Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19)

Ruben Manuel Luciano Colunga Biancatelli, Max Berrill, John D Catravas, Paul E Marik, Ruben Manuel Luciano Colunga Biancatelli, Max Berrill, John D Catravas, Paul E Marik

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma.

Keywords: COVID-19; Coronavirus; SARS-Cov-2; antiviral; flavonoids; immunonutrition; quercetin; vitamin C.

Copyright © 2020 Colunga Biancatelli, Berrill, Catravas and Marik.

Figures

Figure 1
Figure 1
Chemical structure of quercetin. Created with ChemDoodle Web with permission (18).
Figure 2
Figure 2
After exerting its scavenging properties, quercetin is oxidized into its reactive products o-semiquinone and o-quinone/quinone methide (QQ). These compounds can be recycled by antioxidants like ascorbate or NADH or removed by glutathione. If ascorbate or glutathione levels are reduced, QQ can bind protein thiols producing transient toxic compounds. Created with ChemDoodle Web with permission (18).

References

    1. Formica JV, Regelson W. Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol. (1995) 33:1061–80. 10.1016/0278-6915(95)00077-1
    1. Colunga Biancatelli RML, Berrill M, Marik PE. The antiviral properties of vitamin C. Expert Rev Anti Infect Ther. (2019) 18:99–101. 10.1080/14787210.2020.1706483
    1. Marik PE. Vitamin C: an essential “stress hormone” during sepsis. J Thorac Dis. (2020) 12(Suppl. 1):S84–8. 10.21037/jtd.2019.12.64
    1. Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. (2017) 9:1211. 10.3390/nu9111211
    1. Leibovitz B, Siegel BV. Ascorbic acid and the immune response. Adv Exp Med Biol. (1981) 135:1–25. 10.1007/978-1-4615-9200-6_1
    1. Dey S, Bishayi B. Killing of S. aureus in murine peritoneal macrophages by Ascorbic acid along with antibiotics Chloramphenicol or Ofloxacin: correlation with inflammation. Microb Pathog. (2018) 115:239–50. 10.1016/j.micpath.2017.12.048
    1. Furuya A, Uozaki M, Yamasaki H, Arakawa T, Arita Koyama MAH. Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int J Mol Med. (2008) 22:541–5. 10.3892/ijmm_00000053
    1. Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al. . Quercetin, inflammation and immunity. Nutrients. (2016) 8:167. 10.3390/nu8030167
    1. Robaszkiewicz A, Balcerczyk A, Bartosz G. Antioxidative and prooxidative effects of quercetin on A549 cells. Cell Biol Int. (2007) 31:1245–50. 10.1016/j.cellbi.2007.04.009
    1. Uchide N, Toyoda H. Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules. (2011) 16:2032–52. 10.3390/molecules16032032
    1. Nair MP, Kandaswami C, Mahajan S, Chadha KC, Chawda R, NairandSchwartz SAH. The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells. Biochim Biophys Acta. (2002) 1593:29–36. 10.1016/S0167-4889(02)00328-2
    1. Shinozuka K, Kikuchi Y, Nishino C, Mori A, Tawata S. Inhibitory effect of flavonoids on DNA-dependent DNA and RNA polymerases. Experientia. (1988) 44:882–5. 10.1007/BF01941188
    1. Bachmetov L, Gal-Tanamy M, Shapira A, Vorobeychik M, Giterman-Galam T, Sathiyamoorthy P, et al. . Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity. J Viral Hepat. (2012) 19:e81–8. 10.1111/j.1365-2893.2011.01507.x
    1. Spedding G, Ratty A, Middleton E, Jr. Inhibition of reverse transcriptases by flavonoids. Antiviral Res. (1989) 12:99–110. 10.1016/0166-3542(89)90073-9
    1. Cushnie TP, Lamb AJ. Antimicrobial activity of flavonoids. Int J Antimicrob Agents. (2005) 26:343–56. 10.1016/j.ijantimicag.2005.09.002
    1. Debiaggi M, Tateo F, Pagani L, Luini M, Romero E. Effects of propolis flavonoids on virus infectivity and replication. Microbiologica. (1990) 13:207–13.
    1. Winkel-Shirley B, Flavonoid Biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology. Plant Physiol. (2001) 126:485. 10.1104/pp.126.2.485
    1. Burger MC. ChemDoodle web components: HTML5 toolkit for chemical graphics, interfaces, and informatics. J Cheminform. (2015) 7:35. 10.1186/s13321-015-0085-3
    1. Gábor M. Szent-Györgyi and the bioflavonoids: new results and perspectives of pharmacological research into benzo-pyrone derivatives. Commemoration on the 50th anniversary of the award of the Nobel Prize. Prog Clin Biol Res. (1988) 280:1–15.
