org/open-access/multivitamin-supplementation-supports-immune-function-andameliorates-conditions-triggered-by-reduced-air-quality-2376-1318-1000128.php?aid=52511

Nutrients. 2015 Apr;7(4):2574-88.
Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit.
Bozonet SM, Carr AC, Pullar JM, Vissers MC.

Neutrophils are the body’s primary defenders against invading pathogens. These cells migrate to loci of infection where they engulf micro-organisms and subject them to an array of reactive oxygen species and antimicrobial proteins to effect killing. Spent neutrophils subsequently undergo apoptosis and are cleared by macrophages, thereby resolving the inflammatory episode. Neutrophils contain high concentrations of vitamin C (ascorbate) and this is thought to be essential for their function. This may be one mechanism whereby vitamin C enhances immune function. The aim of our study was to assess the effect of dietary supplementation with vitamin C-rich SunGold kiwifruit on four important functions of neutrophils: chemotaxis, oxidant generation, extracellular trap formation, and apoptosis. Fourteen young men (aged 18-30 years) with suboptimal plasma vitamin C status (<50 μmol/L) were supplemented for four weeks with two SunGold kiwifruit/day. Plasma vitamin C status was monitored weekly and neutrophil vitamin C levels were assessed at baseline and post-intervention. Neutrophil function assays were carried out on cells isolated at baseline and post-intervention. Plasma vitamin C levels increased to >70 μmol/L (p < 0.001) within one week of supplementation and there was a significant increase in neutrophil vitamin C status following four weeks’ intervention (p = 0.016). We observed a significant 20% increase in neutrophil chemotaxis post-intervention (p = 0.041) and also a comparable increase in oxidant generation (p = 0.031). Supplementation did not affect neutrophil extracellular trap formation or spontaneous apoptosis. Our data indicate that supplementation with vitamin C-rich kiwifruit is associated with improvement of important neutrophil functions, which would be expected to translate into enhanced immunity.

https://www.ncbi.nlm.nih.gov/pubmed/25912037

J Biol Regul Homeost Agents. 2013 Apr-Jun;27(2):291-5.
Role of vitamins D, E and C in immunity and inflammation.
Shaik-Dasthagirisaheb YB, Varvara G, Murmura G, Saggini A, Caraffa A, Antinolfi P, Tete’ S, Tripodi D, Conti F, Cianchetti E, Toniato E, Rosati M, Speranza L, Pantalone A, Saggini R, Tei M, Speziali A, Conti P, Theoharides TC, Pandolfi F.

Inflammatory responses are operationally characterized by pain, redness, heat and swelling at the site of infection and trauma. Mast cells reside near small blood vessels and, when activated, release potent mediators involved in allergy and inflammation. Vitamin D modulates contraction, inflammation and remodeling tissue. Vitamin D deficiency has been linked to multiple diseases and several data have demonstrated a strong relationship between serum vitamin D levels and tissue function. Therapy targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions. Mast cells are activated by oxidized lipoproteins, resulting in increased expression of inflammatory cytokines and suggesting that the reduction of oxidation of low density lipoprotein by vitamin E may also reduce mast cell activation. Vitamin C is also an anti-oxidant well-known as an anti-scurvy agent in humans. Vitamin C inhibits peroxidation of membrane phospholipids and acts as a scavenger of free radicals and is also required for the synthesis of several hormones and neurotransmitters. In humans, vitamin C reduces the duration of common cold symptoms, even if its effect is not clear. Supplementation of vitamin C improves the function of the human immune system, such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis and delayed-type hypersensitivity. Vitamin C depletion has been correlated with histaminemia which has been shown to damage endothelial-dependent vasodilation. However, the impact of these vitamins on allergy and inflammation is still not well understood.

https://www.ncbi.nlm.nih.gov/pubmed/23830380

J Allergy Clin Immunol. 2012 Jun;129(6):1554-61.
Effects of ultraviolet light on human serum 25-hydroxyvitamin D and systemic immune function.
Milliken SV, Wassall H, Lewis BJ, Logie J, Barker RN, Macdonald H, Vickers MA, Ormerod AD

BACKGROUND: Many immune-mediated diseases are associated with low levels of vitamin D and sunlight. UV light or supplementation with vitamin D can increase regulatory T-cell activity and prevent animal models of autoimmune disease. Increasing population vitamin D levels may therefore alleviate the burden of human immune-mediated disease.

OBJECTIVE: To determine the responses of circulating 25-hydroxyvitamin D [25(OH)D] levels, regulatory T-cell numbers, and immune function to UV light exposure in patients being treated for skin disease.

METHODS: Twenty-four subjects with skin disease from the North of Scotland were recruited between December and March. At baseline, and after 2 and 4 weeks of narrowband UV light exposure, we measured peripheral blood 25(OH)D level, numbers of regulatory T cells (CD4(+)CD25(hi)FoxP3(+)), and T-cell proliferative and cytokine responses to anti-CD3/CD28 stimulation.

RESULTS: Median (interquartile range) narrowband UV-B received during the study was 39.1 (30.9) as standard erythema dose, comparable to a quarter of the median summer sunlight exposure received locally. This increased the 25(OH)D level from a mean ± SD of 34 ± 17 nmol/L to 58 ± 16 nmol/L after 2 weeks and 78 ± 19 nmol/L after 4 weeks. The mean proportion of circulating regulatory T cells increased from 0.5% to 1.6% CD3(+) cells, which significantly correlated with the increased 25(OH)D level. UV treatment was also followed by reduced proliferative and IL-10 responses to anti-CD3/CD28 independent of the 25(OH)D level.

CONCLUSION: Narrowband UV light reduces systemic immune responsiveness via the induction of regulatory T cells. Light and 25(OH)D levels may affect particular immune functions independently. The levels of serum 25(OH)D over which these effects are apparent should guide future interventions.

https://www.ncbi.nlm.nih.gov/pubmed/22502796

Immunol Lett. 2010 Nov;134(1):7-16.
1α,25-Dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells.
Ikeda U, Wakita D, Ohkuri T, Chamoto K, Kitamura H, Iwakura Y, Nishimura T.

1α,25-Dihydroxyvitamin D(3) (1,25D3), the active form of vitamin D(3), is an immunoregulatory hormone with beneficial effects on Th1 cell-mediated inflammatory diseases. Although IL-17-producing CD4(+) T helper (Th17) cells have been recently identified as novel effector cells, the immunomodulating effects of 1,25D3 on Th17 cells have not been well defined. We confirmed here that 1,25D3 inhibited the generation of Th17 cells in vitro. Interestingly, 1,25D3 synergistically suppressed the generation of Th17 cells by the combination with all-trans retinoic acid (ATRA). 1,25D3 and ATRA suppressed the development of allergen-induced contact hypersensitivity (CHS) in a mouse ear swelling model. In addition, we found that 1,25D3 and ATRA significantly inhibited the development of human Th17 cells from both naïve and memory human CD4(+) T cells. 1,25D3 and ATRA effectively suppressed mRNA expressions of IL-1R1, IL-21R, IL-23R, RORC, and AHR in human T cells. ATRA further suppressed IL-6R, whereas 1,25D3 did not. Finally, we found that 1,25D3 and ATRA remarkably blocked IL-22 as well as IL-17 mRNA expression in human memory CD4(+) T cells. Thus, we initially reveal that 1,25D3 and ATRA have synergistic effects on the generation of Th17 cells, suggesting that the combination with ATRA would provide a promising novel therapy for Th17 cell-related immune diseases including skin inflammation.

https://www.ncbi.nlm.nih.gov/pubmed/20655952

Nat Immunol. 2010 Apr;11(4):344-9.
Vitamin D controls T cell antigen receptor signaling and activation of human T cells.
von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C.

Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-gamma1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering led to an upregulation of approximately 75-fold in PLC-gamma1 expression, which correlated with greater TCR responsiveness. Induction of PLC-gamma1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-gamma1, which are required for subsequent classical TCR signaling and T cell activation.

https://www.ncbi.nlm.nih.gov/pubmed/20208539

Biol Reprod. 2009 Mar;80(3):398-406.
Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway.
Liu N, Kaplan AT, Low J, Nguyen L, Liu GY, Equils O, Hewison M.

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D), is a potent inducer of the antimicrobial protein cathelicidin, CAMP (LL37). In macrophages this response is dependent on intracrine synthesis of 1,25(OH)(2)D from precursor 25-hydroxyvitamin D (25OHD), catalyzed by the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1). In view of the fact that trophoblastic cells also express abundant CYP27B1, we postulated a similar intracrine pathway for induction of CAMP in the placenta. Analysis of placenta explants, primary cultures of human trophoblast, and the 3A trophoblastic cell line treated with 1,25(OH)(2)D (1-100 nM) revealed dose-dependent induction of CAMP similar to that observed with primary cultures of human macrophages. Also consistent with macrophages, induction of trophoblastic CAMP was enhanced via intracrine conversion of 25OHD to 1,25(OH)(2)D. However, in contrast to macrophages, induction of CAMP by vitamin D in trophoblasts was not enhanced by costimulation with Toll-like receptor ligands, such as lipopolysaccharide. Despite this, exposure to vitamin D metabolites significantly enhanced antibacterial responses in trophoblastic cells: 3A cells infected with Escherichia coli showed decreased numbers of bacterial colony-forming units compared with vehicle-treated controls when treated with 25OHD (49.6% +/- 10.9%) or 1,25(OH)(2)D (45.4% +/- 9.2%), both P < 0.001. Treatment with 25OHD (1-100 nM) or 1,25(OH)(2)D (0.1-10 nM) also protected 3A cells against cell death following infection with E. coli (13.6%-26.9% and 22.3%-40.2% protection, respectively). These observations indicate that 1,25(OH)(2)D can function as an intracrine regulator of CAMP in trophoblasts, and may thus provide a novel mechanism for activation of innate immune responses in the placenta.

https://www.ncbi.nlm.nih.gov/pubmed/19005165

Nat Rev Immunol. 2008 Sep;8(9):685-98.
Vitamin effects on the immune system: vitamins A and D take centre stage.
Mora JR, Iwata M, von Andrian UH.

Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.

https://www.ncbi.nlm.nih.gov/pubmed/19172691

Free Radic Res. 2008 Mar;42(3):272-80. doi: 10.1080/10715760801898838.
Vitamin E ingestion improves several immune functions in elderly men and women.
De la Fuente M1, Hernanz A, Guayerbas N, Victor VM, Arnalich F.

The effects of diet supplementation with the antioxidant vitamin E (200 mg daily) on several blood neutrophil, lymphocyte and natural killer cell functions have been investigated in healthy elderly men and women before supplementation, after 3 months of supplementation and 6 months after the end of supplementation (post-supplementation). In parallel, samples of healthy adult men and women were used as age controls. In elderly men and women, an impairment of immune functions was observed in comparison with the respective adult controls and the intake of vitamin E resulted in a significant enhancement of immune parameters in both elderly men and women, bringing their values close to those in the adults. These effects were not found in post-supplementation samples in several but not in all functions. The present findings suggest that supplementation with vitamin E can produce an improvement of immune functions and therefore of health in aged people.

https://www.ncbi.nlm.nih.gov/pubmed/18344122

J Pharmacol Exp Ther. 2008 Jan;324(1):23-33.
Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile.
Daniel C, Sartory NA, Zahn N, Radeke HH, Stein JM.

A number of recent studies testify that calcitriol alone or in combination with corticosteroids exerts strong immune modulatory activity. As a new approach, we evaluated the protolerogenic potential of calcitriol and dexamethasone in acute T helper (Th)1-mediated colitis in mice. A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg) was applied to BALB/c mice. Calcitriol and/or dexamethasone were administered i.p. from days 0 to 3 or 3 to 5 following the instillation of the haptenating agent. Assessment of colitis severity was performed daily. Colon tissue was analyzed macroscopically and microscopically, and myeloperoxidase activity, as well as cytokine levels [tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-12p70, IL-1beta, IL-10, IL-4] were determined by enzyme-linked immunosorbent assay, T-bet, GATA family of transcription factors 3, a Th2 master regulator (GATA3), Foxp3, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), IL-23p19 and IL-17 expression by immunoblot analysis. The combination of the steroids most effectively reduced the clinical and histopathologic severity of TNBS colitis. Th1-related parameters were down-regulated, whereas Th2 markers like IL-4 and GATA3 were up-regulated. Apart from known steroid effects, calcitriol in particular promoted regulatory T cell profiles as indicated by a marked increase of IL-10, TGFbeta, FoxP3, and CTLA4. Furthermore, analysis of dendritic cell mediators responsible for a proinflammatory differentiation of T cells revealed a significant reduction of IL-12p70 and IL23p19 as well as IL-6 and IL-17. Thus, our data support a rationale for a steroid-sparing, clinical application of calcitriol derivatives in inflammatory bowel disease. Furthermore they suggest that early markers of inflammatory dendritic cell and Th17 differentiation qualify as new target molecules for both calcitriol and highly selective immune-modulating vitamin D analogs.

https://www.ncbi.nlm.nih.gov/pubmed/17911375

Br J Nutr. 2007 Oct;98 Suppl 1:S29-35.
Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses.
Maggini S, Wintergerst ES, Beveridge S, Hornig DH.

Adequate intakes of micronutrients are required for the immune system to function efficiently. Micronutrient deficiency suppresses immunity by affecting innate, T cell mediated and adaptive antibody responses, leading to dysregulation of the balanced host response. This situation increases susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (active and passive), in individuals with chronic alcohol abuse, in certain diseases, during pregnancy and lactation, and in the elderly. This paper summarises the roles of selected vitamins and trace elements in immune function. Micronutrients contribute to the body’s natural defences on three levels by supporting physical barriers (skin/mucosa), cellular immunity and antibody production. Vitamins A, C, E and the trace element zinc assist in enhancing the skin barrier function. The vitamins A, B6, B12, C, D, E and folic acid and the trace elements iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production. Overall, inadequate intake and status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with these selected micronutrients can support the body’s natural defence system by enhancing all three levels of immunity.

https://www.ncbi.nlm.nih.gov/pubmed/17922955

Ann Nutr Metab. 2007 Aug;51(4):301-23.
Contribution of selected vitamins and trace elements to immune function.
Wintergerst ES, Maggini S, Hornig DH.

Adequate intakes of vitamins and trace elements are required for the immune system to function efficiently. Micronutrient deficiency suppresses immune functions by affecting the innate T-cell-mediated immune response and adaptive antibody response, and leads to dysregulation of the balanced host response. This increases the susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (both active and passive), in individuals with chronic alcohol abuse, in patients with certain diseases, during pregnancy and lactation, and in the elderly. With aging a variety of changes are observed in the immune system, which translate into less effective innate and adaptive immune responses and increased susceptibility to infections. Antioxidant vitamins and trace elements (vitamins C, E, selenium, copper, and zinc) counteract potential damage caused by reactive oxygen species to cellular tissues and modulate immune cell function through regulation of redox-sensitive transcription factors and affect production of cytokines and prostaglandins. Adequate intake of vitamins B(6), folate, B(12), C, E, and of selenium, zinc, copper, and iron supports a Th1 cytokine-mediated immune response with sufficient production of proinflammatory cytokines, which maintains an effective immune response and avoids a shift to an anti-inflammatory Th2 cell-mediated immune response and an increased risk of extracellular infections. Supplementation with these micronutrients reverses the Th2 cell-mediated immune response to a proinflammatory Th1 cytokine-regulated response with enhanced innate immunity. Vitamins A and D play important roles in both cell-mediated and humoral antibody response and support a Th2-mediated anti-inflammatory cytokine profile. Vitamin A deficiency impairs both innate immunity (mucosal epithelial regeneration) and adaptive immune response to infection resulting in an impaired ability to counteract extracellular pathogens. Vitamin D deficiency is correlated with a higher susceptibility to infections due to impaired localized innate immunity and defects in antigen-specific cellular immune response. Overall, inadequate intake and status of these vitamins and minerals may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition.

https://www.ncbi.nlm.nih.gov/pubmed/17726308

J Immunol. 2006 Nov;177(9):6052-61.
Age and Vitamin E-induced Changes in Gene Expression Profiles of T Cells.
Han SN, Adolfsson O, Lee CK, Prolla TA, Ordovas J, Meydani SN.

T cells are vulnerable to age-associated changes. Vitamin E has been shown to improve T cell functions in the old. We studied gene expression profiles of T cells to better understand the underlying mechanisms of age and vitamin E-induced changes in T cell function. Young and old C57BL mice were fed diets containing 30 (control) or 500 (supplemented) ppm of vitamin E for 4 wks. Gene expression profiles of T cells were assessed using microarray analysis with/without anti-CD3/anti-CD28 stimulation. Genes associated with cytokines/chemokines, transcriptional regulation, signal transduction, cell cycle, and apoptosis were significantly up-regulated upon stimulation. Higher SOCS3 and lower growth factor independent 1 (Gfi-1) expression in old T cells may contribute to age-associated decline in proliferation. Higher Gadd45 and lower Bcl2 expression may contribute to increased apoptosis in old T cells. Vitamin E supplementation resulted in higher expression of genes involved in cell cycle regulation (Ccnb2, Cdc2, Cdc6) in old T cells. Vitamin E supplementation resulted in higher up-regulation of IL-2 expression in young and old T cells and lower up-regulation of IL-4 expression in old T cells following stimulation. These findings suggest that aging has significant effects on the expression of genes associated with signal transduction, transcriptional regulation, and apoptosis pathways in T cells, and vitamin E has a significant impact on the expression of genes associated with cell cycle and Th1/Th2 balance in old T cells. Further studies are needed to determine whether these changes are due to the effects of aging at a single-cell level or to the shift in the ratio of naïve:memory T cells with age.

https://pubmed.ncbi.nlm.nih.gov/17056531/

Am J Clin Nutr. 1999 Jun;69(6):1273-81.
Effect of 50- and 100-mg vitamin E supplements on cellular immune function in noninstitutionalized elderly persons.
Pallast EG, Schouten EG, de Waart FG, Fonk HC, Doekes G, von Blomberg BM, Kok FJ.

BACKGROUND: It has been suggested that vitamin E can counteract the age-associated decline in cellular immune responsiveness (CIR). Particularly, T helper cell type 1 (Th1) activity, ie, interferon (IFN) gamma-producing Th1 activity and, hence, delayed-type hypersensitivity (DTH) would be enhanced by vitamin E supplementation.
OBJECTIVE: Our aim was to study the effects of 6 mo supplementation with 50 and 100 mg vitamin E on CIR in the elderly.
DESIGN: A double-blind, placebo-controlled trial was conducted in 161 healthy elderly subjects aged 65-80 y. CIR was measured in vivo by means of DTH skin tests and in vitro by assessing the production of interleukin (IL) 2, IFN-gamma (a typical Th1 cytokine), and IL-4 (a typical Th2 cytokine) by peripheral blood mononuclear cells after stimulation with phytohemagglutinin.
RESULTS: Both DTH and IL-2 production showed a trend toward increased responsiveness with increasing dose of vitamin E. However, IFN-gamma production decreased whereas IL-4 production increased in the groups receiving vitamin E. Only the change in the number of positive DTH reactions was borderline significantly larger in the 100-mg vitamin E group than in the placebo group (P = 0.06, Bonferroni adjusted). Subjects receiving 100 mg vitamin E with low baseline DTH reactivity or who were physically less active had a significantly larger increase in the cumulative diameter of the skin induration resulting from the DTH test than did the placebo group (P = 0.03), although this difference was not significant after Bonferroni correction (P = 0.07).
CONCLUSION: Possible beneficial effects of 100-mg vitamin E supplementation may be more pronounced in particular subgroups of elderly subjects.

https://www.ncbi.nlm.nih.gov/pubmed/10357750

Am J Clin Nutr. 1996 Dec;64(6):960-5.
Supplementation with vitamins C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults.
Jeng KC, Yang CS, Siu WY, Tsai YS, Liao WJ, Kuo JS.

The effect of supplementation with vitamins C and E on cytokine production of healthy adult volunteers was studied in a single-blind trial. Ten subjects in each group received daily vitamin C (1 g ascorbic acid), vitamin E (400 mg dl-alpha-tocopheryl acetate), or vitamins C and E for 28 d. Plasma concentrations of alpha-tocopherol, ascorbate, and lipid peroxides as well as the production of cytokines by peripheral blood mononuclear cells (PBMCs) were measured before, during, and at the end of the supplementation and 1 wk later. PBMCs were cultured in the presence of absence of lipopolysaccharide for 24 h. The interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) in the culture supernates were assayed by enzyme-linked immunosorbent assay methods. Production of IL-1 beta and TNF-alpha in the group supplemented with vitamins C and E was significantly higher (P < 0.05) than that of the groups given vitamin E or vitamin C alone. The enhancing effect of supplementation with a combination of vitamins E and C coincided with peak plasma alpha-tocopherol and ascorbate concentrations and the lowest plasma lipid peroxide concentrations (P < 0.05) on day 14. In addition, an in vitro experiment with PBMCs showed that vitamins E and C reduced lipopolysaccharide-induced prostaglandin E2 production and enhanced TNF-alpha production. These results indicate that combined supplementation with vitamins C and E is more immunopotentiating than supplementation with either vitamin alone in healthy adults.

https://www.ncbi.nlm.nih.gov/pubmed/8942423

J Invest Dermatol. 1991 Aug;97(2):230-9.
Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin.
Milde P, Hauser U, Simon T, Mall G, Ernst V, Haussler MR, Frosch P, Rauterberg EW.

Increasing evidence suggests an immunoregulatory function of the potent steroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) which has been successfully applied for treatment of psoriasis. The skin is both a site of production and a target of 1,25(OH)2D3. In vitro, 1,25(OH)2D3 inhibits proliferation and stimulates differentiation of keratinocytes. We investigated the in situ expression of vitamin D-receptors (VDR) in normal and psoriatic skin by immunochemical methods. The VDR were visualized using the monoclonal antibody (MoAb) 9A7g to the VDR and the labeled avidinbiotin technique. Immunoreactivity was consistently confined to nuclei in all skin biopsies. In normal skin specimens (n = 10) VDR antigens were expressed in keratinocytes of all epidermal layers (except those of the stratum corneum) and in cells of the epidermal appendages. Double labeling experiments with MoAb to cluster-defined antigens indicated that melanocytes and approximately 75% of Langerhans cells exhibit 1,25(OH)2D3 receptors in normal skin biopsies (n = 5). Depending on their localization in skin compartments 42-62% of CD11b+ positive macrophages and 45-75% of CD3+ T lymphocytes expressed VDR. Non-lesional psoriatic skin specimens (n = 8) revealed nearly identical staining patterns. Lesional psoriatic skin specimens (n = 8) exhibited a significant increase of VDR expression both in basal and suprabasal epidermal layers as measured by computer-assisted morphometry and showed a remarkable change of the immune cell pattern: the densitity and proportion of VDR positive T lymphocytes and macrophages were higher in the epidermal and the perivascular papillary loop compartment. These in vivo findings strongly support the hypothesis that 1,25(OH)2D3 modulates immune response and cell proliferation/differentiation in human skin.

https://www.ncbi.nlm.nih.gov/pubmed/1649228

Am J Clin Nutr. 1990 Sep;52(3):557-63.
Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects.
Meydani SN, Barklund MP, Liu S, Meydani M, Miller RA, Cannon JG, Morrow FD, Rocklin R, Blumberg JB.

The effect of vitamin E supplementation on the immune response of healthy older adults was studied in a double-blind, placebo-controlled trial. Subjects (n = 32) resided in a metabolic research unit and received placebo or vitamin E (800 mg dl-alpha-tocopheryl acetate) for 30 d. Alpha-tocopherol content of plasma and peripheral blood mononuclear cells (PBMCs), delayed-type hypersensitivity skin test (DTH), mitogen-stimulated lymphocyte proliferation, as well as interleukin (IL)-1, IL-2, prostaglandin (PG) E2, and serum lipid peroxides were evaluated before and after treatment. In the vitamin E-supplemented group 1) alpha-tocopherol content was significantly higher (p less than 0.0001) in plasma and PBMCs, 2) cumulative diameter and number of positive antigen responses in DTH response were elevated (p less than 0.05), 3) IL-2 production and mitogenic response to optimal doses of concanavalin A were increased (p less than 0.05), and 4) PGE2 synthesis by PBMCs (p less than 0.005) and plasma lipid peroxides (p less than 0.001) were reduced. Short-term vitamin E supplementation improves immune responsiveness in healthy elderly individuals; this effect appears to be mediated by a decrease in PGE2 and/or other lipid-peroxidation products.

https://www.ncbi.nlm.nih.gov/pubmed/2203257

Infect Immun. 1975 Aug;12(2):252-6.
Ascorbate and phagocyte function. Stankova L, Gerhardt NB, Nagel L, Bigley RH.

