The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents

Evans JM1, Luby R2, Lukaczer D2, Rountree R3, Stone PM4, Guilliams TG5, Yanuck S6, Messier H7, Ramsdell K2, Hanaway PJ8

 

1The Center for Functional Medicine, Stamford CT

2The Institute for Functional Medicine, Federal Way, WA

3Boulder Wellcare, Boulder, CO

4Stone Medical, Ashland, OR

5Point Institute, Stevens Point, WI

6The Yanuck Center for Life and Health, Chapel Hill, NC

7Medical Intelligence Learning Lab, Inc (MILLI), San Jose, CA

8The Institute for Functional Medicine COVID-19 Task Force, Federal Way, WA


Download the pdf


Abstract

As the novel infection with SARS-CoV-2 emerges, objective assessment of the scientific plausibility of nutraceutical and botanical interventions for prevention and treatment is important. We evaluate twelve such interventions with mechanisms of action that modulate the immune system, impair viral replication, and/or have been demonstrated to reduce severity of illness. These are examples of interventions that, mechanistically, can help protect patients in the presence of the prevalent and infectious SARS-CoV-2 virus. While there are limited studies to validate these agents to specifically prevent COVID-19, they have been chosen based upon their level of evidence for effectiveness and safety profiles, in the context of other viral infections. These agents are to be used in a patient-specific manner in concert with lifestyle interventions known to strengthen immune response

Citation

Evans JM, Luby R, Lukaczer D, Rountree R, Stone PM, Guilliams TG, Yanuck S, Messier H, Ramsdell K, Hanaway PJ. The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents. Integr Med (Encinitas). 2020;19(Suppl 1):34‐42  

 

Background and Introduction

Health professionals and the public must be well informed about the SARS-CoV-2 virus, the disease it causes (COVID-19), and how it spreads. This information is readily available and not within the scope of this document. At this time, there are no specific vaccines or uniformly successful treatments for COVID-19. In this context of insufficient evidence, the scope of this document will be to assess the scientific plausibility of promising prevention approaches and therapeutic (nutraceutical and botanical) interventions and then to offer clinical recommendations.

With respect to interventions, the practice of Functional Medicine emphasizes the primacy of safety, validity, and effectiveness. In the novel context of COVID-19, validity in the form of published evidence is lacking. Therefore, validity relies upon inferences from the mechanisms of action of individual agents and/or published outcomes data supporting their mitigating effects on illness from other viral strains. Likewise, data for the effectiveness of interventions targeting the viral mechanisms of COVID-19 are nascent and rapidly emerging. In this context, the following recommendations represent the Functional Medicine approach to the COVID-19 crisis:

 

  • Adherence to all health recommendations from official sources to decrease viral transmission.
  • Optimizing modifiable lifestyle factors in order to improve overall immune function (an introductory document on boosting immunity is available). This should reduce progression from colonization to illness.
  • Personalized consideration of therapeutic agents that may:
    • Favorably modulate cellular defense and repair mechanisms.
    • Favorably modulate viral-induced pathological cellular processes.
    • Promote viral eradication or inactivation.
    • Mitigate collateral damage from other therapeutic agents.
    • Promote resolution of collateral damage and restoration of function.
  • Treatment of confirmed COVID-19 illness (as per conventional standards and practice):
    • May reduce the severity and duration of acute symptoms and complications.
    • May support recovery and reduce long-term morbidity and sequelae.

Additional references are being collated and will be made available in the future.

Clinical Recommendations and Mechanisms of Action

Background and Mechanisms of Action

We encourage practitioners to learn about the mechanism of invasion, replication, and pathophysiology of the SARS-CoV-2 virus. Much of what we know has been extrapolated from basic science research on SARS-CoV-2. Excellent resources are available online, including the free YouTube lectures through Dr. Roger Seheult.

This document discusses the mechanisms of action of a number of different botanical and nutraceutical agents. These agents can be considered as immunoadjuvants, defined as substances that act to accelerate, prolong, or enhance antigen-specific immune responses by potentiating or modulating the immune response.1

A coronavirus such as SARS-CoV-2 can be deadly because of its ability to stimulate a part of the innate immune response called the inflammasome, which can cause uncontrolled release of pro-inflammatory cytokines, leading to cytokine storm and severe, sometimes irreversible, damage to respiratory epithelium.2 The SARS-CoV-2 virus has been shown to activate the NLRP3 inflammasome.3,4 A 2016 review article5 entitled “Natural compounds as regulators of NLRP3 inflammasome-mediated IL-1β production” notes that “resveratrol, curcumin, EGCG [epigallocatechin gallate], and quercetin are potent inhibitors of NLRP3 inflammasome-mediated IL-1β production, typically acting at more than one element of the involved pathways. However, it should be noted that these polyphenols have an even much broader biological effect, as they influence a variety of pathways.” For example, these polyphenols modulate NF-kB upregulation, which is useful to counteract the COVID-19 hyper-inflammation.6

A preprint released on March 23, 2020, identified the ability of plant bioactive compounds to inhibit the COVID-19 main protease (Mpro),7 which is necessary for viral replication. There is much excitement surrounding the recent identification of Mpro, and it is a current potential pharmaceutical drug target. Kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate were the natural compounds that appeared to have the best potential to act as COVID-19 Mpro inhibitors. Though further research is necessary to prove their efficacy, this study provides the biologic plausibility and mechanistic support (COVID-19 protease inhibition) to justify their use.