    1. Khoo NK, White CR, Pozzo-Miller L, Zhou F, Constance C, InoueandParks DAT. Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels. Free Radic Biol Med. (2010) 49:339–47. 10.1016/j.freeradbiomed.2010.04.022
    1. Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schäfer B, Hirsch-Ernst KI, et al. . Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res. (2018) 62:1700447. 10.1002/mnfr.201700447
    1. Brown JP. A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. Mutat Res. (1980) 75:243–77. 10.1016/0165-1110(80)90029-9
    1. Awad HM, Boersma MG, Vervoort Rietjens JIM. Peroxidase-catalyzed formation of quercetin quinone methide-glutathione adducts. Arch Biochem Biophys. (2000) 378:224–33. 10.1006/abbi.2000.1832
    1. Terao J. Dietary flavonoids as antioxidants in vivo: conjugated metabolites of (-)-epicatechin and quercetin participate in antioxidative defense in blood plasma. J Med Invest. (1999) 46:159–68.
    1. Abdelmoaty MA, Ibrahim MA, Ahmed NS, Abdelaziz MA. Confirmatory studies on the antioxidant and antidiabetic effect of quercetin in rats. Indian J Clin Biochem. (2010) 25:188–92. 10.1007/s12291-010-0034-x
    1. Nabavi SM, Nabavi SF, Eslami S, Moghaddam AH. In vivo protective effects of quercetin against sodium fluoride-induced oxidative stress in the hepatic tissue. Food Chem. (2012) 132:931–5. 10.1016/j.foodchem.2011.11.070
    1. Gormaz JG, Quintremil S, Rodrigo R. Cardiovascular disease: a target for the pharmacological effects of quercetin. Curr Top Med Chem. (2015) 15:1735–42. 10.2174/1568026615666150427124357
    1. Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta. (1995) 235:207–19. 10.1016/0009-8981(95)06045-1
    1. Cai Q, Rahn RO, Zhang R. Dietary flavonoids, quercetin, luteolin and genistein, reduce oxidative DNA damage and lipid peroxidation and quench free radicals. Cancer Lett. (1997) 119:99–107. 10.1016/S0304-3835(97)00261-9
    1. Erden Inal M, Kahraman A. The protective effect of flavonol quercetin against ultraviolet a induced oxidative stress in rats. Toxicology. (2000) 154:21–9. 10.1016/S0300-483X(00)00268-7
    1. Morikawa K, Nonaka M, Narahara M, Torii I, Kawaguchi K, Yoshikawa T, et al. . Inhibitory effect of quercetin on carrageenan-induced inflammation in rats. Life Sci. (2003) 74:709–21. 10.1016/j.lfs.2003.06.036
    1. Dimova S, Mugabowindekwe R, Willems T, Brewster ME, Noppe M, Ludwig A, et al. . Safety-assessment of 3-methoxyquercetin as an antirhinoviral compound for nasal application: effect on ciliary beat frequency. Int J Pharm. (2003) 263:95–103. 10.1016/S0378-5173(03)00363-6
    1. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. (2000) 351(Pt. 1):95–105. 10.1042/bj3510095
    1. Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, et al. . Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol. (1999) 128:999–1010. 10.1038/sj.bjp.0702879
    1. Agullo G, Gamet-Payrastre L, Manenti S, Viala C, Rémésy C, Chap H, et al. . Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem Pharmacol. (1997) 53:1649–57. 10.1016/S0006-2952(97)82453-7
    1. Peet GW, Li J. IkappaB kinases alpha and beta show a random sequential kinetic mechanism and are inhibited by staurosporine and quercetin. J Biol Chem. (1999) 274:32655–61. 10.1074/jbc.274.46.32655
    1. De Palma AM, Vliegen I, De Clercq E, Neyts J. Selective inhibitors of picornavirus replication. Med Res Rev. (2008) 28:823–84. 10.1002/med.20125
    1. Itsuka H, Ohsawa C, Ohiwa T, Umeda I, Suhara Y. Antipicornavirus flavone Ro 09-0179. Antimicrob Agents Chemother. (1982) 22:611–16. 10.1128/AAC.22.4.611
    1. Kaul TN, Middleton E, Jr. Ogra PL. Antiviral effect of flavonoids on human viruses. J Med Virol. (1985) 15:71–9. 10.1002/jmv.1890150110
    1. Evers DL, Chao CF, Wang X, Zhang Z, Huong SM, Huang ES. Human cytomegalovirus-inhibitory flavonoids: studies on antiviral activity and mechanism of action. Antiviral Res. (2005) 68:124–34. 10.1016/j.antiviral.2005.08.002
    1. Zandi K, Teoh BT, Sam SS, Wong PF, Mustafa MR, Abubakar S. Antiviral activity of four types of bioflavonoid against dengue virus type-2. Virol J. (2011) 8:560. 10.1186/1743-422X-8-560
    1. Veckenstedt A, Béládi I, Mucsi I. Effect of treatment with certain flavonoids on Mengo virus-induced encephalitis in mice. Arch Virol. (1978) 57:255–60. 10.1007/BF01315089
    1. Güttner J, Veckenstedt A, Heinecke H, Pusztai R. Effect of quercetin on the course of mengo virus infection in immunodeficient and normal mice. A histologic study. Acta Virol. (1982) 26:148–55.