Scorbutic guinea pig neutrophils (PMN) were found to produce H2O2 and kill Staphylococcus aureus as well as control PMN, suggesting that ascorbate does not contribute significantly to phagocyte H2O2 production or bacterial killing. Total and reduced ascorbate contents of human PMN was observed to fall upon phagocytosis, whereas dehydroascorbate increased to a lesser extent. These observations are consistent with the view that ascorbate constitutes a functional part of the PMN’s redox-active components and may thus function to protect cell constituents from denaturation by the oxidants produced during phagocytosis.

https://www.ncbi.nlm.nih.gov/pubmed/1150324

Free Radic Biol Med. 2011 Oct;51(7):1399-405.
Roles of superoxide and myeloperoxidase in ascorbate oxidation in stimulated neutrophils and H2O2-treated HL60 cells.
Parker A, Cuddihy SL, Son TG, Vissers MC, Winterbourn CC.

Ascorbate is present at high concentrations in neutrophils and becomes oxidized when the cells are stimulated. We have investigated the mechanism of oxidation by studying cultured HL60 cells and isolated neutrophils. Addition of H(2)O(2) to ascorbate-loaded HL60 cells resulted in substantial oxidation of intracellular ascorbate. Oxidation was myeloperoxidase-dependent, but not attributable to hypochlorous acid, and can be explained by myeloperoxidase (MPO) exhibiting direct ascorbate peroxidase activity. When neutrophils were stimulated with phorbol myristate acetate, about 40% of their intracellular ascorbate was oxidized over 20 min. Ascorbate loss required NADPH oxidase activity but in contrast to the HL60 cells did not involve myeloperoxidase. It did not occur when exogenous H(2)O(2) was added, was not inhibited by myeloperoxidase inhibitors, and was the same for normal and myeloperoxidase-deficient cells. Neutrophil ascorbate loss was enhanced when endogenous superoxide dismutase was inhibited by cyanide or diethyldithiocarbamate and appears to be due to oxidation by superoxide. We propose that in HL60 cells, MPO-dependent ascorbate oxidation occurs because cellular ascorbate can access newly synthesized MPO before it becomes packaged in granules: a mechanism not possible in neutrophils. In neutrophils, we estimate that ascorbate is capable of competing with superoxide dismutase for a small fraction of the superoxide they generate and propose that the superoxide responsible is likely to come from previously identified sites of intracellular NADPH oxidase activity. We speculate that ascorbate might protect the neutrophil against intracellular effects of superoxide generated at these sites.

https://www.ncbi.nlm.nih.gov/pubmed/21791243

Am J Clin Nutr. 1991 Dec;54(6 Suppl):1214S-1220S.
Reduced bactericidal activity in neutrophils from scorbutic animals and the effect of ascorbic acid on these target bacteria in vivo and in vitro.
Goldschmidt MC.

Actinomycetes, involved in oral and periodontal diseases, cause serious infections in immunocompromised hosts. Severely scorbutic guinea pig leukocytes killed only 12% of phagocytosed actinomycetes, had distorted nuclear morphology, had 16 times less ascorbate, and had no chemotactic responses in vitro. Ascorbate reversed these indices and also prevented nitrosamine formation by oral organisms. Degranulating leukocytes release lactoferrin and ascorbate that chelate iron, essential for microorganisms. Ascorbic acid, 2,2′-bipyridine and 1,10-phenanthroline were bactericidal to several bacterial pathogens at millimolar concentrations. Iron alone reversed this effect. In in vivo experiments an Actinomyces viscosus monoflora was implanted in rhesus monkeys. Plaque and serum samples showed decreased (by six orders of magnitude) bacterial counts and decreased actinomycete antibody titers in animals given 1 g ascorbate/d. Removing ascorbate returned counts and titers to preascorbate concentrations. Fifteen marmosets, receiving twice daily topical applications of ascorbate or water, had comparatively lower gingival, calculus, and plaque indices and only slightly lowered actinomycete counts.

https://www.ncbi.nlm.nih.gov/pubmed/1962573

Int J Vitam Nutr Res. 1988;58(3):326-34.
The effect of ascorbic acid deficiency on leukocyte phagocytosis and killing of actinomyces viscosus.
Goldschmidt MC, Masin WJ, Brown LR, Wyde PR.

The ascorbic acid content of guinea pig leukocytes is reduced by a factor of 16:1 between normal and scorbutic guinea pigs. Ascorbic acid deficiencies do not appear to affect phagocytic activity but do change leukocyte morphology. A deficiency of this vitamin appears to significantly interfere with the in vitro bactericidal effectiveness of circulating leukocytes against ingested, cell-associated, and extracellular bacterial cells of the oral pathogen, Actinomyces viscosus. Leukocytes from scorbutic guinea pigs killed 13% of ingested and cell-associated Actinomyces viscosus compared to 83% killed by normal leukocytes by both acridine orange staining and viable count. Degranulation resulted in extracellular killing in normal but not scorbutic leukocytes. This decreased bactericidal activity can be reversed by adding supplements of the vitamin to the diet of scorbutic animals. Chemotactic responses were much lower in vivo and absent in vitro in scorbutic leukocytes. The acridine orange staining technique is an excellent indicator of leukocyte health. This study supports the important role for ascorbic acid in leukocyte function and also discusses its probable protective and bactericidal activities related to oral pathogens.

https://www.ncbi.nlm.nih.gov/pubmed/2461911

J Nutr. 1991 Jan;121(1):126-30.
Effect of ascorbic acid nutriture on blood histamine and neutrophil chemotaxis in guinea pigs.
Johnston CS, Huang SN.

Histamine suppresses certain immune responses, including neutrophil chemotaxis. The present study examined whether the histamine-lowering effect of ascorbate was accompanied by enhanced chemotaxis in guinea pigs. Animals were fed low ascorbate, adequate or high ascorbate diets (0.5, 2.0 or 50 mg ascorbate.100 g body wt-1.d-1) for 4 wk. Mean liver ascorbate paralleled dietary intake, and these values differed significantly. Blood histamine was significantly depressed in the high ascorbate group compared to the adequate and low ascorbate groups, and liver ascorbate was inversely correlated to blood histamine levels (r = -0.64, P less than 0.001). The random migration of neutrophils was not significantly affected by vitamin dosage. Leukocyte chemotaxis was significantly impaired in low ascorbate animals compared to that of animals with adequate ascorbate nutriture. Leukocyte chemotaxis in high ascorbate animals did not differ significantly from that in the adequate or low ascorbate groups. Furthermore, chemotaxis was significantly lower when cells extracted from animals with adequate ascorbate nutriture were incubated in low ascorbate or high ascorbate serum rather than in autologous serum. These data suggest that the histamine-lowering effect of supplemental ascorbate does not appear to enhance leukocyte chemotaxis and that serum from guinea pigs fed low or high levels of ascorbate appears to contain factors that depress chemotaxis.

https://www.ncbi.nlm.nih.gov/pubmed/1992049

Br J Dermatol. 1980 Jan;102(1):49-56.
Neutrophil dysfunction and repeated infections: influence of levamisole and ascorbic acid.
Rebora A, Dallegri F, Patrone F.

Neutrophil function was studied in several patients with recurrent infections, mainly of the skin. Twelve patients showed impairment of neutrophil functions, either chemotaxis or bacterial killing and phagocytosis. Levamisole was given in four cases: improvement of neutrophil function and long-lasting clinical remission occurred in three of them, whilst in the fourth the drug was not tolerated. Ascorbic acid was administered to three other patients, with satisfactory improvement of neutrophil function and long-lasting clinical remission.

https://www.ncbi.nlm.nih.gov/pubmed/7378281

Am J Clin Nutr. 1980 Jan;33(1):71-6.
The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune functions in normal volunteers.
Anderson R, Oosthuizen R, Maritz R, Theron A, Van Rensburg AJ.

Certain functions of the blood neutrophils and lymphocytes from normal adult volunteers were evaluated after the ingestion of increasing doses of ascorbate. Serum immunoglobulins and levels of C’3 and total hemolytic complement were also measured. Enhancement of neutrophil motility to a chemotactic stimulus of endotoxin-activated autologous serum was observed in normal adult volunteers after the ingestion of 2 and 3 g ascorbate daily. No alteration was observed at lower doses. Other neutrophil functions evaluated that remained unaltered by ascorbate, were postphagocytic hexose monophosphate shunt activity and myeloperoxidase mediated iodination of ingested protein. Stimulation of lymphocyte transformation to the mitogens phytohaemagglutinin and concanavalin A was detected after the daily ingestion of 1, 2, and 3 g of ascorbate. Mitogen-induced protein synthesis was unaffected. Serum levels of IgG, IgA, IgM, C’3, and C’4 and total complement activity were unaltered by ascorbate.

https://www.ncbi.nlm.nih.gov/pubmed/7355784

Am J Clin Nutr. 1981 Sep;34(9):1906-11.
Ascorbate-mediated stimulation of neutrophil motility and lymphocyte transformation by inhibition of the peroxidase/H2O2/halide system in vitro and in vivo.
Anderson R.

Neutrophil migration, postphagocytic hexose-monophosphate shunt activity and myeloperoxidase-mediated iodination of ingested Candida albicans and lymphocyte mitogen-induced transformation were assessed in six normal volunteers before and 1 h after a single intravenous injection of 1 g ascorbate. Increased neutrophil motility was observed which was associated with decreased myeloperoxidase-mediated iodination of C. albicans and a slight increase in hexose-monophosphate shunt activity. Lymphocyte transformation was also increased. Alterations in these activities were related to serum ascorbate levels. To investigate the relationship of ascorbate-mediated increased neutrophil motility and lymphocyte transformation to decreased peroxidase activity neutrophils and lymphocytes from normal individuals were exposed to the horseradish peroxidase/H2O2/sodium iodide system in the presence and absence of ascorbate and tested for migratory and proliferative responses respectively. Exposure to the horseradish peroxidase/H2O2/halide system caused inhibition of neutrophil motility and lymphocyte responsiveness to mitogens. However, inclusion of ascorbate protected both the neutrophils and lymphocytes from the inhibitory effects of the horseradish peroxidase/H2O2/halide system.

https://www.ncbi.nlm.nih.gov/pubmed/7282616

Am J Clin Nutr. 1976 Jul;29(7):762-5.
Macrophage function in vitamin C-deficient guinea pigs.
Ganguly R, Durieux MF, Waldman RH.

Guinea pigs were fed a vitamin C-deficient diet and at various time periods thereafter their peritoneal cells were tested for biological activity. The serum levels of vitamin C in the deficient animals indicated a progressive state of ascorbic acid deficiency with time and this correlated well with clinical signs and symptoms of scurvy. Fewer macrophages were obtained from the peritoneal cavities of deficient animals and in structural appearance under the phase contrast and light microscope they were smaller in size. They showed no significant impairment in phagocytosis of bacterial cells. The macrophages, however, exhibited significantly reduced migration on glass as compared to the normal cells. In vitro addition of vitamin C partially reversed this reduced migration.

https://www.ncbi.nlm.nih.gov/pubmed/937230

Nutrients. 2013 Aug;5(8):3131-51.
Vitamin C: a novel regulator of neutrophil extracellular trap formation.
Mohammed BM, Fisher BJ, Kraskauskas D, Farkas D, Brophy DF, Fowler AA 3rd, Natarajan R.

Introduction: Neutrophil extracellular trap (NET) formation was recently identified as a novel mechanism to kill pathogens. However, excessive NET formation in sepsis can injure host tissues. We have recently shown that parenteral vitamin C (VitC) is protective in sepsis. Whether VitC alters NETosis is unknown.
Methods: We used Gulo-/- mice as they lack the ability to synthesize VitC. Sepsis was induced by intraperitoneal infusion of a fecal stem solution (abdominal peritonitis, FIP). Some VitC deficient Gulo-/- mice received an infusion of ascorbic acid (AscA, 200 mg/kg) 30 min after induction of FIP. NETosis was assessed histologically and by quantification for circulating free DNA (cf-DNA) in serum. Autophagy, histone citrullination, endoplasmic reticulum (ER) stress, NFκB activation and apoptosis were investigated in peritoneal PMNs.
Results: Sepsis produced significant NETs in the lungs of VitC deficient Gulo-/- mice and increased circulating cf-DNA. This was attenuated in the VitC sufficient Gulo-/- mice and in VitC deficient Gulo-/- mice infused with AscA. Polymorphonuclear neutrophils (PMNs) from VitC deficient Gulo-/- mice demonstrated increased activation of ER stress, autophagy, histone citrullination, and NFκB activation, while apoptosis was inhibited. VitC also significantly attenuated PMA induced NETosis in PMNs from healthy human volunteers.
Conclusion: Our in vitro and in vivo findings identify VitC as a novel regulator of NET formation in sepsis. This study complements the notion that VitC is protective in sepsis settings.

https://www.ncbi.nlm.nih.gov/pubmed/23939536

J Leukoc Biol. 2014 Dec;96(6):1165-75.
Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells.
Huijskens MJ, Walczak M, Koller N, Briedé JJ, Senden-Gijsbers BL, Schnijderberg MC, Bos GM, Germeraad WT.

The efficacy of donor HSCT is partly reduced as a result of slow post-transplantation immune recovery. In particular, T cell regeneration is generally delayed, resulting in high infection-related mortality in the first years post-transplantation. Adoptive transfer of in vitro-generated human T cell progenitors seems a promising approach to accelerate T cell recovery in immunocompromised patients. AA may enhance T cell proliferation and differentiation in a controlled, feeder-free environment containing Notch ligands and defined growth factors. Our experiments show a pivotal role for AA during human in vitro T cell development. The blocking of NOS diminished this effect, indicating a role for the citrulline/NO cycle. AA promotes the transition of proT1 to proT2 cells and of preT to DP T cells. Furthermore, the addition of AA to feeder cocultures resulted in development of DP and SP T cells, whereas without AA, a preT cell-stage arrest occurred. We conclude that neither DLL4-expressing feeder cells nor feeder cell conditioned media are required for generating DP T cells from CB and G-CSF-mobilized HSCs and that generation and proliferation of proT and DP T cells are greatly improved by AA. This technology could potentially be used to generate T cell progenitors for adoptive therapy.

https://www.ncbi.nlm.nih.gov/pubmed/25157026

Antioxid Redox Signal. 2013 Dec;19(17):2054-67.
Vitamin C promotes maturation of T-cells.
Manning J, Mitchell B, Appadurai DA, Shakya A, Pierce LJ, Wang H, Nganga V, Swanson PC, May JM, Tantin D, Spangrude GJ.

Aims: Vitamin C (ascorbic acid) is thought to enhance immune function, but the mechanisms involved are obscure. We utilized an in vitro model of T-cell maturation to evaluate the role of ascorbic acid in lymphocyte development.
Results: Ascorbic acid was essential for the developmental progression of mouse bone marrow-derived progenitor cells to functional T-lymphocytes in vitro and also played a role in vivo. Ascorbate-mediated enhancement of T-cell development was lymphoid cell-intrinsic and independent of T-cell receptor (TCR) rearrangement. Analysis of TCR rearrangements demonstrated that ascorbic acid enhanced the selection of functional TCRαβ after the stage of β-selection. Genes encoding the coreceptor CD8 as well as the kinase ZAP70 were upregulated by ascorbic acid. Pharmacologic inhibition of methylation marks on DNA and histones enhanced ascorbate-mediated differentiation, suggesting an epigenetic mechanism of Cd8 gene regulation via active demethylation by ascorbate-dependent Fe(2+) and 2-oxoglutarate-dependent dioxygenases.
Innovation: We speculate that one aspect of gene regulation mediated by ascorbate occurs at the level of chromatin demethylation, mediated by Jumonji C (JmjC) domain enzymes that are known to be reliant upon ascorbate as a cofactor. JmjC domain enzymes are also known to regulate transcription factor activity. These two mechanisms are likely to play key roles in the modulation of immune development and function by ascorbic acid.
Conclusion: Our results provide strong experimental evidence supporting a role for ascorbic acid in T-cell maturation as well as insight into the mechanism of ascorbate-mediated enhancement of immune function.

https://www.ncbi.nlm.nih.gov/pubmed/23249337

Gerontology. 1983;29(5):305-10.
Effect of vitamin C supplements on cell-mediated immunity in old people.
Kennes B, Dumont I, Brohee D, Hubert C, Neve P.

Both ageing and vitamin C (VC) deficiency result in immune defect. Since low serum and tissue levels of VC are found in the elderly, we have in a placebo-controlled study, tested the effect of VC supplements (500 mg/day i.m. for 1 month) on various immune parameters. Indeed, VC enhances the proliferative response of T lymphocytes in vitro, and the tuberculin skin hypersensitivity in vivo. Neither the serum concentrations of IgA, IgG and IgM, nor the proportion of E-rosette-forming cells were modified. No significant change was observed in the placebo-treated group.

https://www.ncbi.nlm.nih.gov/pubmed/6604680

S Afr Med J. 1980 Dec;58(24):974-7.
The effect of ascorbate on cellular humoral immunity in asthmatic children.
Anderson R, Hay I, van Wyk H, Oosthuizen R, Theron A.

Ten White children with bronchial asthma and exercise-induced bronchoconstriction were assessed immunologically before and 1, 3 and 6 months after the commencement of standard therapy supplemented with ascorbate 1 g/d. The tests of cellular immune function were neutrophil chemotaxis, phagocytosis and resting and stimulated nitroblue tetrazolium reduction, and lymphocyte mitogen-induced transformation. Humoral functions measured were secretory IgA, serum immunoglobulins, alpha 1-antitrypsin, C3, C4 and total haemolytic complement, antistreptolysin O (ASO) and C-reactive protein. Radio-allergosorbent testing to the common allergens Cynodon dactylon (grass), Dermatophagoides pteronyssinus (mite), house dust and cat epithelium was performed on each child before and 3 and 6 months after treatment. Two children had depressed neutrophil motility, 4 had depressed lymphocyte transformation, and 7 had elevated levels of ASO. These functions normalized after 6 months of ascorbate-supplemented therapy. Serum total IgE levels but not specific IgE levels were likewise reduced after 6 months of therapy. Reduced levels of serum alpha 1-antitrypsin were observed in 2 children, and remained unchanged throughout the study.

https://www.ncbi.nlm.nih.gov/pubmed/7444701

Am J Clin Nutr. 1980 Apr;33(4):839-47.
The effect of variations in vitamin C intake on the cellular immune response of guinea pigs.
Fraser RC, Pavlović S, Kurahara CG, Murata A, Peterson NS, Taylor KB, Feigen GA.

The uptake of tritiated thymidine by isolated peripheral blood lymphocytes obtained from male guinea pigs immunized with bovine serum albumin was studied in animals maintained on various amounts of Vitamin C for 28 days. Animals were pair-fed on ascorbate-free diet and were supplemented intraperitoneally with 0, 25, or 250 mg Na-ascorbate per day. Scorbutic animals lost weight rapidly during the final 2 experimental weeks. Their daily food intake averaged only 4 g/day during the last week; thus, pair-fed ascorbate-supplemented groups were also subjected to acute nutritional stress. Lymphocytes from guinea pigs receiving 250 mg Na-ascorbate per day incorporated in vitro the highest amounts of tritiated thymidine both in the absence of nonspecific mitogen and in the presence of concanavalin A or phytohemagglutinin. Responses to lipopolysaccharide were not conclusive. Total circulating white cells counts and relative numbers of T and B lymphocytes were assessed in a second study made under identical constraints. In scorbutic animals the percentage of B lymphocytes increased and that of T lymphocytes decreased continuously over the 4-week period. The opposite effect was observed in vitamin C-supplemented animals. These studies suggest that very high doses of ascorbate support elevated mitotic activity after 4 weeks of much reduced food intake.

https://www.ncbi.nlm.nih.gov/pubmed/7361703

Int J Vitam Nutr Res. 1977;47(3):248-57.
The effect of ascorbic acid supplementation on some parameters of the human immunological defence system.
Prinz W, Bortz R, Bregin B, Hersch M.

We have investigated the effect of ascorbic acid (vitamin C) supplementation on some parameters of the human immune defence system in a group of 25 healthy, male university students. The subjects ingested 1 g ascorbic acid per day for a period of 75 days. Serum levels of IgA, IgG, IgM, C-3 complement component, cortisol and transcortin were measured before and after the ascorbic acid course. Corresponding measurements were performed on a control group of 20 healthy, male university students receiving no extra-dietary vitamin C. Our results showed that ascorbic acid supplementation caused a statistically significant increase in the serum levels of IgA, IgM and C-3 complement. Our study does not permit of conclusions regarding the mechanisms of action of ascorbic acid.

https://www.ncbi.nlm.nih.gov/pubmed/914459

Immune Netw. 2013 Apr;13(2):70-4.
Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-α/β at the Initial Stage of Influenza A Virus (H3N2) Infection.
Kim Y, Kim H, Bae S, Choi J, Lim SY, Lee N, Kong JM, Hwang YI, Kang JS, Lee WJ.

L-ascorbic acid (vitamin C) is one of the well-known anti-viral agents, especially to influenza virus. Since the in vivo anti-viral effect is still controversial, we investigated whether vitamin C could regulate influenza virus infection in vivo by using Gulo (-/-) mice, which cannot synthesize vitamin C like humans. First, we found that vitamin C-insufficient Gulo (-/-) mice expired within 1 week after intranasal inoculation of influenza virus (H3N2/Hongkong). Viral titers in the lung of vitamin C-insufficient Gulo (-/-) mice were definitely increased but production of anti-viral cytokine, interferon (IFN)-α/β, was decreased. On the contrary, the infiltration of inflammatory cells into the lung and production of pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-α/β, were increased in the lung. Taken together, vitamin C shows in vivo anti-viral immune responses at the early time of infection, especially against influenza virus, through increased production of IFN-α/β.

https://www.ncbi.nlm.nih.gov/pubmed/23700397

Mediators Inflamm. 2017;2017:4024672.
The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression.
Gao YL, Lu B, Zhai JH, Liu YC, Qi HX, Yao Y, Chai YF, Shou ST.

Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo-/- mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25- T cells, as well as the organ functions, were determined. Administration of parenteral Vit C per se markedly improved the outcome of sepsis and sepsis-induced MODS of WT and Gulo-/- mice. The negative immunoregulation of Tregs was inhibited, mainly including inhibiting the expression of forkhead helix transcription factor- (Foxp-) 3, cytotoxic T lymphocyte associated antigen- (CTLA-) 4, membrane associated transforming growth factor-β (TGF-βm+), and the secretion of inhibitory cytokines [including TGF-β and interleukin- (IL-) 10], as well as CD4+ T cells-mediated cellular immunosuppression which was improved by parenteral Vit C in WT and Gulo-/- septic mice. These results suggested that parenteral Vit C has the ability to improve the outcome of sepsis and sepsis-induced MODS and is associated with improvement in cellular immunosuppression.

https://www.ncbi.nlm.nih.gov/pubmed/28210072

Acta Pathol Microbiol Scand B. 1976 Oct;84B(5):280-4.
The effect of ascorbic acid on production of human interferon and the antiviral activity in vitro.
Dahl H, Degré M.