For these reasons, we recommend the following compounds, at standard dosages, to prevent activation of the NLRP3 inflammasome, to decrease NF-kB activation, and to potentially inhibit COVID-19 replication. There is no literature to support a regimen of a single vs. multiple agents. Our recommendation is to use higher dosing and/or multiple agents when patient contextual factors (e.g., patient desire, pre-existing inflammation, multiple co-morbidities, higher risk, etc.) and/or therapeutic decision-making warrant such use.

Download COVID-19: Nutraceutical and Botanical Recommendations for Patients

 

Recommended Interventions

Quercetin

Quercetin has been shown to have antiviral effects against both RNA (e.g., influenza and coronavirus) and DNA viruses (e.g., herpesvirus). Quercetin has a pleiotropic role as an antioxidant and anti-inflammatory, modulating signaling pathways that are associated with post-transcriptional modulators affecting post-viral healing.8

Intervention Quercetin
Suggested dose Regular: 1 gm po bid; phytosome: 500 mg, bid
Mechanism(s) of action against
non-COVID-19 viruses
Promote viral eradication or inactivation:9,10,11,12,13

Inhibition of viral replication

Favorably modulate viral-induced pathological cellular processes:

Modulation of NLRP3 inflammasome activation5,14,15

Mechanistically promote resolution of collateral damage and restoration of function:

Modulation of mast cell stabilization (anti-fibrotic)

Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms

 

Strength of evidence Moderate
Risk of harm16,17 Mimimal

 

Curcumin

Curcumin has been shown to modulate the NLRP3 inflammasome,5 and a preprint suggests that curcumin can target the SARS-CoV-2 main protease to reduce viral replication.18

Intervention Curcumin
Suggested dose 500–1,000 mg po bid (of absorption-enhanced curcumin)
Mechanism(s) of action against non-COVID-19 viruses Favorably modulate viral-induced pathological cellular processes:

Modulation of NLRP3 inflammasome activation5,19-21

Outcomes data supporting their mitigating effects on illness from other viral strains No data available

 

Strength of evidence Conditional
Risk of harm22-27 Mimimal

 

Epigallocatechin Gallate (EGCG)

Green tea, in addition to modulating the NLRP3 inflammasome and, based on a preprint, potentially targeting the SARS-CoV-2 main protease (Mpro)7 to reduce viral replication, has also been shown to prevent influenza in healthcare workers.28

Intervention Epigallocatechin gallate (EGCG)
Suggested dose 4 cups daily or 225 mg po qd
Mechanism(s) of action against
non-COVID-19 viruses
Favorably modulate viral-induced pathological cellular processes:

Modulation of NLRP3 inflammasome activation5,28,29

Outcomes data supporting their mitigating effects on illness from other viral strains No data available

 

Strength of evidence Conditional
Risk of harm30-35 Significant (rare)—Hepatotoxicity

 

N-Acetylcysteine (NAC)

N-Acetylcysteine promotes glutathione production, which has been shown to be protective in rodents infected with influenza. In a little-noticed six-month controlled clinical study enrolling 262 primarily elderly subjects, those receiving 600 mg NAC twice daily, as opposed to those receiving placebo, experienced significantly fewer influenza-like episodes and days of bed confinement.36    

Intervention N-Acetylcysteine (NAC)
Suggested dose 600-900 mg po bid
Mechanism(s) of action against non-COVID-19 viruses36 Favorably modulate cellular defense and repair mechanisms:

Repletion of glutathione and cysteine

Outcomes data supporting their mitigating effects on illness from other viral strains Reduce progression from colonization to illness

Reduce the severity and duration of acute symptoms

Strength of evidence Limited
Risk of harm37-41 Mimimal

 

Resveratrol

Resveratrol, a naturally occurring polyphenol, shows many beneficial health effects.42 It has been shown to modulate the NLRP3 inflammasome.5 In addition, resveratrol was shown to have in vitro activity against MERS-CoV.43

Intervention Resveratrol
Suggested dose 100–150 mg po qd
Mechanism(s) of action against non-COVID-19 viruses Favorably modulate viral-induced pathological cellular processes

Modulation of NLRP3 inflammasome activation5

Outcomes data supporting their mitigating effects on illness from other viral strains MERS-CoV43

Influenza44,45

Strength of evidence Conditional
Risk of harm46-53 Mimimal

 

Vitamin D

Activated vitamin D,1,25(OH) D, a steroid hormone, is an immune system modulator that reduces the expression of inflammatory cytokines and increases macrophage function. Vitamin D also stimulates the expression of potent antimicrobial peptides (AMPs), which exist in neutrophils, monocytes, natural killer cells, and epithelial cells of the respiratory tract.54 Vitamin D increases anti-pathogen peptides through defensins and has a dual effect due to suppressing superinfection. Evidence suggests vitamin D supplementation may prevent upper respiratory infections.55 However, there is some controversy as to whether it should be used and the laboratory value that should be achieved. Research suggests that concerns about vitamin D (increased IL-1beta in cell culture) are not seen clinically. The guidance we suggest is that a laboratory range of >50 and < 80ng/mL serum 25-hydroxy vitamin D may help to mitigate morbidity from COVID-19 infection.