    1. Nieman DC, Henson DA, Gross SJ, Jenkins DP, Davis JM, Murphy EA, et al. . Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc. (2007) 39:1561–9. 10.1249/mss.0b013e318076b566
    1. Nieman DC, Henson DA, Davis JM, Angela Murphy E, Jenkins DP, Gross SJ, et al. . Quercetin's influence on exercise-induced changes in plasma cytokines and muscle and leukocyte cytokine mRNA. J Appl Physiol. (2007) 103:1728–35. 10.1152/japplphysiol.00707.2007
    1. Nieman DC, Henson DA, Davis JM, Dumke CL, Gross SJ, Jenkins DP, et al. . Quercetin ingestion does not alter cytokine changes in athletes competing in the Western States Endurance Run. J Interferon Cytokine Res. (2007) 27:1003–11. 10.1089/jir.2007.0050
    1. Chen JY, Chang C-Y, Feng P-H, Chu C-C, So EC, Hu M-L. Plasma vitamin C is lower in postherpetic neuralgia patients and administration of vitamin C reduces spontaneous pain but not brush-evoked pain. Clin J Pain. (2009) 25:562–9. 10.1097/AJP.0b013e318193cf32
    1. Marik PE, Hooper MH. Doctor-your septic patients have scurvy! Crit Care. (2018) 22:23. 10.1186/s13054-018-1950-z
    1. Fowler AA, III, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, et al. . Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. (2019) 322:1261–70. 10.1001/jama.2019.11825
    1. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. (2017) 21:300. 10.1186/s13054-017-1891-y
    1. Anderson R, Smit MJ, Joone GK, Van Staden AM. Vitamin C and cellular immune functions. Protection against hypochlorous acid-mediated inactivation of glyceraldehyde-3-phosphate dehydrogenase and ATP generation in human leukocytes as a possible mechanism of ascorbate-mediated immunostimulation. Ann N Y Acad Sci. (1990) 587:34–48. 10.1111/j.1749-6632.1990.tb00131.x
    1. Lahiri S, Lloyd BB. The effect of stress and corticotrophin on the concentrations of vitamin C in blood and tissues of the rat. Biochem. J. (1962) 84:478–83. 10.1042/bj0840478
    1. Manning J, Mitchell B, Appadurai DA, Shakya A, Pierce LJ, Wang H, et al. . Vitamin C promotes maturation of T-cells. Antioxid Redox Signal. (2013) 19:2054–67. 10.1089/ars.2012.4988
    1. Valero N, Mosquera J, Alcocer S, Bonilla E, Salazar J, Álvarez-Mon M. Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis. Brain Res. (2015) 1622:368–76. 10.1016/j.brainres.2015.06.034
    1. Li W, Maeda N, Beck MA. Vitamin C deficiency increases the lung pathology of influenza virus-infected gulo-/- mice. J Nutr. (2006) 136:2611–16. 10.1093/jn/136.10.2611
    1. Cai Y, Li Y-F, Tang L-P, Tsoi B, Chen M, Chen H, et al. . A new mechanism of vitamin C effects on A/FM/1/47(H1N1) virus-induced pneumonia in restraint-stressed mice. BioMed Res Int. (2015) 2015:675149. 10.1155/2015/675149
    1. Banic S. Prevention of rabies by vitamin C. Nature. (1975) 258:153–4. 10.1038/258153a0
    1. Kimbarowski JA, Mokrow NJ. Colored precipitation reaction of the urine according to Kimbarowski (FARK) as an index of the effect of ascorbic acid during treatment of viral influenza. Das Deutsche Gesundheitswesen. (1967) 22:2413–18.