The effects of ascorbic acid on interferon production and on the antiviral effect of interferon in cultures of human cells were investigated. Ascorbic acid enhanced the interferon levels produced by human embryo skin and human embryo lung fibroblasts, induced by Newcastle disease virus and by polyinosinic-polycytidylic acid. The same concentrations of ascorbic acid had no effect on interferon production in two lymphoblastoid cell lines induced by Sendai virus. Leucocyte interferon assayed in lung fibroblasts titrated 0.2-0.3 log10 units higher in the presence of 5 mug ascorbic acid than in the absence of the latter.

https://www.ncbi.nlm.nih.gov/pubmed/970135

Genes Nutr. 2014 May;9(3):390.
Vitamin C supplementation modulates gene expression in peripheral blood mononuclear cells specifically upon an inflammatory stimulus: a pilot study in healthy subjects.
Canali R, Natarelli L, Leoni G, Azzini E, Comitato R, Sancak O, Barella L, Virgili F.

In order to study the effects of vitamin C supplementation on gene expression and compare its action between physiological and inflammatory conditions, a pilot study was set up utilizing microarray and qPCR technologies. Five healthy volunteers were supplemented with 1 g vitamin C (Redoxon(®)) per day for five consecutive days. Peripheral blood mononuclear cells (PBMNC) were isolated before and just after the last supplementation, and RNA was isolated for the Affymetrix gene 1.0 ST chip analysis. PBMNC were also, ex vivo, treated with LPS, and gene expression was quantified by means of a “Human NFkB Signaling” qPCR array. Only a very moderate effect on the baseline gene expression modulation was associated with vitamin C supplementation. However, in spite of the limited number of subjects analyzed, vitamin C supplementation resulted in a markedly different modulation of gene expression upon the inflammatory stimulus, specifically at the level of the MyD88-dependent pathway and of the anti-inflammatory cytokine IL-10 synthesis. This study suggests that vitamin C supplementation in healthy subjects, not selected according to a specific genetic profile, consuming an adequate amount of vitamin C, and having a satisfactory vitamin C plasma concentration at the baseline, does not result in a significant modification of gene expression profile. Under this satisfactory micronutrient status, supplementation of vitamin C is “buffered” within a homeostatic physiological equilibrium. Differently, following a second “hit” constituted of an inflammatory stimulus such as LPS, able to trigger a critical burst to the normal physiological state, the higher availability of ascorbic acid emerges, and results in a significant modulation of cell response.

https://www.ncbi.nlm.nih.gov/pubmed/24604612

J Biol Chem. 1993 Jul;268(21):15531-5.
Ascorbic acid recycling in human neutrophils.
Washko PW, Wang Y, Levine M.

Ascorbic acid (vitamin C) accumulation in activated human neutrophils is increased as much as 10-fold above the mM concentrations present in normal neutrophils. Internal concentrations as high as 14 mM are achieved when external vitamin is at physiologic concentration. The mechanism is by oxidation of external vitamin to dehydroascorbic acid, preferential transmembrane translocation of dehydroascorbic acid, and intracellular reduction to ascorbic acid within minutes. These data indicate that vitamin C accumulation is enhanced in activated human neutrophils and that human neutrophils utilize and recycle oxidized external vitamin C under physiologic conditions.

https://www.ncbi.nlm.nih.gov/pubmed/8340380

Br J Nutr. 2009 May;101(10):1432-9.
In vivo vitamin C supplementation increases phosphoinositol transfer protein expression in peripheral blood mononuclear cells from healthy individuals.
Griffiths HR, Willetts RS, Grant MM, Mistry N, Lunec J, Bevan RJ.

Ascorbate can act as both a reducing and oxidising agent in vitro depending on its environment. It can modulate the intracellular redox environment of cells and therefore is predicted to modulate thiol-dependent cell signalling and gene expression pathways. Using proteomic analysis of vitamin C-treated T cells in vitro, we have previously reported changes in expression of five functional protein groups associated with signalling, carbohydrate metabolism, apoptosis, transcription and immune function. The increased expression of the signalling molecule phosphatidylinositol transfer protein (PITP) was also confirmed using Western blotting. Herein, we have compared protein changes elicited by ascorbate in vitro, with the effect of ascorbate on plasma potassium levels, on peripheral blood mononuclear cell (PBMC) apoptosis and PITP expression, in patients supplemented with vitamin C (0-2 g/d) for up to 10 weeks to investigate whether in vitro model systems are predictive of in vivo effects. PITP varied in expression widely between subjects at all time-points analysed but was increased by supplementation with 2 g ascorbate/d after 5 and 10 weeks. No effects on plasma potassium levels were observed in supplemented subjects despite a reduction of K+ channel proteins in ascorbate-treated T cells in vitro. Similarly, no effect of vitamin C supplementation on PBMC apoptosis was observed, whilst ascorbate decreased expression of caspase 3 recruitment domain protein in vitro. These data provide one of the first demonstrations that proteomics may be valuable in developing predictive markers of nutrient effects in vivo and may identify novel pathways for studying mechanisms of action in vivo.

https://www.ncbi.nlm.nih.gov/pubmed/18947437

S Afr Med J. 1979 Sep;56(12):476-80.
Effects of ascorbate on leucocytes: Part IV. Increased neutrophil function and clinical improvement after oral ascorbate in 2 patients with chronic granulomatous disease.
Anderson R, Dittrich OC.

A brother and sister with chronic granulomatous disease (CGD) of the autosomal recessive type, and with markedly defective neutrophil motility and elevated serum IgE levels, were treated with a single oral daily dose of 1 g ascorbate for 6 months. Neutrophil function and serum IgE levels were measured repeatedly at approximately monthly intervals. Both children also received prophylactic antibiotics which were always stopped 1 week prior to testing of immune function. Ascorbate treatment was accompanied by significantly increased neutrophil motility and post-phagocytic metabolic activity, and a reduction in serum IgE levels. Enhanced neutrophil function correlated with clinical improvement. Both children have remained free of infection since ascorbate was added to their regimen and have gained weight.

https://www.ncbi.nlm.nih.gov/pubmed/550375

J Cell Physiol. 1979 Jul;100(1):119-26.
Enhancement of chemotactic response and microtubule assembly in human leukocytes by ascorbic acid.
Boxer LA, Vanderbilt B, Bonsib S, Jersild R, Yang HH, Baehner RL.

The incubation of human leukocytes with ascorbic acid increased chemotaxis of the cells. In addition, ascorbic acid promoted the assembly of intracellular polymorphonuclear leukocyte (PMN) with colchicine blocked the effect of ascorbic acid on promoting microtubule assembly. Not only did ascorbic acid promote the assembly of microtubules in vivo, but it enhanced the assembly of bovine brain tubulin into microtubules in vitro as quantitated by a glass-fiber filtration assay and by promotion of viscosity changes. The enhancement in leukocyte mobility by ascorbate at concentrations achievable in normal tissues correlates with its ability to assemble microtubule organelles.

https://www.ncbi.nlm.nih.gov/pubmed/468916

Acta Vitaminol Enzymol. 1982;4(1-2):163-8.
Effects of ascorbic acid on neutrophil function. Studies on normal and chronic granulomatous disease neutrophils.
Patrone F, Dallegri F, Bonvini E, Minervini F, Sacchetti C.

Ascorbic acid is able to stimulate neutrophil oxidative metabolism in normal neutrophils, as well as other several functions of these cells, either in the normal state or in the defective one. In the present study, we have investigated the effects of ascorbic acid on the hexose monophosphate shunt (HMPS) and on the bactericidal activity of neutrophils from Chronic Granulomatous Disease (CGD) patients. Furthermore, we have investigated the effects of ascorbic acid on the antibody dependent cell cytotoxicity (ADCC) of normal neutrophils. Ascorbic acid in vitro was able to significantly improve both HMPS activity and bacterial killing of CGD neutrophils. Its prolonged administration to such patients led to consistent clinical improvement, possibly related to the enhancement of chemotaxis, although the effects on HMPS and bacterial killing seen in vitro could not be confirmed. Ascorbic acid was also able to interfere with neutrophil ADCC with different results depending on its concentration and the experimental conditions.

https://www.ncbi.nlm.nih.gov/pubmed/7124564

Clin Exp Immunol. 1983 Jan;51(1):99-102.
Ascorbate (1g/day) does not help the phagocyte killing defect of X-linked chronic granulomatous disease.
Foroozanfar N, Lucas CF, Joss DV, Hugh-Jones K, Hobbs JR.

Three patients with X-linked chronic granulomatous disease of childhood (CGD) were treated with a single daily dose of 1 g of vitamin C over a period of 8 months. Prior to this clinical trial, isolated leucocytes from patients and normals were incubated with different concentrations of ascorbate and intracellular killing activity was investigated. Contrary to previous reports, there was no improvement of polymorphonuclear (PMN) intracellular killing activity after oral administration of ascorbate, nor could in vitro ascorbate correct defective, or enhance, killing activity of normal PMNs.

https://www.ncbi.nlm.nih.gov/pubmed/6339127

J Pulm Respir Med. 2014;4:6.
Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis
Natarajan R, Fisher BJ, Syed AA, Fowler AA.

Objective: Severe sepsis is a leading cause of mortality and morbidity in the critically ill with no reliably effective treatments. The goal of this study was to determine whether intravenous ascorbic acid impacted novel biomarkers in sepsis.
Methods: This is a retrospective study of a phase I, randomized, double-blinded, placebo controlled safety trial of intravenous ascorbic acid in severe sepsis. In the safety trial, 24 patients were randomized to receive full ICU standard of care support plus intravenous ascorbic acid (50 or 200 mg/kg/24h) for 4 days or placebo. Novel biomarkers of sepsis such as circulating cell free DNA (cf-DNA), mitochondrial DNA (mtDNA), endogenous antimicrobial proteins (alpha-4-defensin [α4D] and bactericidal permeability interacting protein [BPI]) and the red cell distribution width (RDW) were measured.
Results: Cf-DNA values were higher in non-survivors at baseline and remained elevated for 96 hours. MtDNA levels increased in the placebo group, but declined in the treatment groups without reaching statistical significance. RDW increased significantly only in the placebo group, while expression of the antimicrobial proteins increased significantly only in the treatment groups.
Conclusion: Ascorbic acid infusion may improve sepsis outcomes by reducing cf- and mtDNA levels while augmenting endogenous antimicrobial proteins and preserving RDW.

https://www.omicsonline.org/open-access/impact-of-intravenous-ascorbic-acid-infusion-on-novel-biomarkers-in-patients-with-severe-sepsis-2161-105X.1000214.php?aid=32719

Arch Biochem Biophys. 1995 Feb;317(1):208-14.
Ascorbic acid transport and distribution in human B lymphocytes.
Bergsten P, Yu R, Kehrl J, Levine M.

Ascorbic acid (vitamin C) transport was investigated in human B lymphocytes. The vitamin was transported by two components. The first was a high-affinity activity with an apparent Km of 7-10 microM and Vmax of 0.14 mM/h (3.11 x 10(-4) mumol x h-1 x mg protein-1). The activity was concentration and temperature dependent, saturable, and inhibited by carbonylcyanide-p-trifluoromethoxyphenylhydrazone and ouabain and generated ascorbic acid accumulation against a concentration gradient. Kinetics for the second component were indeterminate because ascorbate was not accumulated against a concentration gradient. Subcellular fractionation revealed that intracellular ascorbic acid in human B lymphocytes was > 90% localized to the cytosol and not protein bound. Kinetic parameters of high-affinity ascorbic acid transport could operate effectively with plasma concentrations normally found in humans.

https://www.ncbi.nlm.nih.gov/pubmed/7872786

Cytotherapy. 2015 May;17(5):613-20.
Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy.
Huijskens MJ, Walczak M, Sarkar S, Atrafi F, Senden-Gijsbers BL, Tilanus MG, Bos GM, Wieten L, Germeraad WT.

Background Aims: Natural killer (NK) cell-based immunotherapy is a promising treatment for a variety of malignancies. However, generating sufficient cell numbers for therapy remains a challenge. To achieve this, optimization of protocols is required.
Methods: Mature NK cells were expanded from peripheral blood mononuclear cells PBMCs in the presence of anti-CD3 monoclonal antibody and interleukin-2. Additionally, NK-cell progenitors were generated from CD34(+) hematopoietic stem cells or different T/NK-cell progenitor populations. Generated NK cells were extensively phenotyped, and functionality was determined by means of cytotoxicity assay.
Results: Addition of ascorbic acid (AA) resulted in more proliferation of NK cells without influencing NK-cell functionality. In more detail, PBMC-derived NK cells expanded 2362-fold (median, range: 90-31,351) in the presence of AA and were capable of killing tumor cells under normoxia and hypoxia. Moreover, hematopoietic stem cell-derived progenitors appeared to mature faster in the presence of AA, which was also observed in the NK-cell differentiation from early T/NK-cell progenitors.
Conclusions: Mature NK cells proliferate faster in the presence of phospho-L-AA, resulting in higher cell numbers with accurate functional capacity, which is required for adoptive immunotherapy.

https://www.ncbi.nlm.nih.gov/pubmed/25747742

Age Ageing. 1991 May;20(3):169-74.
The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial.
Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW.

Thirty elderly long-stay patients were randomly allocated to receive either placebo or dietary supplementation with vitamins A, C and E for 28 days. Nutritional status and cell-mediated immune function were assessed before and after the period of supplementation. Following vitamin supplementation, cell-mediated immune function improved as indicated by a significant increase in the absolute number of T cells (p less than 0.05), T4 subsets (p less than 0.05), T4 to T8 ratio (p less than 0.01) and the proliferation of lymphocytes in response to phytohaemagglutinin (p less than 0.01). In contrast, no significant changes were noted in the immune function of the placebo group. We conclude that supplementation with the dietary antioxidants vitamins A, C and E can improve aspects of cell-mediated immune function in elderly long-stay patients.

https://www.ncbi.nlm.nih.gov/pubmed/1853789

Vitam Miner. 2015 May;4:1–15.
Multivitamin supplementation supports immune function and ameliorates conditions triggered by reduced air quality.
Haryanto B, Suksmasari T, Wintergerst E, Maggini S.

Our bodies are normally well protected against continual attack from pathogens and noxious insult by a complex and integrated immune system. However, daily bombardment from indoor and outdoor air pollutants can compromise immune function and ultimately lead to infection (e.g. acute respiratory tract infections, diarrhoea) and conditions such as sick building syndrome (with mucosal, skin and general symptoms). All of us may be affected by reduced air quality, although certain factors increase the risk of impaired immunity (e.g. young or advancing age, exposure to tobacco smoke, close proximity to areas of high air pollution, office work, commuting). A major exogenous factor modulating immune function is nutrition; even subclinical deficiencies in various nutrients can have adverse effects on the immune system, which may be exacerbated by environmental threats. In particular, the oxidant-antioxidant balance (vital for communication within the immune system) may be affected. Dietary supplementation can help to restore immune function to the normal range, and an antioxidant-containing multivitamin supplement has been shown to ameliorate the symptoms of sick building syndrome, acute respiratory tract infections and diarrhoea. This review looks at the impact of reduced air quality on the oxidant-antioxidant balance and the role of selected micronutrients (vitamins A, D, E, C, B6, B12, folate and the trace elements copper, iron, selenium and zinc) and multivitamin supplementation.

https://www.omicsonline.org/open-access/multivitamin-supplementation-supports-immune-function-andameliorates-conditions-triggered-by-reduced-air-quality-2376-1318-1000128.php?aid=52511

Mater Sci Eng C Mater Biol Appl. 2020 May;110:110686.
Encapsulation of green tea polyphenol nanospheres in PVA/alginate hydrogel for promoting wound healing of diabetic rats by regulating PI3K/AKT pathway.
Chen G, He L, Zhang P, Zhang J, Mei X, Wang D, Zhang Y, Ren X, Chen Z.

Difficult healing of skin wounds is one of the serious complications of diabetes mellitus. Green tea polyphenols (TP) have been found to have good therapeutic effects on wounds healing. However, TP that is soluble in water and easily been oxidized requires a gel material that provides moisture retention, oxidation prevention, and sustained release of TP to achieve better wound healing effect. Therefore, in this work, novel tea polyphenol nanospheres (TPN) were synthesized and encapsulated in a PVA /alginate hydrogel (TPN@H). The prepared TPN@H was characterized and applicated in model diabetic rats for promoting wound healing and regulating immune response. Fourier-transform infrared spectroscopy (FT-IR), UV spectroscopy, scanning electron microscopy (SEM), atomic force microscope (AFM), confocal laser scanning microscopy (CLSM), dynamic light scattering (DLS) and differential scanning calorimetry (DSC) were used for characterization. Animal experiments and molecular mechanism research proved that TPN@H could promote wound healing of diabetic rats by regulating PI3K/AKT signaling pathway.

https://www.ncbi.nlm.nih.gov/pubmed/32204114

Endocr Metab Immune Disord Drug Targets. 2020 Mar. doi: 10.2174/1871530320666200313152648. [Epub ahead of print]
Red Grape Polyphenol Oral Administration improves Immune Response in Women Affected by Nickel-Mediated Allergic Contact Dermatitis.
Magrone T, Jirillo E, Magrone M, Russo MA, Romita P, Massari F, Foti C.

BACKGROUND: Our previous findings demonstrated that in vitro supplementation of polyphenols, extracted from seeds of red grape (Nero di Troia cultivar), to peripheral lymphomonocytes from patients affected by allergic contact dermatitis (ACD) to nickel (Ni) could reduce release of pro-inflammatory cytokines and nitric oxide (NO), while increasing levels of interleukin (IL)-10, an anti-inflammatory cytokine.

OBJECTIVE: To assess whether an intervention with oral administration of polyphenols leads to a reduction of peripheral biomarkers in ACD patients.

METHOD: At T0, 25 patients affected by ACD to Ni were orally administered with 300 mg polyphenols prodie extracted from seeds of red grape (Nero di Troia cultivar) (NATUR-OX®) for 3 months (T1). Other 25 patients affected by ACD to Ni received placebo only for the same period of time. Serum biomarkers were analyzed at T0 and T1. In both groups seven drop outs were recorded.

RESULT: At T1 in comparison to T0, in treated patients, values of IFN-γ, IL-4, IL-17, PTX3 and NO decreased, while IL-10 levels increased when compared with T0 values. Conversely, in placebo-treated patients no modifications of biomarkers were evaluated at T1.

CONCLUSION: Present laboratory data rely on the anti-oxidant, anti-inflammatory and anti-allergic properties of polyphenols.

https://www.ncbi.nlm.nih.gov/pubmed/32167433

Aging (Albany NY). 2020 Jan;12(1):8-34.
Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity.
Verdura S, Cuyàs E, Cortada E, Brunet J, Lopez-Bonet E, Martin-Castillo B, Bosch-Barrera J, Encinar JA, Menendez JA.

New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.

https://www.ncbi.nlm.nih.gov/pubmed/31901900

Front Immunol. 2020 Jan;10:2981.
The Regulation of Host Intestinal Microbiota by Polyphenols in the Development and Prevention of Chronic Kidney Disease.
Bao N, Chen F, Dai D.

Polyphenols are essential antioxidants in our regular diet, and have shown potential antibacterial effects. Other important biological effects, such as anticancer or antibacterial activities, have been demonstrated by some polyphenols. In recent years, the benefits of polyphenols to human health have attracted increasing attention from the scientific community. Recent studies have shown that polyphenols such as anthocyanin, catechin, chlorogenic acid, and resveratrol can inhibit pathogenic bacteria such as Escherichia coli and Salmonella to help regulate intestinal microflora. An imbalance of intestinal microflora and the destruction of intestinal barrier function have been found to have a potential relationship with the occurrence of chronic kidney disease (CKD). Specifically, they can aberrantly trigger the immune system to cause inflammation, increase the production of uremic toxins, and further worsen the condition of CKD. Therefore, the maintenance of intestinal microflora and the intestinal tract in a stable and healthy state may be able to “immunize” patients against CKD, and treat pre-existing disease. The use of common antibiotics may lead to drug resistance in pathogens, and thus beneficial polyphenols may be suitable natural substitutes for antibiotics. Herein we review the ability of different polyphenols, such as anthocyanin, catechin, chlorogenic acid, and resveratrol, to regulate intestinal microorganisms, inhibit pathogenic bacteria, and improve inflammation. In addition, we review the ability of different polyphenols to reduce kidney injury, as described in recent studies.

https://www.ncbi.nlm.nih.gov/pubmed/31969882

Recent Pat Inflamm Allergy Drug Discov. 2019;13(2):84-104.
Effects of Flavonoids and Its Derivatives on Immune Cell Responses.
Martínez G, Mijares MR, De Sanctis JB.

BACKGROUND: Various pieces of evidence have shown that people who consume foods rich in polyphenolic and flavonoids compounds have a lower incidence of inflammatory, autoimmune diseases and cancer.

OBJECTIVE: The study aimed to review the most potent compounds that affect the immune response and diseases associated with it.

METHODS: Publications in PubMed and EmBase, from 1974-2018, and patents form Free patents online, Scifinder, Espacenet and Mendeley in which flavonoids, their semi-synthetic and synthetic derivatives are involved in immunosuppressive or immunostimulatory responses in vitro and in vivo.

RESULTS: In vitro, flavonoids and their derivatives inhibit various transcriptional factors, which modulate differentiation, proliferation, activation of immune cells and enhance regulatory T cell generation. Some flavonoids exert anti-inflammatory effects through: Blockade of NF-κB, and NLRP3 inflammasome, inhibition of pro-inflammatory cytokine production, IL-1β, IL-2, IL-6, TNF-α, IL-17A, down regulation of chemokines, and reduction of reactive oxygen and nitrogen species. Nevertheless, several reports have shown that some flavonoids enhance immune response by enhancing: oxygen and nitrogen radicals, antibody production, cytotoxic activity against tumours by increasing activating receptors and down regulating inhibitory receptors. In consequence, flavonoids may be potentially useful for treatment of infectious diseases and cancer.

CONCLUSION: The most potent flavonoids in inflammation that modify immune responses are apigenin, quercetin and Epigallocatechin-3-Gallate (EGCG) although, other compounds are still under study and cannot be excluded. The most relevant patents concerning the use of flavones and other polyphenols were revised. A promising future of these compounds in different therapies is discussed.

https://www.ncbi.nlm.nih.gov/pubmed/31814545

Anticancer Agents Med Chem. 2019;19(10):1223-1231.
The Possibility of Preventive and Therapeutic Use of Green Tea Catechins in Prostate Cancer.
Rogovskii VS, Popov SV, Sturov NV, Shimanovskii NL.

BACKGROUND: Prostate cancer is one of the most frequent types of cancer. Despite the existence of various treatment strategies, treatment of prostate cancer still presents serious difficulties (especially in advanced stages). Polyphenols have been extensively assessed in terms of their potential use for prostate cancer treatment and prevention. Catechins are among the most well-known polyphenols in this respect.

OBJECTIVE: In this review, we summarize clinical study results concerning catechin applications with regard to prostate cancer treatment and prevention. We discuss some of the main mechanisms of the anticarcinogenic action of catechins.

CONCLUSION: The main mechanisms of the anticarcinogenic action of catechins are subdivided into two major types: (i) direct action on cancer cells and (ii) indirect effect based on catechins’s impact on the microenvironment of cancer cells, particularly in relation to the immune system. At this level catechins might reduce tumor-associated inflammation and immune tolerance.

https://www.ncbi.nlm.nih.gov/pubmed/30947675

Ecotoxicol Environ Saf. 2019 Oct;182:109425.
Resveratrol alleviates chronic “real-world” ambient particulate matter-induced lung inflammation and fibrosis by inhibiting NLRP3 inflammasome activation in mice.
Ding S, Wang H, Wang M, Bai L, Yu P, Wu W.

BACKGROUND: Inhalation of fine particulate matter (PM_2.5) induces the occurrence of lung inflammation and fibrosis, but its molecular mechanism remains unclear. Resveratrol (RES) is known to have anti-inflammatory properties in many pulmonary diseases. Here, we aimed to investigate the effect of long-term “real-world” ambient PM exposure on lung inflammation and fibrosis and further explore the protective effect and mechanism of RES.