Intervention Vitamin D
Suggested dose 5,000 IU po qd in the absence of serum levels
Mechanism(s) of action against non-COVID-19 viruses55-78 Favorably modulate cellular defense and repair mechanisms:

Activation of macrophages

Stimulation of anti-microbial peptides

Modulation of defensins

Modulation of TH17 cells

Favorably modulate viral-induced pathological cellular processes:

Reduction in cytokine expression

Modulation of TGF beta

Outcomes data supporting their mitigating effects on illness from other viral strains Reduce progression from colonization to illness

Reduce the severity and duration of acute symptoms and complications

Strength of evidence Limited
Risk of harm79-82 Mimimal

 

Melatonin

Melatonin has been shown to have an inhibitory effect on the NLRP3 inflammasome.83 This has not gone unnoticed by the COVID-19 research community, with two recent published papers proposing the use of melatonin as a therapeutic agent in the treatment of patients with COVID-19.84,85

Intervention Melatonin
Suggested dose 5–20 mg qd
Mechanism(s) of action against non-COVID-19 viruses83,84 Favorably modulate viral-induced pathological cellular processes

Modulation of NLRP3 inflammasome activation83,84

Outcomes data supporting their mitigating effects on illness from other viral strains Research in progress
Strength of evidence Conditional
Risk of harm86-94 Mimimal

 

Vitamin A

Vitamin A is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. Vitamin A is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. Vitamin A is involved in the development of the immune system and plays regulatory roles in cellular immune responses and humoral immune processes through the modulation of T helper cells, sIgA, and cytokine production. Vitamin A has demonstrated a therapeutic effect in the treatment of various infectious diseases.95

Intervention Vitamin A
Suggested dose Up to 10 000–25 000 IU/d
Mechanism(s) of action against non-COVID-19 viruses95,96 Favorably modulate cellular defense and repair mechanisms:

Modulation of helper T cells

Modulation of sIgA

Favorably modulate viral-induced pathological cellular processes:

Modulation of cytokine production

Outcomes data supporting their mitigating effects on illness from other viral strains No data available
Strength of evidence Conditional
Risk of harm97-102 Mimimal, if does not exceed this dose; caution: pregnancy

 

Elderberry

Elderberry (Sambucus nigra) is seen in many medicinal preparations and has widespread historical use as an anti-viral herb.103 Based on animal research, elderberry is likely most effective in the prevention of and early infection with respiratory viruses.104 One in-vitro study reported an increase in TNF-alpha levels related to a specific commercial preparation of elderberry,105 leading some to caution that its use could initiate a “cytokine storm.” However, these data were not confirmed when the same group performed similar studies, which were published in 2002.106 Therefore, these data suggest it is highly implausible that consumption of properly prepared elderberry products (from berries or flowers) would contribute to an adverse outcome related to overproduction of cytokines or lead to an adverse response in someone with COVID-19.

Intervention Elderberry
Suggested dose 500 mg po qd (of USP standard of 17% anthocyanosides)
Mechanism(s) of action against non-COVID-19 viruses103,107-112 Favorably modulate cellular defense and repair mechanisms

Favorably modulate viral-induced pathological cellular processes

Outcomes data supporting their mitigating effects on illness from other viral strains No data available
Strength of evidence Strong
Risk of harm103,107,113,114 Mild; caution with autoimmune disease; uncooked/unripe plant parts toxic; USDA GRAS

 

Palmitoylethanolamide (PEA)

PEA is a naturally occurring anti-inflammatory palmitic acid derivative that interfaces with the endocannabinoid system. There was a significantly favorable outcome in five of six double blind placebo-controlled trials looking at acute respiratory disease due to influenza.115 Dosing was generally 600 mg three times daily for up to three weeks. There are multiple mechanisms of action associated with PEA, from inhibition of TNF-alpha and NF-kB to mast cell stabilization. In influenza, it is thought that PEA works by attenuating the potentially fatal cytokine storm.

Intervention Palmitoylethanolamide (PEA)
Suggested dose 300 mg po bid to prevent infection, 600 mg po tid x two weeks to treat infection
Mechanism(s) of action against non-COVID-19 viruses115 Favorably modulate cellular defense and repair mechanisms

Favorably modulate viral-induced pathological cellular processes

Outcomes data supporting their mitigating effects on illness from other viral strains No data available
Strength of evidence PEA = conditional (treatment)

PEA = strong (prevention)

Risk of harm116-119 Mimimal

 

Vitamin C

Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. Supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections.120 Vitamin C has been used in hospital ICUs to treat COVID-19.

Intervention Vitamin C
Suggested dose 1–3 grams po qd
Mechanism(s) of action against non-COVID-19 viruses120 Favorably modulate cellular defense and repair mechanisms

Favorably modulate viral-induced pathological cellular processes

Outcomes data supporting their mitigating effects on illness from other viral strains No data available
Strength of evidence Strong
Risk of harm121 Mimimal

 

Zinc

Zinc contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. There is also evidence that it suppresses viral attachment and replication.  Zinc deficiency is common, especially in those populations most at risk for severe SARS-CoV-2 infections, and is challenging to accurately diagnosis with laboratory measures. Supplementation with zinc is supported by evidence that it both prevents viral infections and reduces their severity and duration. Moreover, it has been shown to reduce the risk of lower respiratory infection, which may be of particular significance in the context of COVID-19.

Intervention Zinc
Suggested Dose 30–60 mg daily in divided doses

Zinc acetate, citrate, picolinate or glycinate orally. Zinc gluconate as lozenge.

Mechanism(s) of action against non-COVID-19 viruses120-127 Favorably modulate innate and adaptive immune system

Favorably modulate viral-induced pathological cellular processes, attachment and replication

Outcomes data supporting their mitigating effects on illness from other viral strains Prevention, reduced severity of symptoms, reduced duration of illness, prevention of lower respiratory tract infection
Strength of evidence Strong
Risk of harm128 Mimimal

 

Evaluative Criteria

In the recommendations above, the following criteria are used to identify strength of evidence and risk of harm.