    1. Kim MS, Kim DJ, Na CH, Shin BS. A study of intravenous administration of vitamin c in the treatment of acute herpetic pain and postherpetic neuralgia. Ann Dermatol. (2016) 28:677–83. 10.5021/ad.2016.28.6.677
    1. Kim GN, Yoo WS, Park MH, Chung JK, Han YS, Chung IY, et al. . Clinical features of herpes simplex keratitis in a Korean tertiary referral center: efficacy of oral antiviral and ascorbic acid on recurrence. Kor J Ophthalmol. (2018) 32:353–60. 10.3341/kjo.2017.0131
    1. Hah YS, Chung HJ, Sontakke SB, Chung I-Y, Ju S. Ascorbic acid concentrations in aqueous humor after systemic vitamin C supplementation in patients with cataract: pilot study. BMC Ophthalmol. (2017) 17:121. 10.1186/s12886-017-0515-2
    1. Gonzalez MJ, Berdiel MJ, Duconge J, Levy T, Alfaro I, Morales R, et al. High dose intravenous vitamin C and influenza: a case report. J Orthomol Med. (2018) 33:1–3.
    1. Fowler Iii AA, Kim C, Lepler L, Malhotra R, Debesa O, Natarajan R., et al. . Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med. (2017) 6:85–90. 10.5492/wjccm.v6.i1.85
    1. Davis JM, Murphy EA, McClellan JL, Carmichael MD, Gangemi JD. Quercetin reduces susceptibility to influenza infection following stressful exercise. Am J Physiol Regul Integr Comp Physiol. (2008) 295:R505–9. 10.1152/ajpregu.90319.2008
    1. Biskind MS, Martin WC. The use of citrus flavonoids in respiratory infections. Am J Dig Dis. (1954) 21:177. 10.1007/BF02886384
    1. Liu S, Wu S, Jiang S. HIV entry inhibitors targeting gp41: from polypeptides to small-molecule compounds. Curr Pharm Des. (2007) 13:143–62. 10.2174/138161207779313722
    1. Yang J, Li M, Shen X, Liu S. Influenza A virus entry inhibitors targeting the hemagglutinin. Viruses. (2013) 5:352–73. 10.3390/v5010352
    1. Xia S, Liu Q, Wang Q, Sun Z, Su S, Duand L, et al. . Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. Virus Res. (2014) 194:200–10. 10.1016/j.virusres.2014.10.007
    1. Wu W, Li R, Li X, He J, Jiang S, Liu S, et al. . Quercetin as an antiviral agent inhibits Influenza A Virus (IAV) entry. Viruses. (2015) 8:6. 10.3390/v8010006
    1. Ganesan S, Faris AN, Comstock AT, Wang Q, Nanua S, Hershenson MB, et al. . Quercetin inhibits rhinovirus replication in vitro and in vivo. Antiviral Res. (2012) 94:258–71. 10.1016/j.antiviral.2012.03.005
    1. Ganesan S, Faris AN, Comstock AT, Chattoraj SS, Chattoraj A, Burgess JR, et al. . Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression. Respir Res. (2010) 11:131. 10.1186/1465-9921-11-131
    1. Nanua S, Zick SM, Andrade JE, Sajjan US, Burgess JR, Lukacs NW, et al. . Quercetin blocks airway epithelial cell chemokine expression. Am J Respir Cell Mol Biol. (2006) 35:602–10. 10.1165/rcmb.2006-0149OC
    1. Rogerio AP, Kanashiro A, Fontanari C, da Silva EV, Lucisano-Valim YM, Soares EG, et al. . Anti-inflammatory activity of quercetin and isoquercitrin in experimental murine allergic asthma. Inflamm Res. (2007) 56:402–8. 10.1007/s00011-007-7005-6
    1. Chiang LC, Chiang W, Liu MC, Lin CC. In vitro antiviral activities of Caesalpinia pulcherrima and its related flavonoids. J Antimicrob Chemother. (2003) 52:194–8. 10.1093/jac/dkg291
    1. Ono K, Nakane H. Mechanisms of inhibition of various cellular DNA and RNA polymerases by several flavonoids. J Biochem. (1990) 108:609–13. 10.1093/oxfordjournals.jbchem.a123251
    1. Ono K, Nakane H, Fukushima M, Chermann JC, Barré-Sinoussi F. Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases. Eur J Biochem. (1990) 190:469–76. 10.1111/j.1432-1033.1990.tb15597.x