METHODS AND RESULTS: RES (50 and 100 mg/kg.bw) was administered to C57BL/6J mice that were exposed to ambient PM for 5 months. The control group breathed filtered air without RES, and the PM group was exposed to PM without RES. The inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) and lung fibrosis were evaluated by enzyme-linked immune sorbent assay (ELISA) kits and Masson’s trichrome staining. The real-time PCR and Western blot analysis were used to determine the signal pathway. In vivo, PM exposure markedly elevated the levels of inflammatory cytokines and TGF-β1 in BALF, induced lung fibrosis. Meanwhile, PM exposure triggered autophagy process and activated the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in lung. Also, RES treatment abolished PM-induced lung inflammation and fibrosis, and inhibited autophagic process and NLRP3 inflammasome activation. In vitro, PM_2.5-induced cytotoxicity in BEAS-2B cells dose-dependently. Besides, RES alleviated PM_2.5-induced cytotoxicity, inhibited autophagic process and NLRP3 inflammasome activity and decreased IL-1β production in BEAS-2B cells.

CONCLUSION: Long-term PM exposure induced lung inflammation and fibrosis, and RES intervention alleviated these adverse effects via inhibiting autophagy-related NLRP3 inflammasome activation.

https://www.ncbi.nlm.nih.gov/pubmed/31295660

Eur J Nutr. 2019 Oct;58(7):2943-2957.
Diet Supplemented With Phytochemical Epigallocatechin Gallate and Probiotic Lactobacillus Fermentum Confers Second Generation Synbiotic Effects by Modulating Cellular Immune Responses and Antioxidant Capacity in Aging Mice.
Sharma R, Kumari M, Kumari A, Sharma A, Gulati A, Gupta M, Padwad Y.

Erratum in Correction to: Diet supplemented with phytochemical epigallocatechin gallate and probiotic Lactobacillus fermentum confers second generation synbiotic effects by modulating cellular immune responses and antioxidant capacity in aging mice. Sharma R, Kumari M, Kumari A, Sharma A, Gulati A, Gupta M, Padwad Y. Eur J Nutr. 2019 Oct;58(7):2959-2960.

Purpose: In the present study, we systematically identified and evaluated a synbiotic combination of phytochemical epigallocatechin gallate (EGCG) and probiotic bacteria in amelioration of immunosenescence and oxidative stress in aged mice.
Methods: Inhibitory effects of EGCG against different bacterial species were evaluated in vitro, followed by analysis to identify potential combination of EGCG and probiotic bacteria against alleviation of oxidative and inflammatory stress ex vivo. The best synbiotic combination, vis-à-vis prebiotic and probiotic supplementation alone, was then evaluated in aged Swiss albino mice for modulation of various immunological and antioxidative parameters.
Results: EGCG strongly inhibited the growth of pathogenic microbes as compared to probiotic bacteria. A combination of EGCG with probiotic Lactobacillus fermentum (LF) provided evidence of additive effects in the amelioration of oxidative and inflammatory stress-induced cell death. In vivo study revealed that combined supplementation of LF and EGCG significantly enhanced neutrophil oxidative index, CD3+ cell numbers and activation status, Th1/Th2 cytokines in splenic supernatants as well as liver Nrf-2 expression in comparison with treatments with LF or EGCG alone. The combined application of EGCG and LF did not simply result in additive or synergistic effects in relation with individual treatments.
Conclusion: These observations suggest that EGCG could be considered as a potential prebiotic that can offer second generation synbiotic health beneficial effects for the alleviation of some of the deleterious aspects of immunosenescence and aging.

https://pubmed.ncbi.nlm.nih.gov/30607562/?from_term=Antioxidant+and+Immune&from_filter=years.2000-2020&from_page=2&from_pos=9

Int Immunopharmacol. 2019 Aug;73:181-192.
The potential therapeutic benefit of resveratrol on Th17/Treg imbalance in immune thrombocytopenic purpura.
Guo NH, Fu X, Zi FM, Song Y, Wang S, Cheng J.

BACKGROUND: Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by the restrained production of new platelets and the persistent reduction of existing platelets. An imbalance between Th17 and Treg cells is associated with a decrease in platelets. However, few therapeutic strategies aim to modulate this imbalance between Th17 and Treg cells in ITP.

METHODS: ITP patients and healthy controls were enrolled in this study. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of the aryl hydrocarbon receptor (AhR), cytochrome P450 family 1 member A1 (CYP1A1), RAR-related orphan receptor gamma t (ROR-γt) and forkhead-box P3 (Foxp3). ELISA was employed to measure the secretion of IL-17A, IL-22 and IL-10. Flow cytometry was used to assess the proportion of Th17 and Treg cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to measure cell viability.

RESULTS: The proportion of Th17 cells and the secretion of the pro-inflammatory cytokines IL-17A and IL-22 were both elevated, whereas the proportion of Treg cells and the production of the anti-inflammatory cytokine IL-10 were both reduced in ITP patients compared to healthy controls. The ratio of Th17/Treg cells and the expression of IL-17A and IL-22 displayed a positive correlation with the severity of ITP. Low and moderate concentrations of resveratrol did not affect the viability of CD4⁺ T cells from ITP patients but repressed Th17 differentiation and promoted Treg differentiation. Moreover, resveratrol could markedly downregulate the production of IL-17A and IL-22 and upregulate the secretion of IL-10 in CD4⁺ T cells in a time- and concentration-dependent manner. Mechanistic studies revealed that resveratrol exerted its beneficial function mainly through suppressing the AhR pathway, which led to the impaired expression of ROR-γt and reduced secretion of IL-17A and IL-22, as well as enhanced expression of Foxp3 and augmented secretion of IL-10. The induction of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in CD4⁺ T cells led to a Th17/Treg imbalance and the upregulation of IL-17A and IL-22, an effect that could be reversed by resveratrol treatment.

CONCLUSION: This study revealed that resveratrol reversed the Th17/Treg imbalance by a mechanism involving the suppression of the AhR pathway. Since ITP is characterized by a Th17/Treg imbalance, resveratrol might be beneficial for the treatment of this condition.

https://www.ncbi.nlm.nih.gov/pubmed/31102993

Life Sci. 2019 Aug;230:208-217.
Protective effect of a polyphenols-rich extract from Inonotus Sanghuang on bleomycin-induced acute lung injury in mice.
Su X, Liu K, Xie Y, Zhang M, Wang Y, Zhao M, Guo Y, Zhang Y, Wang J.

Mushroom Phellinus linteus (“Sanghuang” in Chinese) is a popular medicinal polypore used to treat several disorders through its various biological functions. Inonotus sanghuang is claimed to produce general immune-potentiating and strengthening, anti-inflammatory, anti-tumor and anti-microbial properties, but its effect on acute lung inflammation and oxidative stress are not clearly understood. To determine the effect and mechanism of the polyphenols-rich ethyl acetate fraction from wild I. sanghuang extract (ISE) on acute lung injury (ALI) induced by bleomycin (BLM), female C57BL/6 mice were fed ISE (0%, 0.15% or 0.6% in diet) for 4 weeks prior to challenge with BLM. Bronchoalveolar lavage fluid (BALF) from lung, spleen and lung tissues were collected on day 3 after BLM challenge for histological, oxidative stress, molecular and biochemical analysis. ISE supplementation improved pathological features in lung injury scores and reduced lung wet-to-dry ratios. Moreover, ISE reduced inflammatory cell infiltration and the pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α in BALF, decreased the MPO activity and the MDA level and increased the SOD, CAT and GSH-Px activities in lung tissue homogenates. Further mechanism analysis demonstrated that dietary ISE inhibited NF-κB signal. Finally, peripheral immune function analysis showed that ISE had less effect on immune response including splenocyte producing inflammatory cytokines and T cell proliferation except for IL-1β and IL-2. Our findings indicate the possibility that dietary ISE attenuates ALI induced by BLM through correcting the inflammation and oxidation balance at least in part via inhibiting NF-κB signal in vivo, suggesting that ISE might be a valuable medicinal food effective in improving lung injury.

https://www.ncbi.nlm.nih.gov/pubmed/31152815

Nutrients. 2018 Nov;10(11). pii: E1618.
The Immunomodulatory and Anti-Inflammatory Role of Polyphenols.
Yahfoufi N, Alsadi N, Jambi M, Matar C.

This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. They inactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll-like receptor (TLR) and pro-inflammatory genes’ expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions.

https://www.ncbi.nlm.nih.gov/pubmed/30400131

Int J Mol Sci. 2018 Oct;19(10). pii: E3058.
Resveratrol Attenuates Staphylococcus Aureus-Induced Monocyte Adhesion through Downregulating PDGFR/AP-1 Activation in Human Lung Epithelial Cells.
Lee IT, Lin CC, Yang CC, Hsiao LD, Wu MY, Yang CM.

Staphylococcus aureus (S. aureus) is a very common Gram-positive bacterium. It is widely distributed in air, soil, and water. S. aureus often causes septicemia and pneumonia in patients. In addition, it is considered to play a key role in mediating cell adhesion molecules upregulation. Resveratrol is a natural antioxidant with diverse biological effects, including the modulation of immune function, anti-inflammation, and cancer chemoprevention. In this study, we proved that S. aureus-upregulated vascular cell adhesion molecule-1 (VCAM-1) expression in human lung epithelial cells (HPAEpiCs) was inhibited by resveratrol. We also observed that resveratrol downregulated S. aureus-enhanced leukocyte count in bronchoalveolar lavage (BAL) fluid in mice. In HPAEpiCs, S. aureus stimulated c-Src, PDGFR, p38 MAPK, or JNK1/2 phosphorylation, which was inhibited by resveratrol. S. aureus induced the adhesion of THP-1 cells (a human monocytic cell line) to HPAEpiCs, which was also reduced by resveratrol. Finally, we found that S. aureus induced c-Src/PDGFR/p38 MAPK and JNK1/2-dependent c-Jun and ATF2 activation and in vivo binding of c-Jun and ATF2 to the VCAM-1 promoter, which were inhibited by resveratrol. Thus, resveratrol functions as a suppressor of S. aureus-induced inflammatory signaling, not only by inhibiting VCAM-1 expression but also by diminishing c-Src, PDGFR, JNK1/2, p38 MAPK, and AP-1 activation in HPAEpiCs.

https://www.ncbi.nlm.nih.gov/pubmed/30301269

Animal. 2017 May;11(5):771-777.
Effect of Dietary Supplementation of Grape Seed Extract on the Growth Performance, Lipid Profile, Antioxidant Status and Immune Response of Broiler Chickens.
Farahat MH, Abdallah FM, Ali HA, Hernandez-Santana A.

Grape seed extracts (GSE) contain several beneficial bioactive constituents; therefore, can be utilized as a potential feed additive in broiler chickens. An experiment was conducted to investigate the effect of supplementation of broiler chicken diets with GSE as a natural antioxidant at levels of 125, 250, 500, 1000 and 2000 ppm on the growth performance, serum lipid profile, liver glutathione-reduced, thigh muscle malondialdehyde and humoral immune response against Newcastle disease virus vaccines. This experiment was performed during the life-span of chickens from 0 to 42 days of age. The results of broilers fed on diet supplemented by GSE were compared with those fed on the basal diet (control) or the basal diet supplemented by butylated hydroxytoluene as a synthetic antioxidant (BHT, 125 ppm). No significant differences were observed in the growth performance, percent livability, total lipid, high and very low-density lipoprotein cholesterols when the use of GSE or BHT were compared with the control. Total cholesterol and low-density lipoprotein cholesterol were significantly decreased after intake of GSE compared with BHT in the feed diet. The glutathione-reduced level in liver tissues was significantly increased by inclusion of GSE, but not by BHT. Inclusion of GSE or BHT decreased significantly the malondialdehyde level found in meat tissue. The antibody titer against Newcastle disease virus vaccines was significantly elevated in 28 and 35-day-old broiler chickens fed with a diet supplemented with GSE or BHT, the former providing a higher response. It can be concluded that GSE can be used as an effective natural antioxidant and immunostimulant agent in broiler chicken diets, and that 125 to 250 ppm can be considered as the optimum dosage.

https://pubmed.ncbi.nlm.nih.gov/27804907/?from_term=Antioxidant+and+Immune&from_filter=years.2000-2020&from_page=3&from_pos=6

Oxid Med Cell Longev. 2017;2017:9210862.
Immune Profile of Obese People and In Vitro Effects of Red Grape Polyphenols on Peripheral Blood Mononuclear Cells.
Magrone T, Jirillo E, Spagnoletta A, Magrone M, Russo MA, Fontana S, Laforgia F, Donvito I, Campanella A, Silvestris F, De Pergola G.

Erratum in
Corrigendum to “Immune Profile of Obese People and In Vitro Effects of Red Grape Polyphenols on Peripheral Blood Mononuclear Cells”. [Oxid Med Cell Longev. 2017]

The in vitro ability of polyphenols, extracted from red grape, to modulate peripheral blood mononuclear cell responses has been evaluated in 20 obese (Ob) people. With regard to cytokine release in response to phorbol myristate acetate (PMA), levels of interleukin-2 (IL-2), interferon-γ (IFN-γ), IL-4, IL-10, and IL-17 were higher in the Ob than in healthy (H) subjects. Vice versa, IL-21 concentrations were detected only in H people but they were undetectable in the Ob counterpart. In general terms, levels of IL-1β, IL-6, IL-8, and tumor necrosis factor-α were higher in Ob people when compared to H controls. On the other hand, polyphenols did not modify IFN-γ, IL-4, and IL-17 levels. However, an increase in IL-2 was observed in H individuals, whereas its levels were decreased in the Ob counterpart. Polyphenols significantly increased IL-10 release from H donors, whereas a trend to increase was observed in Ob people. In addition, polyphenols were able to significantly increase levels of H IL-21, while this was not the case in Ob people. Since IL-21 is an inducer of Th17 cells, it is likely that polyphenols may suppress the sources of this cytokine via production of IL-10. Accordingly, polyphenols decreased IL-1β and IL-6 release in comparison to H controls.

https://www.ncbi.nlm.nih.gov/pubmed/28243360

Biofactors. 2016 Jul;42(4):418-30.
Curcuma longa polyphenols improve insulin-mediated lipid accumulation and attenuate proinflammatory response of 3T3-L1 adipose cells during oxidative stress through regulation of key adipokines and antioxidant enzymes.
Septembre-Malaterre A, Le Sage F, Hatia S, Catan A, Janci L, Gonthier MP.

Plant polyphenols may exert beneficial action against obesity-related oxidative stress and inflammation which promote insulin resistance. This study evaluated the effect of polyphenols extracted from French Curcuma longa on 3T3-L1 adipose cells exposed to H2 O2 -mediated oxidative stress. We found that Curcuma longa extract exhibited high amounts of curcuminoids identified as curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exerted free radical-scavenging activities. Curcuma longa polyphenols improved insulin-mediated lipid accumulation and upregulated peroxisome proliferator-activated receptor-gamma gene expression and adiponectin secretion which decreased in H2 O2 -treated cells. Curcuminoids attenuated H2 O2 -enhanced production of pro-inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nuclear factor κappa B. Moreover, they reduced intracellular levels of reactive oxygen species elevated by H2 O2 and modulated the expression of genes encoding superoxide dismutase and catalase antioxidant enzymes. Collectively, these findings highlight that Curcuma longa polyphenols protect adipose cells against oxidative stress and may improve obesity-related metabolic disorders.

https://www.ncbi.nlm.nih.gov/pubmed/27094023

Immunol Cell Biol. 2016 Feb;94(2):117-23.
Immunological aspects of sport nutrition.
Gleeson M.

Prolonged bouts of exercise and heavy training regimens are associated with depression of immune system functions that can increase the risk of picking up opportunistic infections such as the common cold and influenza. Some common sport nutrition practices including high-carbohydrate diets and carbohydrate ingestion during exercise, training with low-glycogen stores, intentional dieting for weight loss, ingestion of high-dose antioxidant supplements and protein ingestion post exercise may influence immune system status in athletes. In order to maintain robust immunity, athletes need to consume a well-balanced diet that is sufficient to meet their requirements for energy, carbohydrate, protein and micronutrients. Dietary deficiencies of protein and specific micronutrients are well known to be potential causes of immune dysfunction and an adequate intake of some essential minerals including iron and zinc and the vitamins A, D, E, B6 and B12 are important to maintain a healthy immune function. Vitamin D may be a particular concern as recent studies have emphasised its importance in limiting infection episode incidence and duration in both the general population and in athletes and many individuals exhibit inadequate vitamin D status during the winter months. There is only limited evidence that individual amino acids, β-glucans, herbal extracts and zinc are capable of boosting immunity or reducing infection risk in athletes. The ingestion of carbohydrate during exercise and daily consumption of probiotics, vitamin D3, bovine colostrum and plant polyphenol containing supplements or foodstuffs currently offer the best chance of success, particularly for those individuals who are prone to illness.

https://www.ncbi.nlm.nih.gov/pubmed/26634839

Br J Nutr. 2010 Oct;104(8):1156-64.
Immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold: a double-blind, randomised, placebo-controlled, multi-centric clinical study.
Schütz K, Sass M, de With A, Graubaum HJ, Grünwald J.

In the present study, the immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold was evaluated. For this purpose, ninety-eight patients reporting common cold symptoms that began no longer than 24 h before the study intervention were randomly assigned to consume either the test beverage or placebo twice per d for 10 d. The severity of the disease was expressed as the total score of the five cold symptoms ‘general feeling of sickness’, ‘headache and/or joint aches’, ‘sore throat and/or difficulty swallowing’, ‘hoarseness and/or cough’ and ‘stuffy nose/sniffle’. Consequently, the decrease from 10.2 (sd 3.1) points at the beginning to 2.1 (sd 2.7) points by the end of the study in the verum group demonstrated a clear improvement, whereas in the placebo group only a reduction from 10.5 (sd 3.0) to 6.3 (sd 3.8) points could be observed. The mean difference between the groups (primary efficacy criterion) of 3.9 points was highly significant (P < 0.01). At the end of the study there were highly significantly (P < 0.01) more patients in the verum group complaint free than in the placebo group (secondary efficacy criterion). In addition to these self-reported values, several local findings of the physical examination were also significantly improved in the verum group.

https://www.ncbi.nlm.nih.gov/pubmed/20487584

Nutrition. 2009 May;25(5):499-505.
Regulatory effects of a fermented food concentrate on immune function parameters in healthy volunteers.
Schoen C, Schulz A, Schweikart J, Schütt S, von Baehr V.

OBJECTIVE: Nutrition is known to influence the immune system and can thereby modulate resistance to infection. The objective of this clinical trial was to assess the influence of a cascade-fermented food consisting of fruits, nuts, and vegetables rich in polyphenols (Regulat) on the immune system in healthy volunteers.

METHODS: The clinical trial was double-blinded and placebo-controlled. In total, 48 healthy men 20-48 y of age with a body mass index of 20-28 kg/m(2) were enrolled in the clinical trial. The group was characterized according to lifestyle parameters and only men with regular low to moderate intake of fruit and vegetables were enrolled. The intervention lasted for a period of 4 wk. Volunteers received Regulat twice daily or a placebo product (essence of vinegar).

RESULTS: The intake of Regulat significantly enhanced intracellular glutathione content in lymphocytes (P < 0.05), monocytes (P < 0.05), and natural killer cells (P < 0.01). Furthermore, activation of natural killer cell cytotoxicity in response to interleukin-2 stimulation (P < 0.05), a reduction of total lipid peroxidation, and a reduction of soluble vascular cell adhesion molecule-1 (P < 0.01) and soluble intercellular adhesion molecule-1 (P < 0.05) as inflammatory blood markers were found in the Regulat but not in the placebo group.

CONCLUSION: In summary, the results from this intervention study demonstrate promising physiologic effects of immune regulation on the innate immune system and antioxidative and anti-inflammatory parameters after Regulat supplementation. However, these promising results need to be confirmed in more volunteers with a more prolonged application to ensure significant beneficial effects of Regulat in the general population.

https://www.ncbi.nlm.nih.gov/pubmed/19121921

Eur J Nutr. 2006 Dec;45(8):428-38.
Diet supplementation for 5 weeks with polyphenol-rich cereals improves several functions and the redox state of mouse leucocytes.
Alvarez P, Alvarado C, Mathieu F, Jiménez L, De la Fuente M.

BACKGROUND: Cereals naturally contain a great variety of polyphenols, which exert a wide range of physiological effects both in vitro and in vivo. Many of their protective effects, including an improvement of the function and redox state of immune cells in unhealthy or aged subjects come from their properties as powerful antioxidant compounds. However, whether cereal-based dietary supplementation positively affects the immune function and cellular redox state of healthy subjects remains unclear.

AIM OF THE STUDY: To investigate the effects of supplementation (20% wt/wt) for 5 weeks with four different cereal fractions on healthy mice.

METHODS: Several parameters of function and redox state of peritoneal leukocytes were measured. The cereals, named B (wheat germ), C (buckwheat flour), D (fine rice bran) and E (wheat middlings) contained different amounts of gallic acid, p-hydroxybenzoic acid, vanillic acid, sinapic acid, p-coumaric acid, ferulic acid, quercetin, catechin, rutin and oryzanol as major polyphenols.

RESULTS: In general, all cereal fractions caused an improvement of the leukocyte parameters studied such as chemotaxis capacity, microbicidal activity, lymphoproliferative response to mitogens, interleukin-2 (IL-2) and tumor necrosis factor (TNFalpha) release, as well as oxidized glutathione (GSSG), GSSG/GSH ratio, catalase (CAT) activity and lipid oxidative damage. We observed similar effects among the cereal fractions.

CONCLUSIONS: The results suggest that some of these effects may due, at least partially, to the antioxidant activity of the polyphenols naturally present in cereals. Since an appropriate function of the leukocytes has been proposed as marker of the health state, a short-term intake of cereals seems to be sufficient to exert a benefit in the health of the general population. However, further studies are needed to assess the optimal doses and to find out which active polyphenols are able to mediate the observed physiological effects before recommending their regular consumption.

https://www.ncbi.nlm.nih.gov/pubmed/17036262

Nutr J. 2006 Nov;5:28.
Effect of a mixture of micronutrients, but not of bovine colostrum concentrate, on immune function parameters in healthy volunteers: a randomized placebo-controlled study.
Wolvers DA, van Herpen-Broekmans WM, Logman MH, van der Wielen RP, Albers R.

BACKGROUND: Supplementation of nutritional deficiencies helps to improve immune function and resistance to infections in malnourished subjects. However, the suggested benefits of dietary supplementation for immune function in healthy well nourished subjects is less clear. Among the food constituents frequently associated with beneficial effects on immune function are micronutrients such as vitamin C, vitamin E, beta-carotene and zinc, and colostrum. This study was designed to investigate the effects these ingredients on immune function markers in healthy volunteers.

METHODS: In a double-blind, randomized, parallel, 2*2, placebo-controlled intervention study one hundred thirty-eight healthy volunteers aged 40-80 y (average 57 +/- 10 y) received one of the following treatments: (1) bovine colostrum concentrate 1.2 g/d (equivalent to approximately 500 mg/d immunoglobulins), (2) micronutrient mix of 288 mg vitamin E, 375 mg vitamin C, 12 mg beta-carotene and 15 mg zinc/day, (3) combination of colostrum and micronutrient mix, or (4) placebo. Several immune function parameters were assessed after 6 and 10 weeks. Data were analyzed by analysis of variance. Groups were combined to test micronutrient treatment versus no micronutrient treatment, and colostrum treatment versus no colostrum treatment.

RESULTS: Overall, consumption of the micronutrient mix significantly enhanced delayed-type hypersensitivity (DTH) responses (p < 0.05). Adjusted covariance analysis showed a positive association between DTH and age. Separate analysis of younger and older age groups indicated that it was the older population that benefited from micronutrient consumption. The other immune function parameters including responses to systemic tetanus and oral typhoid vaccination, phagocytosis, oxidative burst, lymphocyte proliferation and lymphocyte subset distribution were neither affected by the consumption of micronutrients nor by the consumption of bovine colostrum concentrate.