Strength of Evidence Risk of Harm
Strength of Evidence
Conditional
Clinical experience and/or expert opinion and/or conflicting studies; biological mechanism at least partly explained.
Risk of Harm
Mimimal
Risk of self-limited symptoms; no risk of loss of function or corrective intervention anticipated; observation only.
Strength of Evidence
Limited
One study showing correlation between intervention and outcome; compelling ATMs and/or PCFs; biological mechanism at least partly explained.
Risk of Harm
Mild
Risk of symptoms; no risk of loss of function or quality of life; minor evaluative and/or therapeutic intervention needed.
Strength of Evidence
Moderate
Two independent studies (one of which is
LOE = 1 or 2) showing correlation between intervention and outcome; biological mechanism at least partly explained.
Risk of Harm
Significant
Risk of temporary loss of function or quality of life; significant evaluative and/or therapeutic intervention needed.
Strength of Evidence
Strong
Two independent studies (both LOE = 1 or 2) showing correlation between intervention and outcome; biological mechanism fully explained or partly explained and having one additional correlative study.
Risk of Harm
Severe
Risk of permanent symptoms, loss of function, quality of life, or death; long-term evaluative and/or therapeutic intervention needed.

Note: This resource is only intended to identify botanical and nutraceutical and botanical agents that may boost your immune system. It is not meant to recommend any treatments, nor have any of these been proven effective against coronavirus. None of these practices are intended to be used in lieu of other recommended treatments. Always consult your physician or healthcare provider prior to initiation. For up-to-date information on COVID-19, please consult the Centers for Disease Control and Prevention at www.cdc.gov.

 

Acknowledgements

We would like to thank the Institute for Functional Medicine (IFM) CEO, Amy R. Mack, the IFM COVID-19 Task Force, members of the IFM staff, and consultants working with IFM for their contributions to this document.

 