CONCLUSION: Consumption of bovine colostrum had no effect on any of the immune parameters assessed. The micronutrient mix enhanced cellular immunity as measured by DTH, with an increased effect by incremental age, but did not affect any of the other immune parameters measured. Although correlations between decreased DTH and enhanced risk of certain infection have been reported, it remains unclear whether and enhanced DTH response actually improves immune defense. The present data suggests that improvement of immune parameters in a population with a generally good immune and nutritional status is limited and that improvement of immune function in this population may be difficult.

https://www.ncbi.nlm.nih.gov/pubmed/17118191

Nutrition. 2006 Sep;22(9):913-21.
Improvement of leukocyte functions in prematurely aging mice after five weeks of diet supplementation with polyphenol-rich cereals.
Alvarez P, Alvarado C, Puerto M, Schlumberger A, Jiménez L, De la Fuente M.

OBJECTIVE: We investigated the beneficial effects of diet supplementation with two types of cereals naturally rich in polyphenolic compounds on several functions of peritoneal leukocytes from prematurely aging mice (PAM).

METHODS: Two-hundred sixty healthy mice, 8 wk of age, were recruited and their behavioral responses were tested in a simple T-maze to identify PAM. Then the mice were fed a diet supplemented with 20% (wt/wt) of two different cereal fractions, named B (wheat germ) and C (buckwheat flour), rich in polyphenols (gallic acid, catechin, p-hydroxybenzoic acid, vanillic acid, p-coumaric acid, sinapic acid, ferulic acid, quercetin, and rutin), or a standard diet (controls) for 5 wk. Several parameters of innate (adherence to tissues, chemotaxis, phagocytosis, microbicidal capacity, and natural killer activity) and acquired immune (lymphoproliferation and interleukin-2 release) responses were measured.

RESULTS: The PAM control group showed worse immune functions (P < 0.001 to 0.05) compared with the non-PAM control group. The PAM group that received cereal B showed increases in phagocytosis (P < 0.01), microbicidal activity (P < 0.001 to 0.01), natural killer activity (P < 0.001) and lymphoproliferation in response to lipopolysaccharide (P < 0.01) and interleukin-2 release (P < 0.001), and the PAM group that received cereal C showed a similar pattern, with increases in macrophage chemotaxis (P < 0.01), phagocytosis (P < 0.01), microbicidal activity (P < 0.001 to 0.01), natural killer activity (P < 0.01), lymphoproliferative response to concanavalin A and lipopolysaccharide (P < 0.001), and interleukin-2 release (P < 0.001).

CONCLUSIONS: Dietary supplementation with polyphenol-rich cereals appears to have a protective effect on immune cell functions in mice with premature senescence. Thus, regular intake of these compounds could delay normal aging and improve quality of life.

https://www.ncbi.nlm.nih.gov/pubmed/16809023

Phytother Res. 2006 Jan;20(1):53-7.
Prevention of oxidative injury by flavonoids from stems and leaves of Scutellaria baicalensis Georgi in PC12 cells.
Shang YZ, Qin BW, Cheng JJ, Miao H.

Reactive oxygen species (ROS) are important mediators in a number of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The neuroprotective effects of flavonoids from the stems and leaves of Scutellaria baicalensis Georgi (SSF) against hydrogen peroxide (H2O2)-induced rat pheochromocytoma line PC12 injury were evaluated by cell lesion, free radicals and ATPase disorders. Following a 30 min exposure of the cells to H2O2 (100 microm), a marked decrease in cell survival and activity of superoxide dismutase (SOD) and Na+-K+-ATPase as well as an increase of malondialdehyde (MDA) production and lactate dehydrogenase (LDH) release were observed. Pretreatment of the cells with SSF (18-76 microg/mL) prior to H2O2 exposure notably elevated the cell survival and activity of SOD and Na+-K+-ATPase, and lowered the MDA level and LDH release. Neuroprotection by SSF was also observed in animal models. The present results indicated that SSF exerts neuroprotective effects against H2O2 toxicity, which might be of importance and might contribute to its clinical efficacy for the treatment of neurodegenerative disease.

https://www.ncbi.nlm.nih.gov/pubmed/16397922

Fish Shellfish Immunol. 2020 Mar;100:418-426.
Assessment of chemical, biological and immunological properties of “Damiana de California” Turnera diffusa Willd extracts in Longfin yellowtail (Seriola rivoliana) leukocytes.
Reyes-Becerril M, Ginera P, Silva-Jara J, Macias A, Velazquez-Carriles C, Alcaraz-Meléndez L, Angulo C.

In Mexican herbal medicines or natural remedies, Turnera diffusa (Turneraceae) known as “Damiana de California”, has ethnopharmacological relevance, including aphrodisiac, diuretic, and antimicrobial activities. To explore the immunological effect of infusion and methanolic extracts from Damiana de California, this study investigated its chemical, biological, antimicrobial and immunological properties in Longfin yellowtail Seriola rivoliana leukocytes. The analysis of chemical compounds revealed a considerable level of total phenolic and flavonoid contents in the infusion compared with methanolic extract. Furthermore, the antioxidant activity showed high hydroxyl radical scavenging activity in infusion extract compared with BHT positive control. Superoxide radical scavenging activity and ion chelation were higher in methanolic extract followed by infusion treatment. Interestingly, notable antimicrobial activity was observed in both extracts of T. diffusa against Vibrio parahaemolyticus. An in vitro study was performed using leukocytes of S. rivoliana treated with infusion or methanolic extracts at 12.5, 25 and 50 μg/mL for 24 h. Remarkably, infusion extract induced proliferation at any concentration but not the methanolic extract, which was diminished in a dose-dependent fashion. The immunostimulation study demonstrated that the phagocytosis activity increased in those leukocytes stimulated with methanolic extract but diminished the respiratory burst activity, in contrast to the activity observed in those leukocytes stimulated with infusion treatment. Finally, leukocytes incubated with the extracts and confronted with V.parahaemolyticus up-regulated the transcription of proinflammatory cytokine IL-1β gene in a dose response relationship. These findings suggest that the infusion treatment has potential therapeutic properties, promoting the antioxidant capacity and enhancing immune parameters in Longfin yellowtail S. rivoliana.

https://www.ncbi.nlm.nih.gov/pubmed/32209397

Acta Odontol Scand. 2020 Mar 11:1-8.
Immune modulatory and antioxidant effects of locally administrated vitamin C in experimental periodontitis in rats.
Aytekin Z, Arabacı T, Toraman A, Bayır Y, Albayrak M, Üstün K.

Background: Vitamin C is an important water-soluble vitamin with antioxidant and immune-modulatory actions. The aim of this study was to investigate the effects of locally applied vitamin C on alveolar bone resorption in rats with experimental periodontitis.Methods: Twenty-one male Sprague-Dawley rats divided into three groups with seven animals in each group: (1) control, (2) experimental periodontitis and 3) experimental periodontitis-local vitamin C treatment group. After ligature was removed, 50 μL vitamin C was locally administered into the subperiosteum of the buccal gingiva of periodontitis vitamin C (PvitC) group rats for three times in intervals of 2 days. At the end of the study, the animals were scarified, and serum and gingival samples were collected for analysis of serum IL-1β, oxidative stress index (OSI), CTX and malondialdehyde (MDA) levels and gingival MMP-8 immunostaining. Alveolar bone loss and attachment loss were determined based on measurements on histological sections obtained from rat mandibles.Results: Serum MDA and OSI levels which are related to the oxidative stress were significantly lower in the PvitC group as compared with those in the P group (p < .05). Serum CTX levels which are related to the bone resorption were significantly lower in the PvitC group as compared with those in the P group (p < .05). The numeric density of MMP-8-positive cells was significantly lower in the PvitC group compared to P group (p < .05). Alveolar bone loss and attachment loss were significantly lower in the PvitC group compared to P group (p < .05)Conclusions: The local vitamin C administration provided protection against inflammation-induced alveolar bone resorption by decreasing oxidative stress and inflammation-induced tissue breakdown vitamin C may be a therapeutic agent that can be used in periodontitis treatment.

https://www.ncbi.nlm.nih.gov/pubmed/32157939

J Food Biochem. 2020 Mar:e13219.
Immunomodulatory effect of curcumin on hepatic cirrhosis in experimental rats.
Abo-Zaid MA, Shaheen ES, Ismail AH.

Cirrhosis is a chronic liver disease. The present work aimed to evaluate the regulatory immune effect of curcumin in hepatic cirrhosis induced by carbon tetrachloride (CCl4) injections in experimental rats’ model. Chronic liver fibrosis was induced in experiment animals by recurrent injections of CCl4 for more than 5 weeks. They were divided into five groups: first group was injected with normal saline, second group with CCl4, third, fourth, and fifth groups were injected with CCl4 (intraperitoneal injection) at dose 3 ml/kg, two times weekly for 6 weeks supplemented with the administration of curcumin with concentrations 250, 200, and 150 mg/kg. Immune response was analyzed to different treatments. Interleukin 10 (IL-10), pro-inflammatory cytokines TNF-α, TGF-1β, and liver histopathological examinations were conducted. The results showed that estimations of IL-10 concentrations were significantly increased in curcumin groups compared with CCl4 group, whereas TNF-α and TGF-1β levels were significantly decreased comparing with CCl4 group. The histopathological examinations for liver tissues showed that curcumin treated groups have almost retained the normal structure of liver tissues. In conclusion, curcumin inhibited hepatic fibrosis and liver fibrogenesis with regulation of the immune system mechanism against invader chemical toxicity. PRACTICAL APPLICATIONS: Curcumin is well documented for its medicinal properties, commonly used as a spice. Our work has thus demonstrated its effectiveness as an immunomodulatory agent. Practically, clinical studies have suggested that curcumin displays a diverse and powerful array of pharmacological effects in nearly all of the human body’s major organ systems. These are: antidiabetes, anti-inflammatory, anticancer, antiaging, antioxidant, antibacterial infection, hepatoprotective, neurodegenerative, and cardiovascular effects.

https://www.ncbi.nlm.nih.gov/pubmed/32215945

J Ethnopharmacol. 2020 Feb;254:112714.
Hepatoprotective effect of total flavonoids of Mallotus apelta (Lour.) Muell.Arg. leaf against carbon tetrachloride-induced liver fibrosis in rats via modulation of TGF-β1/Smad and NF-κB signaling pathways.
Zhang B, Lai L, Tan Y, Liang Q, Bai F, Mai W, Huang Q, Ye Y.

ETHNOPHARMACOLOGICAL RELEVANCE: The Mallotus apelta (Lour.) Muell.Arg. is a well-known traditional Chinese medicine (TCM) used for anti-inflammatory, hemostasis and chronic hepatitis.

AIM: The purpose of this study was to explore the antifibrotic effect of total flavonoids of Mallotus apelta leaf (TFM) and its potential mechanism.

METHODS: Hepatic fibrosis was induced by carbon tetrachloride (CCl₄) in rats. The CCl₄-induced rats received intragastric administration of colchicine (0.2 mg/kg per day), TFM (25, 50, 100 mg/kg per day) and the equal vehicle was given to normal rats. Pathological evaluation in hepatic tissue were examined by hematoxylin and eosin (HE) staining. And the levels of serum biochemical parameters were detected by automatic biochemical analysis. Meanwhile, the collagen deposition in liver was observed by staining with Masson’s trichrome. Collagenic parameters and inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA) kits. Additionally, corresponding assay kit was used to estimate the antioxidant enzyme and lipid peroxidation. In order to explore the potential mechanism of anti-fibrotic effects in TFM, the expressions of liver fibrosis related gene and protein were analyzed by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot.

RESULTS: The CCl₄-induced hepatic fibrosis were inhibited dose-dependently in rats by TFM. The results showed that the key hallmarks of liver injury including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin (ALB) and total protein (TP) in the serum were reversed in CCl₄-induced hepatic fibrosis rats which were treated by TFM. Furthermore, TFM significantly alleviates collagen accumulation and reduces the contents of hydroxyproline (Hyp), Type III precollagen (PC-III), collagen I (Col I), hyaluronic acid (HA) and laminin (LN). RT-PCR and Western blot results showed that TFM markedly inhibits liver fibrosis hallmark factor α-smooth muscle actin (α-SMA) expressions in CCl₄-induced hepatic fibrosis rats. Moreover, TFM alleviated the oxidative stress and lipid peroxidation in rats induced by CCl₄. TFM also attenuated the pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) via inhibiting nuclear factor-κB (NF-κB) activation. Meanwhile, transforming growth factor-β1 (TGF-β1)/Smad signaling pathway was inhibited by TFM treatment.

CONCLUSIONS: TFM can alleviate CCl₄-induced hepatic fibrosis in rats, which potential mechanism may be due to its ability of reducing ECM accumulation, improving antioxidant and regulating TGF-β1/Smad signaling pathways and NF-κB-dependent inflammatory response.

https://www.ncbi.nlm.nih.gov/pubmed/32105750

Antioxidants (Basel). 2019 Dec;9(1).
Recent Advances on the Anti-Inflammatory and Antioxidant Properties of Red Grape Polyphenols: In Vitro and In Vivo Studies.
Magrone T, Magrone M, Russo MA, Jirillo E.

In this review, special emphasis will be placed on red grape polyphenols for their antioxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of proinflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Additionally, the effects of red grape polyphenols will be analyzed in obesity, as a low-grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood-brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great antioxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites, and interaction with microbiota, deserve deeper studies.

https://www.ncbi.nlm.nih.gov/pubmed/31906123

Sci Rep. 2019 Nov;9(1):16134.
Protective effects of seaweed supplemented diet on antioxidant and immune responses in European seabass (Dicentrarchus labrax) subjected to bacterial infection.
Peixoto MJ, Ferraz R, Magnoni LJ, Pereira R, Gonçalves JF, Calduch-Giner J, Pérez-Sánchez J, Ozório ROA.

European seabass (Dicentrarchus labrax) production is often hampered by bacterial infections such as photobacteriosis caused by Photobacterium damselae subsp. piscicida (Phdp). Since diet can impact fish immunity, this work investigated the effect of dietary supplementation of 5% Gracilaria sp. aqueous extract (GRA) on seabass antioxidant capacity and resistance against Phdp. After infection, mortality was delayed in fish fed GRA, which also revealed increased lysozyme activity levels, as well as decreased lipid peroxidation, suggesting higher antioxidant capacity than in fish fed a control diet. Dietary GRA induced a down-regulation of hepatic stress-responsive heat shock proteins (grp-78, grp-170, grp-94, grp-75), while bacterial infection caused a down-regulation in antioxidant genes (prdx4 and mn-sod). Diet and infection interaction down-regulated the transcription levels of genes associated with oxidative stress response (prdx5 and gpx4) in liver. In head-kidney, GRA led to an up-regulation of genes associated with inflammation (il34, ccr9, cd33) and a down-regulation of genes related to cytokine signalling (mif, il1b, defb, a2m, myd88). Additionally, bacterial infection up-regulated immunoglobulins production (IgMs) and down-regulated the transcription of the antimicrobial peptide leap2 in head kidney. Overall, we found that GRA supplementation modulated seabass resistance to Phdp infection.

https://www.ncbi.nlm.nih.gov/pubmed/31695116

JCI Insight. 2018 Sep;3(18). pii: 122299.
Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity.
Pilipow K, Scamardella E, Puccio S, Gautam S, De Paoli F, Mazza EM, De Simone G, Polletti S, Buccilli M, Zanon V, Di Lucia P, Iannacone M, Gattinoni L, Lugli E.

Adoptive T cell transfer (ACT) immunotherapy benefits from early differentiated stem cell memory T (Tscm) cells capable of persisting in the long term and generating potent antitumor effectors. Due to their paucity ex vivo, Tscm cells can be derived from naive precursors, but the molecular signals at the basis of Tscm cell generation are ill-defined. We found that less differentiated human circulating CD8+ T cells display substantial antioxidant capacity ex vivo compared with more differentiated central and effector memory T cells. Limiting ROS metabolism with antioxidants during naive T cell activation hindered terminal differentiation, while allowing expansion and generation of Tscm cells. N-acetylcysteine (NAC), the most effective molecule in this regard, induced transcriptional and metabolic programs characteristic of self-renewing memory T cells. Upon ACT, NAC-generated Tscm cells established long-term memory in vivo and exerted more potent antitumor immunity in a xenogeneic model when redirected with CD19-specific CAR, highlighting the translational relevance of NAC as a simple and inexpensive method to improve ACT.

https://www.ncbi.nlm.nih.gov/pubmed/30232291

J Cosmet Dermatol. 2018 Jun;17(3):461-466.
Turmeric Tonic as a Treatment in Scalp Psoriasis: A Randomized Placebo-Control Clinical Trial.
Bahraini P, Rajabi M, Mansouri P, Sarafian G, Chalangari R, Azizian Z.

Background: Psoriasis is an autoimmune and recurrent chronic inflammatory skin disorder with a strong genetic basis. The characteristic features are hyperproliferation of keratinocytes, leading to redness, thickening, and scaling of the epidermis followed by itching and the appearance of lesions, which in most cases can affect the patients both medically and psychologically. The scalp is one of the most common sites for psoriasis. This condition is predominantly managed with steroids, which are associated with various side effects. Turmeric (Curcuma longa L.), a spice commonly used throughout the world, has been shown to exhibit anti-inflammatory, antimicrobial, antioxidant, and antineoplastic properties. It has been reported to exhibit inhibitory activity on potassium channels in T cells and plays a key role in psoriasis.
Aim: We were prompted to investigate the turmeric tonic as an immune modulation and anti-inflammatory therapy on scalp psoriasis.
Method: Forty patients with mild-to-moderate scalp psoriasis who fulfilled the inclusion criteria were randomly allocated into two groups. The case group received turmeric tonic twice a day for 9 weeks, whereas the other group received a placebo applied in the same manner. Patients were evaluated at the following points: baseline, weeks 3, 6, and 9. The dermatology life quality index (DLQI) questionnaire and PASI (psoriasis area & severity index) scores, as well as medical photos before, during and after treatment were also evaluated. The probable adverse effects were also recorded and reported.
Results: Compared to the placebo, turmeric tonic significantly reduced the erythema, scaling and induration of lesions (PASI score), and also improved the patients’ quality of life (P value < .05).
Conclusions: The clinical effects of turmeric tonic on scalp psoriasis were satisfactory overall. This formulation could be considered as a treatment for scalp psoriasis.

https://pubmed.ncbi.nlm.nih.gov/29607625/?from_term=Antioxidants+Immunity&from_filter=pubt.randomizedcontrolledtrial%2Cyears.1999-2020&from_page=2&from_pos=2

Environ Sci Pollut Res Int. 2017 Dec;24(34):26851-26857.
The Effect of Vitamin E, L-carnitine, and Ginger on Production Traits, Immune Response, and Antioxidant Status in Two Broiler Strains Exposed to Chronic Heat Stress.
Rehman ZU, Chand N, Khan RU.

The present study was designed to find the effect of natural and synthetic antioxidants on the performance of two broiler strains under high ambient temperature. A total of 320 day-old chicks of Hubbard and Cobb were reared for a period for 21 days under the same nutritional and management systems. On day 21 onward, one subgroup was kept as control while other subgroups were provided with vitamin E (250 mg/kg), ginger (2 g/kg), and L-carnitine (500 mg/kg) in basal diets. Body weight and feed conversion ratio (FCR) were significantly (P < 0.05) high in vitamin E-supplemented birds, while feed intake was significantly (P < 0.05) higher in L-carnitine supplemented birds irrespective of the strain. Antibody titer against infectious bursal disease (IBD) and paraoxonase (PON1) was significantly (P < 0.05) higher in vitamin E-supplemented birds compared to the other treatments. The number of heterophils and toal oxidant status (TOS) were significantly (P < 0.05) lower in vitamin E-supplemented birds. Blood glucose was significantly (P < 0.05) lower in vitamin E-supplemented birds, while total protein was significantly (P < 0.05) higher in vitamin E-supplemented group. In conclusion, the supplementation of vitamin E at the rate of 250 mg/kg improved the antioxidant status and immune response in the two broiler strains. Further, the two strains perform similarly in terms of performance and other health status parameters with no significant difference.

https://pubmed.ncbi.nlm.nih.gov/28963619/?from_term=Antioxidant+and+Immune&from_filter=years.2000-2020&from_page=3&from_pos=2

Biogerontology. 2017 Jun;18(3):367-382.
Consumption of Green Tea epigallocatechin-3-gallate Enhances Systemic Immune Response, Antioxidative Capacity and HPA Axis Functions in Aged Male Swiss Albino Mice.
Sharma R, Sharma A, Kumari A, Kulurkar PM, Raj R, Gulati A, Padwad YS.

The present investigation assessed the potential of green tea phytochemical epigallocatechin-3-gallate (EGCG) in alleviating age-associated aberrations in immunity, hypothalamus-pituitary-adrenal (HPA) axis and redox homeostasis using 16 months old male Swiss albino mice. Four groups of animals (n = 6 per group) were supplemented with either aqueous EGCG at 25, 50 and 100 mg/kg/animal or vehicle control for 6 weeks. A concurrent analysis of CD4+ and CD8+ lymphocytes in splenocytes, differential leucocyte population, T cell differentiation markers in peripheral blood mononuclear cells (PBMCs), neutrophil functions, immunoglobulins profile in intestine, circulatory HPA axis hormonal levels as well as inflammatory and oxidative stress in the liver was performed. We observed a remarkable increase in plasma dehydroepiandrosterone (DHEA) levels of 100 mg EGCG fed animals while eosinophils and monocytes counts in blood increased. EGCG consumption increased the fraction of CD3+CD8+ cells in splenocytes and CD28 expression on PBMCs. The immunoglobulins profile revealed decreased production of secretory IgA, IgE and IgG1/IgG2a ratio. Liver extracts showed increase in superoxide dismutase activity and total antioxidant capacity while lipid peroxidation along with inflammatory markers (IL-6 and TNF-α) decreased. Our results collectively show that EGCG consumption during aging strengthens systemic immunity by enhancing cellular immune response and simultaneously attenuating antibody response aided by an increase in adrenal DHEA production. Thus, consumption of green tea may be beneficial in alleviating some of the deleterious aspects of aging and immunosenescence in elderly.

https://pubmed.ncbi.nlm.nih.gov/28341876/

Pharmacol Res. 2017 May;119:303-312.
Anti-inflammatory and antioxidant effects of polyphenols extracted from Antirhea borbonica medicinal plant on adipocytes exposed to Porphyromonas gingivalis and Escherichia coli lipopolysaccharides.
Le Sage F, Meilhac O, Gonthier MP.

In obesity, gut microbiota LPS may translocate into the blood stream and then contribute to adipose tissue inflammation and oxidative stress, leading to insulin resistance. A causal link between periodontal infection, obesity and type 2 diabetes has also been suggested. We evaluated the ability of polyphenols from Antirhea borbonica medicinal plant to improve the inflammatory and redox status of 3T3-L1 adipocytes exposed to LPS of Porphyromonas gingivalis periodontopathogen or Escherichia coli enterobacteria. Our results show that LPS enhanced the production of Toll-like receptor-dependent MyD88 and NFκB signaling factors as well as IL-6, MCP-1, PAI-1 and resistin. Plant polyphenols reduced LPS pro-inflammatory action. Concomitantly, polyphenols increased the production of adiponectin and PPARγ, known as key anti-inflammatory and insulin-sensitizing mediators. Moreover, both LPS increased intracellular ROS levels and the expression of genes encoding ROS-producing enzymes including NOX2, NOX4 and iNOS. Plant polyphenols reversed these effects and up-regulated MnSOD and catalase antioxidant enzyme gene expression. Noticeably, preconditioning of cells with caffeic acid, chlorogenic acid or kaempferol identified among A. borbonica major polyphenols, led to similar protective properties. Altogether, these findings demonstrate the anti-inflammatory and antioxidant effects of A. borbonica polyphenols on adipocytes, in response to P. gingivalis or E. coli LPS. It will be of major interest to assess A. borbonica polyphenol benefits against obesity-related metabolic disorders such as insulin resistance in vivo.

https://www.ncbi.nlm.nih.gov/pubmed/28249816

J Dairy Res. 2017 Feb;84(1):8-13.
High concentration of vitamin E supplementation in sow diet during the last week of gestation and lactation affects the immunological variables and antioxidative parameters in piglets.
Wang L, Xu X, Su G, Shi B, Shan A.

An experiment was conducted to investigate the effects of a high concentration of vitamin E supplementation in sow diet during the last week of gestation and lactation on the performance, milk composition, and vital immunological variables and antioxidative parameters in sows and piglets. The experiment started on day 107 of gestation and lasted until the piglets were weaned on day 21 of lactation. 48 sows were divided into two groups and fed either a basal diet with 44 IU/kg of vitamin E or a basal diet supplemented with additional vitamin E, total content of 250 IU/kg. Sow milk and blood samples were obtained on day 0 (farrowing) and on day 21 of lactation. One 21-day-old piglet per litter was selected to collect plasma. Results showed that supplementation of the maternal diet with 250 IU/kg vitamin E improved the average daily gain (ADG) and weaning weight of piglets (P < 0·05), and the concentrations of immunoglobulin G (IgG) and immunoglobulin A (IgA) in sow plasma, colostrum and milk. The concentrations of fat in the colostrum and milk were significantly increased by supplementation with 250 IU/kg of vitamin E (P < 0·05). The level of plasma IgG, IgA, total antioxidant capacity (T-AOC) and catalase (CAT) were all higher (P < 0·05) in piglets from sows that were fed 250 IU/kg of vitamin E than in those from the control group. The high concentration of vitamin E supplementation to the sows enhanced the concentrations of α-tocopherol in the sow milk and plasma as well as piglet plasma (P < 0·05). In conclusion, the addition to the maternal diet of vitamin E at high concentration improved the weight of piglets at weaning, and enhanced humoral immune function and antioxidant activity in sows and piglets.

https://www.ncbi.nlm.nih.gov/pubmed/27834154

J Inflamm (Lond). 2015 Feb;12:10.
Antioxidant polyphenol-rich extracts from the medicinal plants Antirhea borbonica, Doratoxylon apetalum and Gouania mauritiana protect 3T3-L1 preadipocytes against H2O2, TNFα and LPS inflammatory mediators by regulating the expression of superoxide dismutase and NF-κB genes.
Marimoutou M, Le Sage F, Smadja J, Lefebvre d’Hellencourt C, Gonthier MP, Robert-Da Silva C.

BACKGROUND: Adipose cells responsible for fat storage are the targets of reactive oxygen species (ROS) like H2O2 and pro-inflammatory agents including TNFα and LPS. Such mediators contribute to oxidative stress and alter inflammatory processes in adipose tissue, leading to insulin resistance during obesity. Thus, the identification of natural compounds such as plant polyphenols able to increase the antioxidant and anti-inflammatory capacity of the body is of high interest. We aimed to evaluate the biological properties of polyphenol-rich extracts from the medicinal plants A. borbonica, D. apetalum and G. mauritiana on preadipocytes exposed to H2O2, TNFα or LPS mediators.

METHODS: Medicinal plant extracts were analysed for their polyphenol contents by Folin-Ciocalteu and UPLC-ESI-MS methods as well as for their free radical-scavenging activities by DPPH and ORAC assays. To assess the ability of polyphenol-rich extracts to protect 3T3-L1 preadipocytes against H2O2, TNFα or LPS mediators, several parameters including cell viability (MTT and LDH assays), ROS production (DCFH-DA test), IL-6 and MCP-1 secretion (ELISA) were evaluated. Moreover, the expression of superoxide dismutase, catalase and NF-κB genes was explored (RT-QPCR).

RESULTS: All medicinal plants exhibited high levels of polyphenols with free radical-scavenging capacities. Flavonoids such as quercetin, kaempferol, epicatechin and procyanidins, and phenolic acids derived from caffeic acid including chlorogenic acid, were detected. Polyphenol-rich plant extracts did not exert a cytotoxic effect on preadipocytes but protected them against H2O2 anti-proliferative action. Importantly, they down-regulated ROS production and the secretion of IL-6 and MCP-1 pro-inflammatory markers induced by H2O2, TNFα and LPS mediators. Such a protective action was associated with an increase in superoxide dismutase antioxidant enzyme gene expression and a decrease in mRNA levels of NF-κB pro-inflammatory transcription factor.

CONCLUSION: This study highlights that antioxidant strategies based on polyphenols derived from medicinal plants tested could contribute to regulate adipose tissue redox status and immune process, and thus participate to the improvement of obesity-related oxidative stress and inflammation.

https://www.ncbi.nlm.nih.gov/pubmed/25685071

Free Radic Res. 2014 Apr;48(4):387-401.
Evaluation of antioxidant properties of major dietary polyphenols and their protective effect on 3T3-L1 preadipocytes and red blood cells exposed to oxidative stress.
Hatia S, Septembre-Malaterre A, Le Sage F, Badiou-Bénéteau A, Baret P, Payet B, Lefebvre d’hellencourt C, Gonthier MP.

Obesity has been associated with a marked risk of metabolic diseases and requires therapeutic strategies. Changes in redox status with increased oxidative stress in adipose tissue have been linked with obesity-related disorders. Thus, the biological effect of antioxidants such as polyphenols is of high interest. We aimed to measure antioxidant capacities of 28 polyphenols representative of main dietary phenolic acids, flavonoids, stilbenes and curcuminoids. Then, 14 molecules were selected for the evaluation of their effect on 3T3-L1 preadipocytes and human red blood cells exposed to oxidative stress. Analysis of reducing and free radical-scavenging capacities of compounds revealed antioxidant properties related to their structure, with higher activities for flavonoids such as quercetin and epicatechin. Their effects on preadipocytes’ viability also depended on their structure, dose and time of exposure. Interestingly, most of the compounds exhibited a protective effect on preadipocytes exposed to oxidative stress, by reversing H₂O₂-induced anti-proliferative action and reactive oxygen species production. Polyphenols also exerted an anti-inflammatory effect on preadipocytes exposed to H₂O₂ by reducing IL-6 secretion. Importantly, such antioxidant and anti-inflammatory effects were observed in co-exposition (polyphenol and prooxidant during 24 h) or pretreatment (polyphenol during 24 h, then prooxidant for 24 h) conditions. Moreover, compounds protected erythrocytes from AAPH radical-induced lysis. Finally, these results led to demonstrate that antioxidant and anti-inflammatory properties of polyphenols may depend on structure, dose, time of exposure and cell conditioning with oxidative stress. Such findings should be considered for a better understanding of polyphenols’ benefits in strategies aiming to prevent obesity-related diseases.

https://www.ncbi.nlm.nih.gov/pubmed/24393006

Nutrition. 2006 Jul-Aug;22(7-8):767-77.
Dietary supplementation with antioxidants improves functions and decreases oxidative stress of leukocytes from prematurely aging mice.
Alvarado C, Alvarez P, Puerto M, Gausserès N, Jiménez L, De la Fuente M.

OBJECTIVES: Aging is accompanied by chronic inflammation and oxidative stress, which lead to a marked impairment of immune function and therefore increased mortality. This study assessed the effect of dietary supplementation, for 15 wk, with 5% and 20% (w/w) of biscuits enriched with nutritional doses of vitamins C and E, zinc, selenium, and beta-carotenes on function and oxidative stress parameters of peritoneal leukocytes from middle-aged, prematurely aging mice (PAM) and non-prematurely aging mice (NPAM).

METHODS: After supplementation we measured leukocyte functions (adherence, chemotaxis, phagocytosis, intracellular reactive oxygen species levels, lymphoproliferation, natural killer activity, and interleukin-2 release), antioxidant defenses (superoxide dismutase, glutathione peroxidase, and reduced glutathione), oxidant compounds (extracellular O(2)(-), glutathione disulfide, glutathione disulfide/reduced glutathione ratio, tumor necrosis factor-alpha, nitric oxide, and prostaglandin E(2)), and lipid and DNA oxidative damage, measured by malondialdehyde and 8-oxo,7,8-dihydro-2′-deoxyguanosine levels, respectively.

RESULTS: In general, leukocyte functions were improved and redox homeostasis was restored after intake of antioxidants. In consequence, malondialdehyde and 8-oxo,7,8-dihydro-2′-deoxyguanosine in PAM and NPAM were strikingly decreased after 5% and 20% supplementation (malondialdehyde, P < 0.001 in PAM; P < 0.01 in NPAM after both treatments; 8-oxo,7,8-dihydro-2′-deoxyguanosine, P < 0.01 after 5% supplementation and P < 0.001 after 20% supplementation in PAM and NPAM). Moreover, the effect of the antioxidants was stronger in PAM than in NPAM, and 20% supplementation was more effective than 5%.

CONCLUSION: Our data suggest that improvement of leukocyte function and restoration of redox balance after consumption of adequate levels of antioxidants from adulthood may be useful to attain healthy aging, especially in animals with premature aging.

https://www.ncbi.nlm.nih.gov/pubmed/16815491

Dev Comp Immunol. 2006;30(12):1168-80.
Oxidative stress in leukocytes from young prematurely aging mice is reversed by supplementation with biscuits rich in antioxidants.
Alvarado C, Alvarez P, Jiménez L, De la Fuente M.

Aging is associated with a progressive dysregulation of immune responses as a result of increased oxidative stress. Therefore, we have assessed the oxidative stress status of peritoneal leukocytes from young prematurely aging mice (PAM) as compared with non-prematurely aging mice (NPAM), as well as the effects on this oxidative stress of a dietary supplementation with biscuits rich in antioxidants (vitamin C, vitamin E, beta-carotenes, zinc and selenium). We found that, in the peritoneal leukocytes, the levels of several parameters of oxidation such as extracellular superoxide anion (O(2)(-)), Prostaglandin E(2) (PGE(2)), nitric oxide, oxidized glutathione (GSSG) and lipid peroxidation (malondialdehyde, MDA) were higher in PAM as compared with NPAM, whereas the antioxidant defences such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, as well as reduced glutathione (GSH) levels, were decreased. Consequently, young PAM showed an oxidative stress in their leukocytes, which is characteristic of mice of an older chronological age. Antioxidant diet supplementation was able to restore redox homeostasis, increasing the antioxidant and decreasing the oxidant levels. Accordingly, supplementation with adequate levels of antioxidants, from an early age, could be useful to preserve health, especially in prematurely aging populations.

https://www.ncbi.nlm.nih.gov/pubmed/16690124

J Immunol. 2005 Jun;174(12):7633-44.
Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells.
Tan PH, Sagoo P, Chan C, Yates JB, Campbell J, Beutelspacher SC, Foxwell BM, Lombardi G, George AJ.

Dendritic cells (DCs) are central to T cell immunity, and many strategies have been used to manipulate DCs to modify immune responses. We investigated the effects of antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) on DC phenotype and function. Vitamins C and E are both antioxidants, and concurrent use results in a nonadditive activity. We have demonstrated that DC treated with these antioxidants are resistant to phenotypic and functional changes following stimulation with proinflammatory cytokines. Following treatment, the levels of intracellular oxygen radical species were reduced, and the protein kinase RNA-regulated, eukaryotic translation initiation factor 2alpha, NF-kappaB, protein kinase C, and p38 MAPK pathways could not be activated following inflammatory agent stimulation. We went on to show that allogeneic T cells (including CD4(+)CD45RO, CD4(+)CD45RA, and CD4(+)CD25(-) subsets) were anergized following exposure to vitamin-treated DCs, and secreted higher levels of Th2 cytokines and IL-10 than cells incubated with control DCs. These anergic T cells act as regulatory T cells in a contact-dependent manner that is not dependent on IL-4, IL-5, IL-10, IL-13, and TGF-beta. These data indicate that vitamin C- and E-treated DC might be useful for the induction of tolerance to allo- or autoantigens.

https://www.ncbi.nlm.nih.gov/pubmed/15944264

J Nutr. 2000 Dec;130(12):2932-7.
Vitamin E supplementation improves cell-mediated immunity and oxidative stress of Asian men and women.
Lee CY, Man-Fan Wan J.

Vitamin E is an efficient antioxidant and a modulator of the immune system. Although racial differences in both baseline vitamin E level and immunologic subsets are known, no reliable data exist for the Asian population. Furthermore, the extent of the effect of alpha-tocopherol in protecting lymphocyte cells against oxidative stress and its association with cell-mediated immunity have not been elucidated. This study was undertaken to investigate the immunologic and antioxidant effects of vitamin E in healthy ethnic Chinese men and women. Volunteers < 35 y old (n = 26) were supplemented with 233 mg/d dl-alpha-tocopherol for 28 d. The in vitro proliferative response to phytohemagglutinin (PHA) or lipopolysaccharide (LPS) of T-lymphocytes was determined in the study group before and after vitamin E supplementation. Cell-mediated immunity subsets and hydrogen peroxide production in T-lymphocytes were investigated by flow cytometry. The oxidant-antioxidant balance in plasma and urine was studied by spectrophotometric and gas chromatography-mass selective detection methods. The antioxidant properties of vitamin E were established (P: < 0.01) by the elevation of plasma vitamin E, together with depression in both plasma malondialdehyde and urinary DNA adduct 8-hydroxy-2′-deoxyguanosine after supplementation. Our data suggest a specific requirement for vitamin E in total-T and T-helper cell proliferation. We present the first evidence of the beneficial effects of supplemental vitamin E in healthy Chinese individuals on cell-mediated immunity and oxidative stress.

https://www.ncbi.nlm.nih.gov/pubmed/11110849

Nutr. Res. 2000 Feb,20(2):281–296.
Long-term dietary antioxidant supplementation reduces production of selected inflammatory mediators by murine macrophages.
Beharka AA, Han SN, Adolfsson O, Wu D, Smith D, Lipman R, Cao G, Meydani M, Meydani SN.

Although macrophage (Mø)-derived compounds, including proinflammatory cytokines, prostaglandins (PG), and nitric oxide (NO), play important roles in host defense, excessive or inappropriate production of them has been implicated in the pathogenesis of a variety of inflammatory diseases. Aging is also associated with increased production of Mø compounds involved in inflammation. Short term dietary supplementation with selected antioxidants, such as glutathione (GSH) and vitamin E (E), has been shown to reduce age-related changes in Mø production of inflammatory compounds, but information is limited regarding the effects of long-term supplementation. Nor is information available on other less studied compounds with antioxidant properties, such as melatonin, strawberry extract, or combinations of compounds such as E + GSH. Therefore, we sought to determine if long term, from middle to old age, dietary supplementation of C57BL/6NCrlBR mice with E, GSH, E + GSH, melatonin or strawberry extract could modify age related changes in Mø production of pro- and anti-inflammatory compounds. Eighteen-month-old C57BL/6NCrlBR mice were fed one of the following six semi-synthetic diets for 6 months: 1) control (30 ppm vitamin E), 2) vitamin E supplemented (control + 470 ppm vitamin E), 3) glutathione (GSH) supplemented (control + 0.5% glutathione), 4) vitamin E and glutathione supplemented (control + 470 ppm vitamin E + 0.5% glutathione), 5) melatonin supplemented (control + 11 ppm melatonin), or 6) strawberry extract supplemented (control + 1% strawberry extract). Supplementation with vitamin E or melatonin, but not GSH, E + GSH, or strawberry extract, reduced (p<0.05) unstimulated IL-6 and PGE₂ production by peritoneal Mø. Because PGE₂ has been shown to modulate IL-6 production, the reduction in PGE₂ production by vitamin E and melatonin may be partially responsible for the reduction in unstimulated IL-6 production. LPS stimulation resulted in production of IL-1β, IL-6, IL-10, IL-12, IL-15, NO, PGE₂, and TNF-α by peritoneal or bone marrow (BM)-derived Mø. Of these, only NO production was modulated by antioxidant supplementation and then significantly by vitamin E only. Vitamin E supplementation reduced the age-related increase in inducible NO production by peritoneal Mø (p<0.05), but not by BM Mø. In conclusion, vitamin E modulated production of at least three, and melatonin modulated production of at least two, molecules produced by Mø, which are involved in a variety of age-associated chronic and acute inflammatory diseases. Further research is needed to determine the mechanisms and clinical benefits of E and melatonin-induced reduction in Mø inflammatory mediator production.

https://www.sciencedirect.com/science/article/pii/S0271531799001608

Mech Ageing Dev. 1997 Feb;93(1-3):59-77.
Macrophage prostaglandin production contributes to the age-associated decrease in T cell function which is reversed by the dietary antioxidant vitamin E.
Beharka AA, Wu D, Han SN, Meydani SN.

The aging process is associated with a decline in T cell-mediated immunity, including decreased interleukin (IL)-2 production and mitogen-induced T cell proliferation. Because macrophages (M phi) from old mice have higher production of prostaglandin (PG) E2 than young mice, and PGE2 has been shown to suppress T cell-mediated function, we hypothesized that increased production of PGE2 would contribute to decreased T cell function with aging and that decrease in PGE2 production by dietary antioxidants would enhance T cell-mediated function. Experiments were conducted in which combinations of purified M phi and T cells (> 95% pure) from young or old C57BL/6N1A mice were cultured together. Co-cultures containing T cells and M phi from old mice had reduced ConA-stimulated proliferation and IL-2 secretion than those consisting of T cells and M phi from young mice. Addition of M phi from old mice suppressed proliferation and IL-2 secretion by T cells from young mice. Likewise, T cells from old mice secreted more IL-2 when cultured with M phi from young mice compared to those cultured with M phi from old mice. Addition of PGE2, at concentrations produced by old M phi, decreased proliferation and IL-2 production by young but not old T cells. Neither addition of H2O2 at physiological levels, nor catalase changed the response of cultures from young or old mice. However, addition of indomethacin and the antioxidant nutrient vitamin E, both of which decreased PGE2 production, improved T cell proliferation and IL-2 production. These experiments demonstrate that increased production of PGE2 by M phi contributes to the age-associated decline in T cell function. Vitamin E improves T cell responsiveness in old mice mostly by reducing M phi PGE2 production, although a direct effect of vitamin E on T cells was also observed.

https://www.ncbi.nlm.nih.gov/pubmed/9089571

Br J Anaesth. 2003 Feb;90(2):221-32.
Oxidative stress and gene expression in sepsis.
Macdonald J, Galley HF, Webster NR.

Dysregulation of the immuno-inflammatory response, as seen in sepsis, may culminate in host cell and organ damage. Lipopolysaccharide from Gram-negative bacterial cell walls induces gene activation and subsequent inflammatory mediator expression. Gene activation is regulated by a number of transcription factors at the nuclear level, of which nuclear factor kappaB appears to have a central role. The redox (reduction-oxidation) cellular balance is important for normal cellular function, including transcription factor regulation. In sepsis, a state of severe oxidative stress is encountered, with host endogenous antioxidant defences overcome. This has implications for cellular function and the regulation of gene expression. This review gives an overview of the mechanisms by which transcription factor activation and inflammatory mediator overexpression occur in sepsis, together with the events surrounding the state of oxidative stress encountered and the effects on the host’s antioxidant defences. The effect of oxidative stress on transcription factor regulation is considered, together with the role of antioxidant repletion in transcription factor activation and in sepsis in general. Other interventions that may modulate transcription factor activation are also highlighted.

https://www.ncbi.nlm.nih.gov/pubmed/12538380

J Immunol. 2005 Jun;174(12):7633-44.
Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells.
Tan PH, Sagoo P, Chan C, Yates JB, Campbell J, Beutelspacher SC, Foxwell BM, Lombardi G, George AJ.

Dendritic cells (DCs) are central to T cell immunity, and many strategies have been used to manipulate DCs to modify immune responses. We investigated the effects of antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) on DC phenotype and function. Vitamins C and E are both antioxidants, and concurrent use results in a nonadditive activity. We have demonstrated that DC treated with these antioxidants are resistant to phenotypic and functional changes following stimulation with proinflammatory cytokines. Following treatment, the levels of intracellular oxygen radical species were reduced, and the protein kinase RNA-regulated, eukaryotic translation initiation factor 2alpha, NF-kappaB, protein kinase C, and p38 MAPK pathways could not be activated following inflammatory agent stimulation. We went on to show that allogeneic T cells (including CD4(+)CD45RO, CD4(+)CD45RA, and CD4(+)CD25(-) subsets) were anergized following exposure to vitamin-treated DCs, and secreted higher levels of Th2 cytokines and IL-10 than cells incubated with control DCs. These anergic T cells act as regulatory T cells in a contact-dependent manner that is not dependent on IL-4, IL-5, IL-10, IL-13, and TGF-beta. These data indicate that vitamin C- and E-treated DC might be useful for the induction of tolerance to allo- or autoantigens.

https://www.ncbi.nlm.nih.gov/pubmed/15944264

Nat Commun. 2020 Jan;11(1):426.
Prenatal dietary supplements influence the infant airway microbiota in a randomized factorial clinical trial.
Hjelmsø MH, Shah SA, Thorsen J, Rasmussen M, Vestergaard G, Mortensen MS, Brejnrod A, Brix S, Chawes B, Bønnelykke K, Sørensen SJ, Stokholm J, Bisgaard H.

Maternal dietary interventions during pregnancy with fish oil and high dose vitamin D have been shown to reduce the incidence of asthma and wheeze in offspring, potentially through microbial effects in pregnancy or early childhood. Here we analyze the bacterial compositions in longitudinal samples from 695 pregnant women and their children according to intervention group in a nested, factorial, double-blind, placebo-controlled, randomized trial of n-3 long-chain fatty acids and vitamin D supplementation. The dietary interventions affect the infant airways, but not the infant fecal or maternal vaginal microbiota. Changes in overall beta diversity are observed, which in turn associates with a change in immune mediator profile. In addition, airway microbial maturation and the relative abundance of specific bacterial genera are altered. Furthermore, mediation analysis reveals the changed airway microbiota to be a minor and non-significant mediator of the protective effect of the dietary interventions on risk of asthma. Our results demonstrate the potential of prenatal dietary supplements as manipulators of the early airway bacterial colonization.

https://www.ncbi.nlm.nih.gov/pubmed/31969566

Eur J Clin Pharmacol. 2019 Mar;75(3):303-311.
Efficacy of vitamin C for the prevention and treatment of upper respiratory tract infection. A meta-analysis in children.
Vorilhon P, Arpajou B, Vaillant Roussel H, Merlin É, Pereira B, Cabaillot A.

PURPOSE: Upper respiratory tract infection (URTI) is a common infection in children, generally caused by viral respiratory infection. Vitamin C is currently proposed as prophylaxis for URTI. The purpose of this study was to assess the effectiveness of vitamin C administration in children for the prevention and reduced duration of URTI through a systematic literature review.
METHODS: Review of the literature conducted between October 2017 and January 2018 in the main medical databases (CENTRAL, Medline and Embase) and by a gray literature approach. The selection criteria were: double-blind randomized controlled trials (RCTs) comparing vitamin C use to placebo in children aged 3 months to 18 years without chronic infection. Efficacy was assessed in terms of incidence, duration and severity of symptoms of URTI. A meta-analysis was conducted where possible.
RESULTS: Eight RCTs, including 3135 children aged 3 months to 18 years, were selected. Quantitative analysis showed no difference between vitamin C administration and placebo (odds ratio = 0.75, 95% CI [0.54-1.03], p = 0.07, I2 = 74%). Vitamin C administration was found to decrease the duration of URTI by 1.6 days (standardized mean differences = -0.30 [-0.53; -0.08], p = 0.009, I2 = 70%). Children under 6 years of age benefit from more effective vitamin C supplementation associated with echinacea. No serious adverse events were reported.
CONCLUSIONS: Although no preventive effects were found, vitamin C intake reduced the duration of URTI. Considering the frequency of URTI, the inappropriate prescription of antibiotics, and the safe nature of vitamin C, its supplementation is justified, especially in children under 6 years of age and those who present a high frequency of URTI. There is a sound rationale for further trials with greater statistical power among children of this age.

https://www.ncbi.nlm.nih.gov/pubmed/30465062

J Pediatr. 2019 Mar;206:156-163.e3.
Delineation of the Individual Effects of Vitamin E Isoforms on Early Life Incident Wheezing.
Stone CA Jr, Cook-Mills J, Gebretsadik T, Rosas-Salazar C, Turi K, Brunwasser SM, Connolly A, Russell P, Liu Z, Costello K, Hartert TV.

OBJECTIVES: To test the hypothesis that maternal plasma alpha-tocopherol levels are associated with protection from childhood wheeze and that this protection is modified by gamma-tocopherol.