References

  1. Hotchkiss RS, Opal SM. Activating immunity to fight a foe – a new path. N Engl J Med. 2020;382(13):1270-1272. doi:10.1056/NEJMcibr1917242
  2. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):1. doi:10.23812/CONTI-E
  3. Ding S, Xu S, Ma Y, Liu G, Jang H, Fang J. Modulatory mechanisms of the NLRP3 inflammasomes in diabetes. 2019;9(12):E850. doi:10.3390/biom9120850
  4. Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol. 2019;10:50. doi:10.3389/fmicb.2019.00050
  5. Tőzsér J, Benkő S. Natural compounds as regulators of NLRP3 inflammasome-mediated IL-1β production. Mediators Inflamm. 2016;2016:5460302. doi:10.1155/2016/5460302
  6. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0
  7. Adem S, Eyupoglu V, Sarfraz I, Rasul A, Ali M. Identification of potent COVID-19 main protease (Mpro) inhibitors from natural polyphenols: an in silico strategy unveils a hope against CORONA. Published online March 23, 2020. doi:10.20944/preprints202003.0333.v1
  8. Dostal Z, Modriansky M. The effect of quercetin on microRNA expression: a critical review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019;163(2):95-106. doi:10.5507/bp.2019.030
  9. Wu W, Li R, Li X, et al. Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry. Viruses. 2015;8(1):E6. doi:10.3390/v8010006
  10. Kinker B, Comstock AT, Sajjan US. Quercetin: a promising treatment for the common cold. J Anc Dis Prev Rem. 2014;2:2:1000111. doi:10.4172/2329-8731.1000111
  11. Somerville VS, Braakhuis AJ, Hopkins WG. Effect of flavonoids on upper respiratory tract infections and immune function: a systematic review and meta-analysis. Adv Nutr. 2016;7(3):488-497. doi:10.3945/an.115.010538
  12. Qiu X, Kroeker A, He S, et al. Prophylactic efficacy of quercetin 3-β-O-D-glucoside against Ebola virus infection. Antimicrob Agents Chemother. 2016;60(9):5182-5188. doi:10.1128/AAC.00307-16
  13. Wong G, He S, Siragam V, et al. Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection. Virol Sin. 2017;32(6):545-547. doi:10.1007/s12250-017-4057-9
  14. Yi YS. Regulatory roles of flavonoids on inflammasome activation during inflammatory responses. Mol Nutr Food Res. 2018;62(13):e1800147. doi:10.1002/mnfr.201800147
  15. Sun Y, Liu W, Zhang H, et al. Curcumin prevents osteoarthritis by inhibiting the activation of inflammasome NLRP3. J Interferon Cytokine Res. 2017;37(10):449-455. doi:10.1089/jir.2017.0069
  16. Andres S, Pevny S, Ziegenhagen R, et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res. 2018;62(1). doi:10.1002/mnfr.201700447
  17. Ożarowski M, Mikołajczak PŁ, Kujawski R, et al. Pharmacological effect of quercetin in hypertension and its potential application in pregnancy-induced hypertension: review of in vitroin vivo, and clinical studies. Evid Based Complement Alternat Med. 2018;2018:7421489. doi:10.1155/2018/7421489
  18. Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S, Soetjipto S. Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Published online March 13, 2020. doi:10.20944/preprints202003.0226.v1
  19. Yin H, Guo Q, Li X, et al. Curcumin suppresses IL-1β secretion and prevents inflammation through inhibition of the NLRP3 inflammasome. J Immunol. 2018;200(8):2835-2846. doi:10.4049/jimmunol.1701495
  20. Gong Z, Zhao S, Zhou J, et al. Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1β production. Mol Immunol. 2018;104:11-19. doi:10.1016/j.molimm.2018.09.004
  21. Zhao J, Wang J, Zhou M, Li M, Li M, Tan H. Curcumin attenuates murine lupus via inhibiting NLRP3 inflammasome. Int Immunopharmacol. 2019;69:213-216. doi:10.1016/j.intimp.2019.01.046
  22. Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J Pharmacol. 2017;174(11):1325-1348. doi:10.1111/bph.13621
  23. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med. 2003;9(1):161-168. doi:10.1089/107555303321223035
  24. Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical use of curcumin in depression: a meta-analysis. J Am Med Dir Assoc. 2017;18(6):503-508. doi:10.1016/j.jamda.2016.12.071
  25. Ng QX, Soh AYS, Loke W, Venkatanarayanan N, Lim DY, Yeo WS. A meta-analysis of the clinical use of curcumin for irritable bowel syndrome (IBS). J Clin Med. 2018;7(10):E298. doi:10.3390/jcm7100298
  26. Bahramsoltani R, Rahimi R, Farzaei MH. Pharmacokinetic interactions of curcuminoids with conventional drugs: a review. J Ethnopharmacol. 2017;209:1-12. doi:10.1016/j.jep.2017.07.022
  27. Xu J, Qiu JC, Ji X, et al. Potential pharmacokinetic herb-drug interactions: have we overlooked the importance of human carboxylesterases 1 and 2? Curr Drug Metab. 2019;20(2):130-137. doi:10.2174/1389200219666180330124050
  28. Matsumoto K, Yamada H, Takuma N, Niino H, Sagesaka YM. Effects of green tea catechins and theanine on preventing influenza infection among healthcare workers: a randomized controlled trial. BMC Complement Altern Med. 2011;11:15. doi:10.1186/1472-6882-11-15
  29. Lee HE, Yang G, Park YB, et al. Epigallocatechin-3-gallate prevents acute gout by suppressing NLRP3 inflammasome activation and mitochondrial DNA synthesis. Molecules. 2019;24(11):E2138. doi:10.3390/molecules24112138
  30. Mereles D, Hunstein W. Epigallocatechin-3-gallate (EGCG) for clinical trials: more pitfalls than promises? Int J Mol Sci. 2011;12(9):5592-5603. doi:10.3390/ijms12095592
  31. Chow HH, Cai Y, Hakim IA, et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003;9(9):3312-3319.
  32. Isomura T, Suzuki S, Origasa H, et al. Liver-related safety assessment of green tea extracts in humans: a systematic review of randomized controlled trials [published correction appears in Eur J Clin Nutr. 2016;70(11):1221-1229]. Eur J Clin Nutr. 2016;70(11):1340. doi:10.1038/ejcn.2016.78
  33. Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Saf. 2008;31(6):469-484. doi:10.2165/00002018-200831060-00003