STUDY DESIGN: We conducted a prospective nested study in the Infant Susceptibility to Pulmonary Infections and Asthma Following Respiratory Syncytial Virus Exposure birth cohort of 652 children with postpartum maternal plasma vitamin E isoforms used as a surrogate for pregnancy concentrations. Our outcomes were wheezing and recurrent wheezing over a 2-year period, ascertained using validated questionnaires. We assessed the association of alpha- and gamma-tocopherol with wheezing outcomes using multivariable adjusted logistic regression, and tested for interaction between the isoforms with respect to the risk for wheezing outcomes.

RESULTS: Children with wheezing (n = 547, n = 167; 31%) and recurrent wheezing (n = 545, n = 55; 10.1%) over a 2-year period were born to mothers with significantly lower postpartum maternal plasma concentrations of alpha-tocopherol, P = .016 and P = .007, respectively. In analyses of IQR increases, alpha-tocopherol was associated with decreased risk of wheezing (aOR 0.70 [95% CI 0.53,0.92]) and recurrent wheezing (aOR 0.63 [95% CI 0.42,0.95]). For gamma-tocopherol, the aOR for wheezing was 0.79 (95% CI 0.56-1.10) and the aOR for recurrent wheezing was 0.56 (95% CI 0.33-0.94, with nonmonotonic association). The association of alpha-tocopherol with wheezing was modified by gamma-tocopherol (P interaction = .05).

CONCLUSIONS: Increases in postpartum maternal plasma alpha-tocopherol isoform concentrations were associated with decreased likelihood of wheezing over a 2-year period. Gamma-tocopherol modified this association.

https://www.ncbi.nlm.nih.gov/pubmed/30527752

Integr Cancer Ther. 2019 Jan-Dec;18:1534735419828834.
Effects of Phoenix dactylifera Ajwa on Infection, Hospitalization, and Survival Among Pediatric Cancer Patients in a University Hospital: A Nonrandomized Controlled Trial.
Al Jaouni SK, Hussein A, Alghamdi N, Qari M, El Hossary D, Almuhayawi MS, Olwi D, Al-Raddadi R, Harakeh S, Mousa SA.

This nonrandomized controlled trial determined the effects of Phoenix dactylifera palm date (Ajwa) intake on the number of infections and hospitalizations associated with fever, neutropenia, and mortality of pediatric cancer patients admitted between 2008 and 2017 to King Abdulaziz University Hospital (Jeddah, Saudi Arabia). Patients were eligible to be enrolled if they fulfilled the inclusion criteria, were not allergic to Ajwa, and were not enrolled in another study. Of 200 screened patients, 56 were included and 144 were excluded. Of the 56, 26 agreed to take Ajwa, and 30 served as controls. Both groups were assessed based on infection rates, frequency of hospital admissions for fever and neutropenia, and mortality rate. Background information regarding demographics, clinicopathological data, and treatment options was documented. Supplementation of Ajwa significantly reduced hospital admissions (for fever-associated neutropenia) and infections ( P = .009 and P < .001, respectively). Off-treatment did not significantly differ between the Ajwa and control groups. The Ajwa group had a better survival rate in comparison to the non-Ajwa group (stratified log-rank P = .005), where the main cause of death of patients in the non-Ajwa group was disease progression associated with infections (77%). In summary, Ajwa intake during the standard treatment of pediatric cancer patients improved their treatment outcome.

https://www.ncbi.nlm.nih.gov/pubmed/30791734

Virol J. 2018 Jul;15(1):116.
Inhibition of enterovirus 71 replication and viral 3C protease by quercetin.
Yao C, Xi C, Hu K, Gao W, Cai X, Qin J, Lv S, Du C, Wei Y.

BACKGROUND: Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD), which is sometimes associated with severe central nervous system disease in children. There is currently no specific medication for EV71 infection. Quercetin, one of the most widely distributed flavonoids in plants, has been demonstrated to inhibit various viral infections. However, investigation of the anti-EV71 mechanism has not been reported to date.

METHODS: The anti-EV71 activity of quercetin was evaluated by phenotype screening, determining the cytopathic effect (CPE) and EV71-induced cells apoptosis. The effects on EV71 replication were evaluated further by determining virus yield, viral RNA synthesis and protein expression, respectively. The mechanism of action against EV71 was determined from the effective stage and time-of-addition assays. The possible inhibitory functions of quercetin via viral 2Apro, 3Cpro or 3Dpol were tested. The interaction between EV71 3Cpro and quercetin was predicted and calculated by molecular docking.

RESULTS: Quercetin inhibited EV71-mediated cytopathogenic effects, reduced EV71 progeny yields, and prevented EV71-induced apoptosis with low cytotoxicity. Investigation of the underlying mechanism of action revealed that quercetin exhibited a preventive effect against EV71 infection and inhibited viral adsorption. Moreover, quercetin mediated its powerful therapeutic effects primarily by blocking the early post-attachment stage of viral infection. Further experiments demonstrated that quercetin potently inhibited the activity of the EV71 protease, 3Cpro, blocking viral replication, but not the activity of the protease, 2Apro, or the RNA polymerase, 3Dpol. Modeling of the molecular binding of the 3Cpro-quercetin complex revealed that quercetin was predicted to insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and thereby inhibiting EV71 3Cpro activity.

CONCLUSIONS: Quercetin can effectively prevent EV71-induced cell injury with low toxicity to host cells. Quercetin may act in more than one way to deter viral infection, exhibiting some preventive and a powerful therapeutic effect against EV71. Further, quercetin potently inhibits EV71 3Cpro activity, thereby blocking EV71 replication.

https://www.ncbi.nlm.nih.gov/pubmed/30064445

Int J Mol Med. 2018 Jul;42(1):248-258.
Quercetin inhibits NTHi-triggered CXCR4 activation through suppressing IKKα/NF-κB and MAPK signaling pathways in otitis media.
Ma YK, Chen YB, Li P.

Otitis media is one of the most common bacterial infections in children, contributing to hearing loss. A vital bacterial pathogen leading to otitis media development is the nontypeable Haemophilus influenzae (NTHi). Inflammation response is reported as an important characristic for otitis media. Chemokine CXC receptor 4 (CXCR4) is a 352-amino acid seven-span transmembrane G-protein coupled receptor, essential for inflammatory response. However, the possible molecular mechanism indicating the alteration of CXCR4 modulated by NTHi is poorly known. In the present study, NTHi enhanced CXCR4 expression through phosphorylation of IKKα and p38, which relied on nuclear factor-κB (NF-κB) translocation in vitro as well as in the middle ear of mice in vivo. Previously, quercetin, a natural production mainly isolated from rutin, has shown anti-inflammatory effects. Here, we report that quercetin suppressed NTHi-induced CXCR4 expression levels in vitro and in vivo. Quercetin blocked CXCR4 activation through direct IKKβ phosphorylation inhibition, as well as of p38 MAPK restraining. Hence, identification of quercetin may be a potential therapeutic strategy for treating otitis media induced by NTHi through inflammation suppression.

https://www.ncbi.nlm.nih.gov/pubmed/29568908

Free Radic Biol Med. 2018 Jun;121:127-135.
Berberine exerts antioxidant effects via protection of spiral ganglion cells against cytomegalovirus-induced apoptosis.
Zhuang W, Li T, Wang C, Shi X, Li Y, Zhang S, Zhao Z, Dong H, Qiao Y.

Cytomegalovirus (CMV) is the leading cause of sensorineural hearing loss (SNHL) in children because of its damage to the cochlea and spiral ganglion cells. Therefore, it has become a top priority to devise new methods to effectively protect spiral ganglion cells from damage. Berberine (BBR) has gained attention for its vast beneficial biological effects through immunomodulation, and its anti-inflammatory and anti-apoptosis properties. However, the effect of BBR on spiral ganglion cells and molecular mechanisms are still unclear. This study aims to investigate whether BBR has an anti-apoptosis effect in CMV-induced apoptosis in cultured spiral ganglion cells and explore the possible mechanism. In this study, TUNEL and MTT assays significantly demonstrated that low doses of BBR did not promote cell apoptosis and they also inhibited the CMV-induced cultured spiral ganglion cell apoptosis. Immunofluorescence and Western blot assays indicated that the anti-apoptosis effect of BBR was related to Nox3. Mitochondrial calcium and Western blot assays revealed that NMDAR1 mediated this anti-apoptosis effect. Our results demonstrated that BBR exerted an anti-apoptosis effect against CMV in cultured spiral ganglion cells, and the mechanism is related to NMDAR1/Nox3-mediated mitochondrial reactive oxygen species (ROS) generation.

https://www.ncbi.nlm.nih.gov/pubmed/29715550

PLoS One. 2018 Feb;13(2):e0192692.
Protective effects and immunomodulation on piglets infected with rotavirus following resveratrol supplementation.
Cui Q, Fu Q, Zhao X, Song X, Yu J, Yang Y, Sun K, Bai L, Tian Y, Chen S, Jia R, Zou Y, Li L, Liang X, He C, Yin L, Ye G, Lv C, Yue G, Yin Z.

Rotavirus (RV), belonging to Reoviridae family, is the leading cause of acute severe viral diarrhea in children (under 5 years old) and infant animals worldwide. Although vaccines are commonly used to prevent infection, episodes of diarrhea caused by RV frequently occur. Thus, this study was conducted to determine whether resveratrol had protective effects against RV infection in piglets. Following pretreatment with resveratrol dry suspension through adding into the basal diet for 3 weeks, the piglets were orally challenged with RV. We found that resveratrol could alleviate diarrhea induced by RV infection. Resveratrol-treatment inhibited the TNF-α production, indicating that the anti-RV activity of resveratrol may be achieved by reducing the inflammatory response. The IFN-γ level was elevated in 10mg/kg/d resveratrol-treated group and 30mg/kg/d resveratrol-treated group after RV infection. The ratios of CD4+/CD8+ in resveratrol-treated groups were the same as that in mock infected group, suggesting that resveratrol could maintain the immune function in RV-infected piglets. It was found that resveratrol could alleviate diarrhea induced by RV infection. These results revealed that resveratrol dry suspension could be a new control measure for RV infection.

https://www.ncbi.nlm.nih.gov/pubmed/29466421

Microb Pathog. 2018 Jan;114:209-212.
Resveratrol improves efficacy of oral amoxicillin against childhood fast breathing pneumonia in a randomized placebo-controlled double blind clinical trial.
Qiang L, Di Y, Jiang Z, Xu J.

Childhood pneumonia has been considered as a major cause of child morbidity and mortality worldwide. We aimed to investigate the effect of resveratral in synergizing with oral amoxicillin to improve the treatment outcome of oral amoxicillin administration against childhood fast breathing pneumonia. 647 children diagnosed fast breathing pneumonia were recruited and randomized to receive oral amoxicillin plus either resveratrol (AX + RV) or placebo (AX + placebo). The primary outcome was defined as treatment failure up to day 3, while the secondary outcome was defined as treatment failure at day 6 and 12 upon follow up. Incidences of treatment failure up to day 3 was significantly lower in the AX + RV group than the AX + placebo group. From day 6-12, the incidences of treatment failure were increased in both treatment groups. However, treatment failure cases were still much lower in the AX + RV group on both revisits. No serious adverse reaction to treatment drugs were found in either of the two groups. Resveratrol improves efficacy of oral amoxicillin against childhood fast breathing pneumonia, supporting the clincial potential of reseveratrol as a potent adjuvent of oral amoxicillin in the treatment of childhood pneumonia with no adverse effects.

https://www.ncbi.nlm.nih.gov/pubmed/29198820

Zhongguo Dang Dai Er Ke Za Zhi. 2017 Aug;19(8):908-912.
[Myocardial protective effect of L-carnitine in children with hand, foot and mouth disease caused by Coxsackie A16 virus]. [Article in Chinese]
Cui YJ, Song CL, Chen F, Li P, Cheng YB.

OBJECTIVE: To investigate the myocardial protective effect of L-carnitine in children with hand, foot and mouth disease (HFMD) caused by Coxsackie A16 virus and possible mechanisms.

METHODS: A total of 60 HFMD children with abnormal myocardial enzyme after Coxsackie A16 virus infection were enrolled and randomly divided into L-carnitine group and fructose-1,6-diphosphate group (fructose group), with 30 children in each group. The two groups were given L-carnitine or fructose diphosphate in addition to antiviral and heat clearance treatment. Another 30 healthy children who underwent physical examination were enrolled as control group. The changes in myocardial zymogram, malondialdehyde (MDA), superoxide dismutase (SOD), and apoptosis factors sFas and sFasL after treatment were compared between groups.

RESULTS: There was no significant difference in treatment response between the L-carnitine group and the fructose group (P>0.05). One child in the fructose group progressed to critical HFMD, which was not observed in the L-carnitine group. Before treatment, the L-carnitine group and the fructose group had significantly higher indices of myocardial zymogram and levels of MDA, sFas, and sFasL and a significantly lower level of SOD than the control group (P<0.05), while there were no significant differences in these indices between the L-carnitine group and the fructose group (P>0.05). After treatment, the L-carnitine group and the fructose group had significant reductions in the indices of myocardial zymogram and levels of MDA, sFas, and sFasL and a significant increase in the level of SOD (P<0.05); the fructose group had a significantly higher level of creatine kinase (CK) than the control group and the L-carnitine group, and there were no significant differences in other myocardial enzyme indices, MDA, sFas, and sFasL between the L-carnitine group and the fructose group, as well as between the L-carnitine and fructose groups and the control group (P>0.05). SOD level was negatively correlated with aspartate aminotransferase, lactate dehydrogenase (LDH), CK, and creatine kinase-MB (CK-MB) (r=-0.437, -0.364, -0.397, and -0.519 respectively; P<0.05), and MDA level was positively correlated with LDH and CK-MB (r=0.382 and 0.411 respectively; P<0.05).

CONCLUSIONS: L-carnitine exerts a good myocardial protective effect in children with HFMD caused by Coxsackie A16 virus, possibly by clearing oxygen radicals and inhibiting cardiomyocyte apoptosis.

https://www.ncbi.nlm.nih.gov/pubmed/28774367

World J Pediatr. 2017 Apr;13(2):173-182.
Effect of prenatal antioxidant intake on infants’ respiratory infection is modified by a CD14 polymorphism.
Hong SA, Lee E, Kwon SO, Kim KW, Shin YH, Ahn KM, Kim EJ, Lee JG, Oh SY, Hong SJ.

BACKGROUND: Prenatal maternal diet may influence disease susceptibility in offspring with specific genetic backgrounds. We hypothesized that interactions between prenatal antioxidant intake and polymorphisms in immunity genes influence respiratory tract infection (RTI) susceptibility in infants at 12 months of age.

METHODS: This study included 550 infants. In the Cohort for Childhood Origin of Asthma and Allergic Diseases (COCOA) birth cohort study, prenatal maternal diet was assessed by administering a food frequency questionnaire. Infants’ cord blood was genotyped for CD14 (rs2569190), TLR4 (rs1927911), and GSDMB (rs4794820) polymorphisms by the TaqMan method.

RESULTS: Higher prenatal intake of total fruit and vegetables (FV) was associated with the decreased risk of RTI in offspring (P-trend=0.0430). In children with TT genotype at rs2569190, a higher prenatal intake of vitamins A and C, fruits, and total FV decreased RTI risk (P-trend <0.05), while in infants with TC+CC genotype, a higher prenatal intake of fruit increased RTI risk (P-trend <0.05). When analyzing the 3 genotypes, children with TT genotype at rs2569190 were more protected against RTIs compared with those with CC genotype with respect to vitamin C and fruits [odds ratio (OR)=5.04 and OR=10.30, respectively]. In children with CC genotype at rs1927911, RTI risk showed a dose-response association with a higher prenatal intake of vitamin C (P for interaction<0.05). A higher prenatal intake of fruits and total FV reduced RTI risk in infants with GA+AA genotype of rs4794820 (P for interaction<0.05).

CONCLUSIONS: Prenatal antioxidant intake may reduce RTI risk in infants and this relationship may be modified by CD14, TLR4, and GSDMB polymorphisms.

https://www.ncbi.nlm.nih.gov/pubmed/27830580

Sci Rep. 2016 Aug;6:31695.
Curcumin suppresses NTHi-induced CXCL5 expression via inhibition of positive IKKβ pathway and up-regulation of negative MKP-1 pathway.
Konduru AS, Lee BC, Li JD.

Otitis media (OM) is the most common childhood bacterial infection, and leading cause of conductive hearing loss. Nontypeable Haemophilus influenzae (NTHi) is a major bacterial pathogen for OM. OM characterized by the presence of overactive inflammatory responses is due to the aberrant production of inflammatory mediators including C-X-C motif chemokine ligand 5 (CXCL5). The molecular mechanism underlying induction of CXCL5 by NTHi is unknown. Here we show that NTHi up-regulates CXCL5 expression by activating IKKβ-IκBα and p38 MAPK pathways via NF-κB nuclear translocation-dependent and -independent mechanism in middle ear epithelial cells. Current therapies for OM are ineffective due to the emergence of antibiotic-resistant NTHi strains and risk of side effects with prolonged use of immunosuppressant drugs. In this study, we show that curcumin, derived from Curcuma longa plant, long known for its medicinal properties, inhibited NTHi-induced CXCL5 expression in vitro and in vivo. Curcumin suppressed CXCL5 expression by direct inhibition of IKKβ phosphorylation, and inhibition of p38 MAPK via induction of negative regulator MKP-1. Thus, identification of curcumin as a potential therapeutic for treating OM is of particular translational significance due to the attractiveness of targeting overactive inflammation without significant adverse effects.

https://www.ncbi.nlm.nih.gov/pubmed/27538525

Ann Nutr Metab. 2006;50(2):85-94.
Immune-enhancing role of vitamin C and zinc and effect on clinical conditions.
Wintergerst ES, Maggini S, Hornig DH.

Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress. Supplementation of vitamin C was found to improve components of the human immune system such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis, and delayed-type hypersensitivity. Vitamin C contributes to maintaining the redox integrity of cells and thereby protects them against reactive oxygen species generated during the respiratory burst and in the inflammatory response. Likewise, zinc undernutrition or deficiency was shown to impair cellular mediators of innate immunity such as phagocytosis, natural killer cell activity, and the generation of oxidative burst. Therefore, both nutrients play important roles in immune function and the modulation of host resistance to infectious agents, reducing the risk, severity, and duration of infectious diseases. This is of special importance in populations in which insufficient intake of these nutrients is prevalent. In the developing world, this is the case in low- and middle-income countries, but also in subpopulations in industrialized countries, e.g. in the elderly. A large number of randomized controlled intervention trials with intakes of up to 1 g of vitamin C and up to 30 mg of zinc are available. These trials document that adequate intakes of vitamin C and zinc ameliorate symptoms and shorten the duration of respiratory tract infections including the common cold. Furthermore, vitamin C and zinc reduce the incidence and improve the outcome of pneumonia, malaria, and diarrhea infections, especially in children in developing countries.

https://www.ncbi.nlm.nih.gov/pubmed/16373990

Br J Nutr, 115 (10), 1740-7
Antioxidant Status in a Group of Institutionalised Elderly People With Chronic Obstructive Pulmonary Disease
Elena Rodríguez-Rodríguez, Rosa M Ortega, Pedro Andrés, Aránzazu Aparicio, Liliana G González-Rodríguez, Ana M López-Sobaler, Beatriz Navia, José M Perea, Paula Rodríguez-Rodríguez

Chronic obstructive pulmonary disease (COPD) is one of the most important and prevalent diseases suffered by the elderly. Evidence exists that its onset and severity might be conditioned by antioxidant status. The aim of the present study was to investigate the relationship between antioxidant status and COPD in institutionalised elderly people. In all, 183 elderly people aged >65 years (twenty-one had COPD and 160 healthy controls) were studied. The subjects’ diets were investigated via the use of precise individual weighing for 7 d. Body weight, height, and biceps and triceps skinfold thickness were measured, and body fat (kg) and BMI (kg/m2) were calculated. Serum retinol, α-tocopherol, β-carotene and vitamin C levels were determined. Subjects with COPD ate less fruits than healthy controls (117 (sd 52) v. 192 (sd 161) g/d), their coverage of the recommended intake of vitamin C was smaller (150 (sd 45) v. 191 (sd 88) %; note that both exceeded 100 %) and their diets had a lower antioxidant capacity (6558 (sd 2381) v. 9328 (sd 5367) mmol trolox equivalent/d). Those with COPD had lower serum vitamin C and α-tocopherol concentrations than healthy controls (32·4 (sd 15·3) v. 41·5 (sd 14·8) µmol/l and 12·1 (sd 3·2) v. 13·9 (sd 2·8) µmol/l, respectively). In addition, subjects with α-tocopherol <14·1µmol/l (50th percentile) were at 6·43 times greater risk of having COPD than those subjects with ≥14·1µmol/l (OR 6·43; 95 % CI 1·17, 35·24; P<0·05), taking sex, age, use of tobacco, body fat and vitamin E intake as covariables. Subjects with COPD had diets of poorer antioxidant quality, especially with respect to vitamins C and E, compared with healthy controls.

https://www.ncbi.nlm.nih.gov/pubmed/27002926

Int J Vitam Nutr Res, 74 (2), 161-8, Mar 2004
Effects of 6-month Multivitamin Supplementation on Serum Concentrations of Alpha-Tocopherol, Beta-Carotene, and Vitamin C in Healthy Elderly Women
Maike Wolters, Silke Hermann, Andreas Hahn

Objective: The aim of this study was to evaluate the effect of supplementation with nutritional doses of antioxidant nutrients on the serum concentrations of ascorbic acid, alpha-tocopherol, and beta-carotene in healthy elderly women.

Methods: The study was performed as a randomized placebo-controlled, double-blind trial. Two hundred forty-one free-living, healthy women aged 60 years and older were recruited by newspaper advertisement in Hanover, Germany and its environs. As 21 women dropped out, data of 220 women (aged 60-91 years median 63 years) were included in this evaluation. Subjects were randomly assigned to receive either a multivitamin/mineral or placebo capsule with identical appearance for six months containing 36 mg 36mg vitamin E, 150 mg vitamin C, and 9 mg beta-carotene. Serum concentrations of vitamin C, alpha-tocopherol, and beta-carotene were measured initially and after six months of supplementation. Data were analyzed with the SPSS 10.0 program.

Results: Median serum concentrations of alpha-carotene and vitamin E increased significantly in the supplemented group (p=0.000), whereas no significant modifications were observed in the placebo group. Median vitamin C concentration of the supplemented group did not differ from baseline after intervention, but that of the placebo group was significantly decreased after six months (p=0.000). In comparison to estimated desirable serum concentrations of > 30 micromol/L vitamin E, 50 micromol/L vitamin C, and > 0.4 micromol/l beta-carotene at baseline, lower concentrations were found in 21.1%, 6.9%, and 1.0% of all subjects, respectively. After supplementation none of the members of the supplemented group had tocopherol concentrations below 30 micromol/L and only one woman of the supplemented group had a serum beta-carotene concentration below 0.4 micromol/L. The change in serum concentrations of vitamin C and E in the supplemented group depended on the status at baseline.