  34. Oketch-Rabah HA, Roe AL, Rider CV, et al. United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicol Rep. 2020;7:386-402. doi:10.1016/j.toxrep.2020.02.008
  35. Younes M, Aggett P, Aguilar F, et al. Scientific opinion on the safety of green tea catechins. EFSA J. 2018;16(4):e05239. doi:10.2903/j.efsa.2018.5239
  36. McCarty MF, DiNicolantonio JJ. Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus. Prog Cardiovasc Dis. Published online February 12, 2020. doi:10.1016/j.pcad.2020.02.007
  37. Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A review on various uses of N-acetyl cysteine. Cell J. 2017;19(1):11-17. doi:10.22074/cellj.2016.4872
  38. Bauer IE, Green C, Colpo GD, et al. A double-blind, randomized, placebo-controlled study of aspirin and N-acetylcysteine as adjunctive treatments for bipolar depression. J Clin Psychiatry. 2018;80(1):18m12200. doi:10.4088/JCP.18m12200
  39. Berk M, Turner A, Malhi GS, et al. A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo [published correction appears in BMC Med. 2019;17(1):35]. BMC Med. 2019;17(1):18. doi:10.1186/s12916-019-1257-1
  40. Clark RSB, Empey PE, Bayır H, et al. Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children. PLoS One. 2017;12(7):e0180280. doi:10.1371/journal.pone.0180280
  41. Bhatti J, Nascimento B, Akhtar U, et al. Systematic review of human and animal studies examining the efficacy and safety of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) in traumatic brain injury: impact on neurofunctional outcome and biomarkers of oxidative stress and inflammation. Front Neurol. 2018;8:744. doi:10.3389/fneur.2017.00744
  42. Brisdelli F, D’Andrea G, Bozzi A. Resveratrol: a natural polyphenol with multiple chemopreventive properties. Curr Drug Metab. 2009;10(6):530-546. doi:10.2174/138920009789375423
  43. Lin SC, Ho CT, Chuo WH, Li S, Wang TT, Lin CC. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect Dis. 2017;17(1):144. doi:10.1186/s12879-017-2253-8
  44. Palamara AT, Nencioni L, Aquilano K, et al. Inhibition of influenza A virus replication by resveratrol. J Infect Dis. 2005;191(10):1719-1729. doi:10.1086/429694
  45. Euba B, López-López N, Rodríguez-Arce I, et al. Resveratrol therapeutics combines both antimicrobial and immunomodulatory properties against respiratory infection by nontypeable Haemophilus influenzaeSci Rep. 2017;7(1):12860. doi:10.1038/s41598-017-13034-7
  46. Mendes da Silva D, Gross LA, Neto EPG, Lessey BA, Savaris RF. The use of resveratrol as an adjuvant treatment of pain in endometriosis: a randomized clinical trial. J Endocr Soc. 2017;1(4):359-369. doi:10.1210/js.2017-00053
  47. Zhu CW, Grossman H, Neugroschl J, et al. A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: a pilot study. Alzheimers Dement (N Y). 2018;4:609-616. doi:10.1016/j.trci.2018.09.009
  48. Roberts VH, Pound LD, Thorn SR, et al. Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates. FASEB J. 2014;28(6):2466-2477. doi:10.1096/fj.13-245472
  49. Klink JC, Tewari AK, Masko EM, et al. Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways. Prostate. 2013;73(7):754-762. doi:10.1002/pros.22619
  50. Shaito A, Posadino AM, Younes N, et al. Potential adverse effects of resveratrol: a literature review. Int J Mol Sci. 2020;21(6):E2084. doi:10.3390/ijms21062084
  51. Salehi B, Mishra AP, Nigam M, et al. Resveratrol: a double-edged sword in health benefits. Biomedicines. 2018;6(3):E91. doi:10.3390/biomedicines6030091
  52. Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011;1215:161-169. doi:10.1111/j.1749-6632.2010.05853.x
  53. Brantley SJ, Argikar AA, Lin YS, Nagar S, Paine MF. Herb-drug interactions: challenges and opportunities for improved predictions. Drug Metab Dispos. 2014;42(3):301-317. doi:10.1124/dmd.113.055236
  54. Mawson AR. Role of fat-soluble vitamins A and D in the pathogenesis of influenza: a new perspective. 2013;2013:246737. Int Sch Res Notices. doi:10.5402/2013/246737
  55. Martineau AR, Jolliffe DA, Greenberg L, et al. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess. 2019;23(2):1-44. doi:10.3310/hta23020
  56. Zhou J, Du J, Huang L, Wang Y, Shi Y, Lin H. Preventive effects of vitamin D on seasonal influenza A in infants: multicenter, randomized, open, controlled clinical trial. Pediatr Infect Dis J. 2018;37(8):749-754. doi:10.1097/INF.0000000000001890
  57. Tzilas V, Bouros E, Barbayianni I, et al. Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis. Pulm Pharmacol Ther. 2019;55:17-24. doi:10.1016/j.pupt.2019.01.003
  58. Ricca C, Aillon A, Viano M, Bergandi L, Aldieri E, Silvagno F. Vitamin D inhibits the epithelial-mesenchymal transition by a negative feedback regulation of TGF-β activity. J Steroid Biochem Mol Biol. 2019;187:97-105. doi:10.1016/j.jsbmb.2018.11.006
  59. Fischer KD, Agrawal DK. Vitamin D regulating TGF-β induced epithelial-mesenchymal transition [published correction appears in Respir Res. 2015;16:139]. Respir Res. 2014;15:146. doi:10.1186/s12931-014-0146-6
  60. Schrumpf JA, Ninaber DK, van der Does AM, Hiemstra PS. TGF-β1 impairs vitamin D-induced and constitutive airway epithelial host defense mechanisms. J Innate Immun. 2020;12(1):74-89. doi:10.1159/000497415
  61. Liu RM, Gaston Pravia KA. Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Free Radic Biol Med. 2010;48(1):1-15. doi:10.1016/j.freeradbiomed.2009.09.026
  62. Lu L, Lu Q, Chen W, Li J, Li C, Zheng Z. Vitamin D3 protects against diabetic retinopathy by inhibiting high-glucose-induced activation of the ROS/TXNIP/NLRP3 inflammasome pathway. J Diabetes Res. 2018;2018:8193523. doi:10.1155/2018/8193523
  63. Rao Z, Chen X, Wu J, et al. Vitamin D receptor inhibits NLRP3 activation by impeding its BRCC3-mediated deubiquitination. Front Immunol. 2019;10:2783. doi:10.3389/fimmu.2019.02783