Conclusion: A six-month supplementation with physiological doses of antioxidant vitamins improves the blood concentration of these nutrients even in relatively well-nourished elderly women or, as seen for vitamin C, prevents reduction of serum concentrations. Prevalence of suboptimal serum concentrations can be reduced

https://www.ncbi.nlm.nih.gov/pubmed/15255454

Asia Pac J Clin Nutr, 19 (3), 393-401
Comparison of Plasma and Intake Levels of Antioxidant Nutrients in Patients With Chronic Obstructive Pulmonary Disease and Healthy People in Taiwan: A Case-Control Study
Yi-Chin Lin, Tzu-Chin Wu, Pei-Ying Chen, Li-Yun Hsieh, Shu-Lan Yeh

The imbalance of oxidant/antioxidant plays an important role in the development of chronic obstructive pulmonary disease (COPD). There is increasing evidence that individuals with high antioxidative nutrient levels in the diet or in blood tend to maintain better lung function. This study was conducted to determine whether COPD patients in Taiwan have lower plasma concentrations of antioxidative nutrients than do healthy people, and whether the dietary habits of COPD patients in Taiwan affect their intake of vitamin C and carotenoids. Thirty-four COPD patients and 43 healthy persons (with normal lung function) aged 50 years or older were recruited. Fasting venous blood was collected to measure concentrations of vitamins A, C, and E and carotenoids. Endogenous and H2O2-induced additional DNA damage (markers of oxidative stress) in white blood cells were assayed. Dietary intakes of vitamin C and carotenoids were assessed by a food-frequency questionnaire. Compare to the healthy controls, COPD patients had significantly lower plasma concentrations of vitamins A, C, and E; alpha- and beta-carotene; and total carotenoids but significantly higher endogenous and H2O2-induced white blood cell DNA damage. Intakes of vitamin C and several carotenoids were lower in the COPD group, and COPD patients consumed significantly fewer vegetables and fruits than did the healthy controls. In conclusion, COPD patients in Taiwan have lower levels of antioxidative nutrients in their plasma and diet than do healthy people. Intakes of vitamin C and carotenoids are correlated with dietary habits.

https://www.ncbi.nlm.nih.gov/pubmed/20805084

Exp Gerontol. 2020 Mar;135:110922.
T. cruzi infection among aged rats: Melatonin as a promising therapeutic molecule.
Brazão V, Santello FH, Colato RP, do Prado JC Jr.

Although T. cruzi was identified as the cause of Chagas disease more than 100 years ago, satisfactory treatments still do not exist, especially for chronic disease. Here we review work suggesting that melatonin could have promise as a Chagas therapeutic. Melatonin has remarkably diverse actions. It is an immunomodulator, an anti-inflammatory, an antioxidant, a free radical scavenger, and has antiapoptotic and anti-aging effects. The elderly (aged 60 years or more) as a group are growing faster than any other age group. Here we discuss the major effects and the mechanisms of action of melatonin on aged T. cruzi-infected rats. Melatonin’s protective effects may be consequences of its cooperative antioxidant and immunomodulatory actions. Melatonin modulates oxidative damage, inducing an antioxidant response and reversing age-related thymus regression. Its protective actions could be the result of its anti-apoptotic activity, and by its counteracting the excessive production of corticosterone. This review describes our work showing that host age plays an important and variable influence on the progression of systemic T. cruzi infection and supporting the hypothesis that melatonin should be considered as a powerful therapeutic compound with multiple activities that can improve host homeostasis during experimental T. cruzi infection.

https://www.ncbi.nlm.nih.gov/pubmed/32151734

Wiad Lek. 2019 Aug;72(8):1499-1503.
Quercetin potentiates antiradical properties of epigallocatechin-3-gallate in periodontium of rats under systemic and local administration of lipopolisaccharide of salmonella typhi
Yelins’ka AM, Liashenko LI, Kostenko VO.

Introduction: There has been demonstrated that pharmaceutical effect of epigallocatechin-3-gallate (EGCG), a polyphenol, which is found in green tea (Camellia sinensis), is implemented through the activation of Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2).The importance of Keap1 / Nrf2 / antioxidant response element (ARE) system is determined by the fact that the state of NF-κB- and АР-1-associated pathways depends on its activity. Recent studies have demonstrated the property of quercetin to suppress ubiquitin-dependent proteolysis of complex of NF-κB and its inhibitory protein IκB. All this provides preconditions to eliminate the potentiality of NF-κB-dependent expression of the number of genes of pro-oxidant and pro-inflammatory proteins. However, co-effect produced by quercetin and EGCG on the oxidative nitrosative stress markers in the periodontal tissues is still unclear.

The aim: To investigate the co-effect produced by quercetin and an inducer of the Keap1 / Nrf2 / ARE epigallocatechin-3-gallate on markers of oxidative-nitrosative stress in rats’ periodontium under the systemic and local administration of Salmonella typhi lipopolysaccharide (LPS).

Material and methods: The studies were conducted on 30 white rats of the Wistar line, divided into 5 groups: the 1st included intact animals, the 2nd was made up of animals after their exposure to combined systemic and local LPS administration, the 3rd and 4th groups included animals, which were given injections with water-soluble form of quercetin (corvitin) and EGCG respectively, and the 5th group involved rats, which were injected with co-administered corvitin and EGCG. The formation of superoxide anion radical (.О-2 ) was evaluated by a test with nitro blue tetrazolium using spectrophotometry of the periodontal soft tissue homogenate. The total activity of NO-synthase and concentration of peroxynitrite in the homogenate of the soft components of periodontium were evaluated spectrophotometrically.

Results: Co-effect produced by corvitin and EGCG under systemic and local LPS administration is accompanied with reduced О-2 production by NADPH-dependent electron transport chains (microsomal and NOS) by 20.0 % (p <0.05) compared with values for the animals received separate corvitin during the experiment. .О-2 generation by the mitochondrial respiratory chain yielded to comparable data of the 3rd and 4th groups by 27.6 % (p <0.01) and 23.8 % (p <0.05) respectively. No differences were found between the groups exposed to combined or separate action of the above mentioned agents in the experiment when assessing О-2 generation by leukocyte NADPH-oxidase. Combined effect of corvitin and EGCG during systemic and local LSP administration showed the decrease in NOS activity and peroxynitrite concentration in periodontal tissues by 53.3 % (p <0.001) and 27.0 % (p <0.02) compared with the findings in the 3rd group, and by 42.0 % (p <0.01) and 22.3 % (p <0.01) in the 4th group.

Conclusions: The co-administration of water-soluble form of quercetin and epigallocatechin-3-gallate under systemic and local introducing of lipopolysaccharide Salmonella typhi has been proven to be more effective means for preventing and correcting oxidative-nitrosative stress in the periodontal tissues than this occurs at separate administration of each of the polyphenols.

https://www.ncbi.nlm.nih.gov/pubmed/32012499

J Pineal Res. 2018 Oct;65(3):e12510.
Effects of melatonin on thymic and oxidative stress dysfunctions during Trypanosoma cruzi infection.
Brazão V, Colato RP, Santello FH, Vale GTD, Gonzaga NA, Tirapelli CR, Prado JCD Jr.

Although the exact etiology of Chagas disease is not completely elucidated, thymic atrophy and oxidative stress are believed to be important contributors to the pathogenesis during acute Trypanosoma cruzi (T. cruzi) infection. We hypothesized that exogenous melatonin, administered by gavage (5 mg/kg, p.o., gavage) to young (5 weeks old) and middle-aged (18 months old) male Wistar rats, would modulate thymic oxidative damage and reverse the age-related thymus regression during T. cruzi acute infection. Increased levels of superoxide anion (O₂^– ) were detected in the thymus of infected animals, and treatment with melatonin reverted this response. We found reduced TBARS levels as well as a significant increase in superoxide dismutase (SOD) activity in the thymus of all middle-aged melatonin-treated animals, infected or not with T. cruzi. Furthermore, melatonin increased the thymic expression of SOD1 and SOD2 in middle-aged control animals. Nox2 expression was not affected by melatonin treatment in young or middle-aged animals. Melatonin reverted the age-related thymic regression as revealed by the increase in thymus weight, total number of thymocytes, and reduction in age-related accumulation of double-negative thymocytes. This is the first report to directly examine the effects of melatonin treatment on the thymic antioxidant/oxidant status and thymic changes during T. cruzi infection. Our results revealed new antioxidant features that turn melatonin a potentially useful compound for the treatment of Chagas disease, a condition in which an excessive oxidative damage occurs.

https://www.ncbi.nlm.nih.gov/pubmed/29781553

J Pineal Res. 2017 Aug;63(1).
Melatonin: Antioxidant and modulatory properties in age-related changes during Trypanosoma cruzi infection.
Brazão V, Santello FH, Colato RP, Mazotti TT, Tazinafo LF, Toldo MPA, do Vale GT, Tirapelli CR, do Prado JC Jr.

The purpose of this study was to investigate the effects of melatonin on selected biomarkers of innate and humoral immune response as well as the antioxidant/oxidant status (superoxide dismutase-SOD and reduced glutathione levels (GSH) to understand whether age-related changes would influence the development of acute Trypanosoma cruzi (T. cruzi) infection. Young- (5 weeks) and middle-aged (18 months) Wistar rats were orally treated with melatonin (gavage) (05 mg/kg/day), 9 days after infection. A significant increase in both SOD activity and GSH levels was found in plasma from all middle-aged melatonin-treated animals. Melatonin triggered enhanced expression of major histocompatibility class II (MHC-II) antigens on antigen-presenting cell (APC) and peritoneal macrophages in all treated animals. High levels of CD4⁺ CD28-negative T cells (*P<.05) were detected in middle-aged control animals. Melatonin induced a significant reduction (***P<.001) in CD28-negative in CD4⁺ and CD8⁺ T cells in middle-aged control animals. Contrarily, the same group displayed upregulated CD4⁺ CD28⁺ T and CD8⁺ CD28⁺ T cells. Melatonin also triggered an upregulation of CD80 and CD86 expression in all young-treated groups. Significant percentages of B and spleen dendritic cells in middle-aged infected and treated animals were observed. Our data reveal new features of melatonin action in inhibiting membrane lipid peroxidation, through the reduction in 8-isoprostane, upregulating the antioxidant defenses and triggering an effective balance in the antioxidant/oxidant status during acute infection. The ability of melatonin to counteract the immune alterations induced by aging added further support to its use as a potential therapeutic target not only for T. cruzi infection but also for other immunocompromised states.

https://www.ncbi.nlm.nih.gov/pubmed/28370218

Eur J Obstet Gynecol Reprod Biol. 2016 Dec;207:125-128.
Efficacy of an orally administered combination of hyaluronic acid, chondroitin sulfate, curcumin and quercetin for the prevention of recurrent urinary tract infections in postmenopausal women.
Torella M, Del Deo F, Grimaldi A, Iervolino SA, Pezzella M, Tammaro C, Gallo P, Rappa C, De Franciscis P, Colacurci N.

OBJECTIVE: To assess whether the orally administered combination of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin and quercetin could be effective in preventing recurrent cystitis in postmenopausal women and whether its efficacy was conditioned by the concurrent use of local estrogen therapy.

STUDY DESIGN: This was a prospective evaluation of 145 postmenopausal women consecutively recruited from the database of three different investigators. All women should have mild-to-moderate urogenital atrophy and a history of recurrent urinary tract infections (≥2 episodes within 6 months or ≥3 episodes within 12 months documented by positive urine cultures) during the last year. Patients were assigned to three different therapeutic regimens: the first group was treated only with vaginal estrogens, the second group only with HA, CS, curcumin and quercetin per os, and the third group was treated with HA, CS, curcumin and quercetin associated with local estrogens. We evaluated the number of patients with <2 infective episodes in the 6-month follow-up and <3 episodes in the 12-month follow-up (main aim definition) and the reduction of related symptoms through a Visual Analog Scale (VAS) and the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale. Student’s t-test and chi-squared test were used for data analysis as appropriate.

RESULTS: At 6-month follow up, the main aim rate was 8%, 11.1% and 25% in the three groups, respectively (p<0.05 compared to baseline only in group 3). Although the reduction in the number of recurrent episodes became significant in all groups at 1 year follow-up, the main aim rate was almost double in women receiving both local estrogens and oral therapy (group 3) compared to those receiving single treatments. The improvement of related symptoms was significant in all groups at 12-month follow-up.

CONCLUSIONS: In postmenopausal women, the combination of HA, CS, curcumin and quercetin per os was effective in preventing recurrent urinary tract infections, especially if administered with vaginal estrogen therapy.

https://www.ncbi.nlm.nih.gov/pubmed/27838537

PLoS One. 2015 Mar;10(3):e0120130.
Extract from Rumex acetosa L. for prophylaxis of periodontitis: inhibition of bacterial in vitro adhesion and of gingipains of Porphyromonas gingivalis by epicatechin-3-O-(4β→8)-epicatechin-3-O-gallate (procyanidin-B2-Di-gallate).
Schmuch J, Beckert S, Brandt S, Löhr G, Hermann F, Schmidt TJ, Beikler T, Hensel A.

BACKGROUND: The aerial parts of Rumex acetosa L. have been used in traditional European medicine for inflammatory diseases of the mouth epithelial tissue. The following study aimed to investigate the influence of a proanthocyanidin-enriched extract from R. acetosa extract against the adhesion of Porphyromonas gingivalis (P. gingivalis), a pathogen strongly involved in chronic and aggressive periodontitis. A further goal was to define the bioactive lead structures responsible for a potential antiadhesive activity and to characterize the underlying molecular mechanisms of the antiadhesive effects.

METHODOLOGY: An extract of R. acetosa (RA1) with a defined mixture of flavan-3-ols, oligomeric proanthocyanidins and flavonoids, was used. Its impact on P. gingivalis adhesion to KB cells was studied by flow cytometry, confocal laser scanning microscopy and in situ adhesion assay using murine buccal tissue. RA1 and its compounds 1 to 15 were further investigated for additional effects on gingipain activity, hemagglutination and gene expression by RT-PCR.

PRINCIPAL FINDINGS: RA1 (5 to 15 μg/mL) reduced P. gingivalis adhesion in a dose-dependent manner to about 90%. Galloylated proanthocyanidins were confirmed to be responsible for this antiadhesive effect with epicatechin-3-O-gallate-(4β,8)-epicatechin-3′-O-gallate (syn. procyanidin B2-di-gallate) being the lead compound. Ungalloylated flavan-3-ols and oligomeric proanthocyanidins were inactive. RA1 and the galloylated proanthocyanidins strongly interact with the bacterial virulence factor Arg-gingipain, while the corresponding Lys-gingipain was hardly influenced. RA1 inhibited also hemagglutination. In silico docking studies indicated that epicatechin-3-O-gallate-(4β,8)-epicatechin-3′-O-gallate interacts with the active side of Arg-gingipain and hemaglutinin from P. gingivalis; the galloylation of the molecule seems to be responsible for fixation of the ligand to the protein. In conclusion, the proanthocyanidin-enriched extract RA1 and its main active constituent procyanidin B2-di-gallate protect cells from P. gingivalis infection by inhibiting bacterial adhesion to the host cell. RA1 and procyanidin B2-di-gallate appear to be promising candidates for future cytoprotective preparations for oral mouth care products.

https://www.ncbi.nlm.nih.gov/pubmed/25803708

J Clin Periodontol. 2011 May;38(5):457-69.
Polyphenols from Myrothamnus flabellifolia Welw. inhibit in vitro adhesion of Porphyromonas gingivalis and exert anti-inflammatory cytoprotective effects in KB cells.
Löhr G, Beikler T, Podbielski A, Standar K, Redanz S, Hensel A.

AIM: Identification of anti-adhesive plant extracts against cell surface binding of Porphyromonas gingivalis and underlying mechanisms; investigation of potential cytoprotective effects of anti-adhesive extract on KB cells.

MATERIALS AND METHODS: Polyphenol-enriched extract, fully characterized concerning flavan-3-ols and oligomeric proanthocyanidins, from Myrothamnus flabellifolia (MF), traditionally used for periodontitis, was tested for inhibition of P. gingivalis-mediated adhesion to KB cells by flow cytometry, for influence on gingipain activity (protease assay), haemagglutination and by microarray analysis for effects on bacterial transcriptome. The influence of MF on P. gingivalis-induced cytokine gene expression was monitored by RT-PCR and IL-6 titres by ELISA.

RESULTS: MF (100 μg/ml) reduced P. gingivalis adhesion/invasion about 50% by interacting with bacterial OMPs. As shown by RT-PCR, fimbrillin and Arg-gingipain encoding genes were up-regulated by MF. On the protein level, inhibition (70%) of Arg-gingipain activity was observed, while the corresponding Lys-gingipain was hardly influenced. MF also inhibited haemagglutination. While exposure to P. gingivalis resulted in an increased expression of inflammation-related genes in KB cells, pre-treatment of KB cells with MF evoked cytoprotective effects concerning IL-1β, IL-6, IL-8 and TNF-α gene expression as well as IL-6 release rates. Compounds from the plant extract belonging to the class of proanthocyanidins were shown to be responsible for the observed effects and were characterized for their respective structural features.

CONCLUSIONS: While being cytoprotective, MF exerts anti-adhesive effects against P. gingivalis. Thus, MF may be useful for the prevention of P. gingivalis-associated periodontal diseases.

https://www.ncbi.nlm.nih.gov/pubmed/21158896

Am J Clin Nutr. 2007 Oct;86(4):1167-73.
Serum zinc and pneumonia in nursing home elderly.
Meydani SN, Barnett JB, Dallal GE, Fine BC, Jacques PF, Leka LS, Hamer DH.

Erratum in Am J Clin Nutr. 2008 Apr;87(4):1071.

BACKGROUND: Zinc plays an important role in immune function. The association between serum zinc and pneumonia in the elderly has not been studied.
OBJECTIVE: The objective was to determine whether serum zinc concentrations in nursing home elderly are associated with the incidence and duration of pneumonia, total and duration of antibiotic use, and pneumonia-associated and all-cause mortality.
DESIGN: This observational study was conducted in residents from 33 nursing homes in Boston, MA, who participated in a 1-y randomized, double-blind, and placebo-controlled vitamin E supplementation trial; all were given daily doses of 50% of the recommended dietary allowance of essential vitamins and minerals, including zinc. Participants with baseline (n = 578) or final (n = 420) serum zinc concentrations were categorized as having low (<70 microg/dL) or normal (>or=70 microg/dL) serum zinc concentrations. Outcome measures included the incidence and number of days with pneumonia, number of new antibiotic prescriptions, days of antibiotic use, death due to pneumonia, and all-cause mortality.
RESULTS: Compared with subjects with low zinc concentrations, subjects with normal final serum zinc concentrations had a lower incidence of pneumonia, fewer (by almost 50%) new antibiotic prescriptions, a shorter duration of pneumonia, and fewer days of antibiotic use (3.9 d compared with 2.6 d) (P <or= 0.004 for all). Normal baseline serum zinc concentrations were associated with a reduction in all-cause mortality (P = 0.049).
CONCLUSION: Normal serum zinc concentrations in nursing home elderly are associated with a decreased incidence and duration of pneumonia, a decreased number of new antibiotic prescriptions, and a decrease in the days of antibiotic use. Zinc supplementation to maintain normal serum zinc concentrations in the elderly may help reduce the incidence of pneumonia and associated morbidity.

https://www.ncbi.nlm.nih.gov/pubmed/17921398

JAMA. 2004 Aug 18;292(7):828-36.
Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial.
Meydani SN, Leka LS, Fine BC, Dallal GE, Keusch GT, Singh MF, Hamer DH.

Erratum in
• JAMA. 2004 Sep 15;292(11):1305.
• JAMA. 2007 May 2;297(17):1882.

CONTEXT: Respiratory tract infections are prevalent in elderly individuals, resulting in increased morbidity, mortality, and use of health care services. Vitamin E supplementation has been shown to improve immune response in elderly persons. However, the clinical importance of these findings has not been determined.
OBJECTIVE: To determine the effect of 1 year of vitamin E supplementation on respiratory tract infections in elderly nursing home residents.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial was conducted from April 1998 to August 2001 at 33 long-term care facilities in the Boston, Mass, area. A total of 617 persons aged at least 65 years and who met the study’s eligibility criteria were enrolled; 451 (73%) completed the study.
INTERVENTION: Vitamin E (200 IU) or placebo capsule administered daily; all participants received a capsule containing half the recommended daily allowance of essential vitamins and minerals.
MAIN OUTCOME MEASURES: Incidence of respiratory tract infections, number of persons and number of days with respiratory tract infections (upper and lower), and number of new antibiotic prescriptions for respiratory tract infections among all participants randomized and those who completed the study.
RESULTS: Vitamin E had no significant effect on incidence or number of days with infection for all, upper, or lower respiratory tract infections. However, fewer participants receiving vitamin E acquired 1 or more respiratory tract infections (60% vs 68%; risk ratio [RR], 0.88; 95% confidence interval [CI], 0.76-1.00; P =.048 for all participants; and 65% vs 74%; RR, 0.88; 95% CI, 0.75-0.99; P =.04 for completing participants), or upper respiratory tract infections (44% vs 52%; RR, 0.84; 95% CI, 0.69-1.00; P =.05 for all participants; and 50% vs 62%; RR, 0.81; 95% CI, 0.66-0.96; P =.01 for completing participants). When common colds were analyzed in a post hoc subgroup analysis, the vitamin E group had a lower incidence of common cold (0.67 vs 0.81 per person-year; RR, 0.83; 95% CI, 0.68-1.01; P =.06 for all participants; and 0.66 vs 0.83 per person-year; RR, 0.80; 95% CI, 0.64-0.98; P =.04 for completing participants) and fewer participants in the vitamin E group acquired 1 or more colds (40% vs 48%; RR, 0.83; 95% CI, 0.67-1.00; P =.05 for all participants; and 46% vs 57%; RR, 0.80; 95% CI, 0.64-0.96; P =.02 for completing participants). Vitamin E had no significant effect on antibiotic use.
CONCLUSIONS: Supplementation with 200 IU per day of vitamin E did not have a statistically significant effect on lower respiratory tract infections in elderly nursing home residents. However, we observed a protective effect of vitamin E supplementation on upper respiratory tract infections, particularly the common cold, that merits further investigation.

https://www.ncbi.nlm.nih.gov/pubmed/15315997

Clin Infect Dis. 2001 Dec;33(11):1892-900.
Nutritional strategies to boost immunity and prevent infection in elderly individuals. High KP.

Older adults are at risk for malnutrition, which may contribute to their increased risk of infection. Nutritional supplementation strategies can reduce this risk and reverse some of the immune dysfunction associated with advanced age. This review discusses nutritional interventions that have been examined in clinical trials of older adults. The data support use of a daily multivitamin or trace-mineral supplement that includes zinc (elemental zinc, >20 mg/day) and selenium (100 microg/day), with additional vitamin E, to achieve a daily dosage of 200 mg/day. Specific syndromes may also be addressed by nutritional interventions (for example, cranberry juice consumption to reduce urinary tract infections) and may reduce antibiotic use in older adults, particularly those living in long-term care facilities. Drug-nutrient interactions are common in elderly individuals, and care providers should be aware of these interactions. Future research should evaluate important clinical end points rather than merely surrogate markers of immunity.

https://www.ncbi.nlm.nih.gov/pubmed/11692301

Lancet. 1992 Nov;340(8828):1124-7.
Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Chandra RK.

Retraction in Retraction – Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. [Lancet. 2016]

Ageing is associated with impaired immune responses and increased infection-related morbidity. This study assessed the effect of physiological amounts of vitamins and trace elements on immunocompetence and occurrence of infection-related illness. 96 independently living, healthy elderly individuals were randomly assigned to receive nutrient supplementation or placebo. Nutrient status and immunological variables were assessed at baseline and at 12 months, and the frequency of illness due to infection was ascertained. Subjects in the supplement group had higher numbers of certain T-cell subsets and natural killer cells, enhanced proliferation response to mitogen, increased interleukin-2 production, and higher antibody response and natural killer cell activity. These subjects were less likely than those in the placebo group to have illness due to infections (mean [SD] 23 [5] vs 48 [7] days per year, p = 0.002). Supplementation with a modest physiological amount of micronutrients improves immunity and decreases the risk of infection in old age.

https://www.ncbi.nlm.nih.gov/pubmed/1359211

Age Ageing. 1991 May;20(3):169-74.
The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW.

Thirty elderly long-stay patients were randomly allocated to receive either placebo or dietary supplementation with vitamins A, C and E for 28 days. Nutritional status and cell-mediated immune function were assessed before and after the period of supplementation. Following vitamin supplementation, cell-mediated immune function improved as indicated by a significant increase in the absolute number of T cells (p less than 0.05), T4 subsets (p less than 0.05), T4 to T8 ratio (p less than 0.01) and the proliferation of lymphocytes in response to phytohaemagglutinin (p less than 0.01). In contrast, no significant changes were noted in the immune function of the placebo group. We conclude that supplementation with the dietary antioxidants vitamins A, C and E can improve aspects of cell-mediated immune function in elderly long-stay patients.

https://www.ncbi.nlm.nih.gov/pubmed/1853789