  64. Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012;71(1):50-61. doi:10.1017/S0029665111001650
  65. Fitch N, Becker AB, HayGlass KT. Vitamin D [1,25(OH)2D3] differentially regulates human innate cytokine responses to bacterial versus viral pattern recognition receptor stimuli. J Immunol. 2016;196(7):2965-2972. doi:10.4049/jimmunol.1500460
  66. Zdrenghea MT, Makrinioti H, Bagacean C, Bush A, Johnston SL, Stanciu LA. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol. 2017;27(1). doi:10.1002/rmv.1909
  67. Verway M, Bouttier M, Wang TT, et al. Vitamin D induces interleukin-1β expression: paracrine macrophage epithelial signaling controls tuberculosis infection. PLoS Pathog. 2013;9(6):e1003407. doi:10.1371/journal.ppat.1003407
  68. Tulk SE, Liao KC, Muruve DA, Li Y, Beck PL, MacDonald JA. Vitamin D3 metabolites enhance the NLRP3-dependent secretion of IL-1β from human THP-1 monocytic cells. J Cell Biochem. 2015;116(5):711-720. doi:10.1002/jcb.24985
  69. Lee MT, Kattan M, Fennoy I, et al. Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease. Blood Adv. 2018;2(9):969-978. doi:10.1182/bloodadvances.2017013979
  70. Autier P, Mullie P, Macacu A, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;5(12):986-1004. doi:10.1016/S2213-8587(17)30357-1
  71. Sluyter JD, Camargo CA, Waayer D, et al. Effect of monthly, high-dose, long-term vitamin D on lung function: a randomized controlled trial. Nutrients. 2017;9(12):E1353. doi:10.3390/nu9121353
  72. Scragg R. The vitamin D assessment (ViDA) study – design and main findings. J Steroid Biochem Mol Biol. 2020;198:105562. doi:10.1016/j.jsbmb.2019.105562
  73. Turin A, Bax JJ, Doukas D, et al. Interactions among vitamin D, atrial fibrillation, and the renin-angiotensin-aldosterone system. Am J Cardiol. 2018;122(5):780-784. doi:10.1016/j.amjcard.2018.05.013
  74. Zaheer S, Taquechel K, Brown JM, Adler GK, Williams JS, Vaidya A. A randomized intervention study to evaluate the effect of calcitriol therapy on the renin-angiotensin system in diabetes. J Renin Angiotensin Aldosterone Syst. 2018;19(1):1470320317754178. doi:10.1177/1470320317754178
  75. Cremer A, Tambosco C, Corcuff JB, et al. Investigating the association of vitamin D with blood pressure and the renin-angiotensin-aldosterone system in hypertensive subjects: a cross-sectional prospective study. J Hum Hypertens. 2018;32(2):114-121. doi:10.1038/s41371-017-0005-2
  76. Zittermann A, Ernst JB, Prokop S, et al. Effects of vitamin D supplementation on renin and aldosterone concentrations in patients with advanced heart failure: the EVITA trial. Int J Endocrinol. 2018;2018:5015417. doi:10.1155/2018/5015417
  77. Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014;4:7027. doi:10.1038/srep07027
  78. Xu J, Yang J, Chen J, Luo Q, Zhang Q, Zhang H. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin-angiotensin system. Mol Med Rep. 2017;16(5):7432-7438. doi:10.3892/mmr.2017.7546
  79. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. 2010;303(18):1815-1822. doi:10.1001/jama.2010.594
  80. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med.2016;176(2):175-183. doi:10.1001/2015.7148
  81. Schwartz JB. Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence. Clin Pharmacol Ther. 2009;85(2):198-203. doi:10.1038/clpt.2008.165
  82. Žofková Hypercalcemia. Pathophysiological aspects. Physiol Res. 2016;65(1):1-10. doi:10.33549/physiolres.933059
  83. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an anti-inflammatory agent modulating inflammasome activation. Int J Endocrinol. 2017;2017:1835195. doi:10.1155/2017/1835195
  84. Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020;6:14. doi:10.1038/s41421-020-0153-3
  85. Zhang R, Wang X, Ni L, et al. COVID-19: melatonin as a potential adjuvant treatment. Life Sci. Published online March 23, 2020. doi:10.1016/j.lfs.2020.117583
  86. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: a critical systematic review of clinical evidence. Complement Ther Med. 2019;42:65-81. doi:10.1016/j.ctim.2018.11.003
  87. Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clin Drug Investig. 2016;36(3):169-175. doi:10.1007/s40261-015-0368-5
  88. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;2:CD001520. doi:10.1002/14651858.CD001520
  89. Leite Pacheco R, de Oliveira Cruz Latorraca C, Adriano Leal Freitas da Costa A, Luiza Cabrera Martimbianco A, Vianna Pachito D, Riera R. Melatonin for preventing primary headache: a systematic review. Int J Clin Pract. 2018;72(7):e13203. doi:10.1111/ijcp.13203
  90. Abdelgadir IS, Gordon MA, Akobeng AK. Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis. Arch Dis Child. 2018;103(12):1155-1162. doi:10.1136/archdischild-2017-314181
  91. Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review. CNS Drugs. 2019;33(12):1167-1186. doi:10.1007/s40263-019-00680-w
  92. Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71(8):901-909. doi:10.1007/s00228-015-1873-4
  93. Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, von Känel R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res. 2008;44(2):127-133. doi:10.1111/j.1600-079X.2007.00499.x
  94. McGlashan EM, Nandam LS, Vidafar P, Mansfield DR, Rajaratnam SMW, Cain SW. The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose. Psychopharmacology (Berl). 2018;235(11):3201-3209. doi:10.1007/s00213-018-5019-0
  95. Huang Z, Liu Y, Qi G, Brand D, Zheng SG. Role of vitamin A in the immune system. J Clin Med. 2018;7(9):E258. doi:10.3390/jcm7090258
  96. Cui D, Moldoveanu Z, Stephensen CB. High-level dietary vitamin A enhances T-helper type 2 cytokine production and secretory immunoglobulin A response to influenza A virus infection in BALB/c mice. J Nutr. 2000;130(5):1132-1139. doi:10.1093/jn/130.5.1132
  97. Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino S, Milunsky A. Teratogenicity of high vitamin A intake. N Engl J Med. 1995;333(21):1369-1373. doi:10.1056/NEJM199511233332101
  98. Bartlett H, Eperjesi F. Possible contraindications and adverse reactions associated with the use of ocular nutritional supplements. Ophthalmic Physiol Opt. 2005;25(3):179-194. doi:10.1111/j.1475-1313.2005.00294.x
  99. Bendich A, Langseth L. Safety of vitamin A. Am J Clin Nutr. 1989;49(2):358-371. doi:10.1093/ajcn/49.2.358
  100. Cruz S, da Cruz SP, Ramalho A. Impact of vitamin A supplementation on pregnant women and on women who have just given birth: a systematic review. J Am Coll Nutr. 2018;37(3):243-250. doi:10.1080/07315724.2017.1364182
  101. Oliveira JM, Allert R, East CE. Vitamin A supplementation for postpartum women. Cochrane Database Syst Rev. 2016;3:CD005944. doi:10.1002/14651858.CD005944.pub3
  102. García-Cortés M, Robles-Díaz M, Ortega-Alonso A, Medina-Caliz I, Andrade RJ. Hepatotoxicity by dietary supplements: a tabular listing and clinical characteristics. Int J Mol Sci. 2016;17(4):537. doi:10.3390/ijms17040537
  103. Porter RS, Bode RF. A review of the antiviral properties of black elder (Sambucus nigra ) products. Phytother Res. 2017;31(4):533-554. doi:10.1002/ptr.5782
  104. Chen C, Zuckerman DM, Brantley S, et al. Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication. BMC Vet Res. 2014;10:24. doi:10.1186/1746-6148-10-24
  105. Barak V, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines. Eur Cytokine Netw. 2001;12(2):290-296.
  106. Barak V, Birkenfeld S, Halperin T, Kalickman I. The effect of herbal remedies on the production of human inflammatory and anti-inflammatory cytokines. Isr Med Assoc J. 2002;4(11 Suppl):919-922.
  107. Ulbricht C, Basch E, Cheung L, et al. An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration. J Diet Suppl. 2014;11(1):80-120. doi:10.3109/19390211.2013.859852
  108. Frank T, Janssen M, Netzet G, Christian B, Bitsch I, Netzel M. Absorption and excretion of elderberry (Sambucus nigra) anthocyanins in healthy humans. Methods Find Exp Clin Pharmacol. 2007;29(8):525-533. doi:10.1358/mf.2007.29.8.1116309
  109. Badescu M, Badulescu O, Badescu L, Ciocoiu M. Effects of Sambucus nigra and Aronia melanocarpa extracts on immune system disorders within diabetes mellitus. Pharm Biol. 2015;53(4):533-539. doi:10.3109/13880209.2014.931441
  110. Curtis PJ, Kroon PA, Hollands WJ, et al. Cardiovascular disease risk biomarkers and liver and kidney function are not altered in postmenopausal women after ingesting an elderberry extract rich in anthocyanins for 12 weeks. J Nutr. 2009;139(12):2266-2271. doi:10.3945/jn.109.113126
  111. Fallah AA, Sarmast E, Fatehi P, Jafari T. Impact of dietary anthocyanins on systemic and vascular inflammation: systematic review and meta-analysis on randomised clinical trials. Food Chem Toxicol. 2020;135:110922. doi:10.1016/j.fct.2019.110922
  112. Li S, Wu B, Fu W, Reddivari L. The anti-inflammatory effects of dietary anthocyanins against ulcerative colitis. Int J Mol Sci. 2019;20(10):E2588. doi:10.3390/ijms20102588
  113. Elderberry for influenza. Med Lett Drugs Ther. 2019;61(1566):32. [https://secure.medicalletter.org/w1566f]
  114. Hawkins J, Baker C, Cherry L, Dunne E. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: a meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019;42:361-365. doi:10.1016/j.ctim.2018.12.004
  115. Keppel Hesselink JM, de Boer T, Witkamp RF. Palmitoylethanolamide: a natural body-own anti-inflammatory agent, effective and safe against influenza and common cold. Int J Inflam. 2013;2013:151028. doi:10.1155/2013/151028
  116. Cordaro M, Cuzzocrea S, Crupi R. An update of palmitoylethanolamide and luteolin effects in preclinical and clinical studies of neuroinflammatory events. Antioxidants (Basel). 2020;9(3):E216. doi:10.3390/antiox9030216
  117. Davis MP, Behm B, Mehta Z, Fernandez C. The potential benefits of palmitoylethanolamide in palliation: a qualitative systematic review. Am J Hosp Palliat Care. 2019;36(12):1134-1154. doi:10.1177/1049909119850807
  118. Gabrielsson L, Mattsson S, Fowler CJ. Palmitoulethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol. 2016;82(4):932-942. doi:10.1111/bcp.13020
  119. Natural Medicines Database. Palmitoylethanolamide (PEA). Accessed March 30, 2020. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1596
  120. Fischer, W.C. and Black, R.E. Zinc and the risk for infectious disease. Annu Rev Nutr. 2004; 24:255-275. doi:10.1146/annurev.nutr.23.011702.073054
  121. Fraker, P.J.; King, L.E. et al. The dynamic link between the integrity of the immune system and zinc status. J Nutr. 2000; 130(5S Suppl):1399S-1406S.
  122. Shankar, A.H. and Prasad, A.S. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 1998; 68(2 Suppl):447S-463S.
  123. The Role of Zinc and Zinc Homeostasis in Macrophage Function. J Immunol Res. 2018 Dec 6;2018:6872621.
  124. Meydani SN, Barnett JB, Dallal GE, et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr. 2007 Oct;86(4):1167-73. Doi: 10.1093/ajcn/86.4.1167
  125. Barnett JB, Dao MC, Hamer DH, et al. Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2016 Mar;103(3):942-51. doi:10.3945/ajcn.115.115188
  126. Maares M, Haase H. Zinc and immunity: An essential interrelation. Arch Biochem Biophys. 2016 Dec 1;611:58-65.
  127. te Velthuis AJ, van den Worm SH, et al. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010 Nov 4;6(11):e1001176.
  128. King JC, Brown KH, Gibson RS, et al. Biomarkers of Nutrition for Development (BOND)-Zinc Review. J Nutr. 2016.

 

Partners

All contents © Copyright -2020 Alternative Therapies in Health and Medicine. All rights reserved. Alternative Therapies in Health and Medicine is a registered trademark.
All rights reserved. Terms and Conditions.