    1. Vrijsen R, Everaert L, Boeyé A. Antiviral activity of flavones and potentiation by ascorbate. J Gen Virol. (1988) 69:1749–51. 10.1099/0022-1317-69-7-1749
    1. Vrijsen R, Everaert L, Van Hoof LM, Vlietinck AJ, Vanden Berghe DA, Boeyé A., et al. . The poliovirus-induced shut-off of cellular protein synthesis persists in the presence of 3-methylquercetin, a flavonoid which blocks viral protein and RNA synthesis. Antiviral Res. (1987) 7:35–42. 10.1016/0166-3542(87)90037-4
    1. Castrillo JL, Carrasco L. Action of 3-methylquercetin on poliovirus RNA replication. J Virol. (1987) 61:3319–21. 10.1128/JVI.61.10.3319-3321.1987
    1. Li BW, Zhang FH, Serrao E, Chen H, Sanchez TW, Yang LM, et al. . Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75. Bioorg Med Chem. (2014) 22:3146–58. 10.1016/j.bmc.2014.04.016
    1. Áy É, Hunyadi A, Mezei M, Minárovits J, Hohmann J. Flavonol 7-O-glucoside herbacitrin inhibits HIV-1 replication through simultaneous integrase and reverse transcriptase inhibition. Evid Based Complement Alternat Med. (2019) 2019:1064793. 10.1155/2019/1064793
    1. Harakeh S, Jariwalla RJ, Pauling L. Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells. Proc Natl Acad Sci USA. (1990) 87:7245–9. 10.1073/pnas.87.18.7245
    1. Xu HX, Wan M, Dong H, But PP, Foo LY. Inhibitory activity of flavonoids and tannins against HIV-1 protease. Biol Pharm Bull. (2000) 23:1072–6. 10.1248/bpb.23.1072
    1. Gonzalez O, Fontanes V, Raychaudhuri S, Loo R, Loo J, Arumugaswami V, et al. . The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production. Hepatology. (2009) 50:1756–64. 10.1002/hep.23232
    1. Hosokawa N, Hirayoshi K, Kudo H, Takechi H, Aoike A, Kawai K, et al. . Inhibition of the activation of heat shock factor in vivo and in vitro by flavonoids. Mol Cell Biol. (1992) 12:3490–8. 10.1128/MCB.12.8.3490
    1. Hosokawa N, Hirayoshi K, Nakai A, Hosokawa Y, Marui N, Yoshidaand M, et al. . Flavonoids inhibit the expression of heat shock proteins. Cell Struct Funct. (1990) 15:393–401. 10.1247/csf.15.393
    1. Alvarez P, Alvarado C, Puerto M, Schlumberger A, Jiménez L, De la Fuente M., et al. . Improvement of leukocyte functions in prematurely aging mice after five weeks of diet supplementation with polyphenol-rich cereals. Nutrition. (2006) 22:913–21. 10.1016/j.nut.2005.12.012
    1. Exon JH, Magnuson BA, South EH, Hendrix K. Effect of dietary chlorogenic acid on multiple immune functions and formation of aberrant crypt foci in rats. J Toxicol Environ Health A. (1998) 53:375–84. 10.1080/009841098159231
    1. Cinatl J, Cinatl J, Weber B, Rabenau H, Gumbel H, Chenot J, et al. . In vitro inhibition of human cytomegalovirus replication in human foreskin fibroblasts and endothelial cells by ascorbic acid 2-phosphate. Antiviral Res. (1995) 27:405–18. 10.1016/0166-3542(95)00024-G
    1. Kim Y, Kim H, Bae S, Choi J, Lim SY, Lee N, et al. . 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. Immune Netw. (2013) 13:70–74. 10.4110/in.2013.13.2.70
    1. Mikirova N. Hunninghake R. Effect of high dose vitamin C on Epstein-Barr viral infection. Med Sci Monit. (2014) 20:725–32. 10.12659/MSM.890423
    1. Kataoka A, Imai H, Inayoshi S, Tsuda T. Intermittent high-dose vitamin C therapy in patients with HTLV-I associated myelopathy. J Neurol Neurosurg Psychiatry. (1993) 56:1213–16. 10.1136/jnnp.56.11.1213
    1. Nakagawa M, Nakahara K, Maruyama Y, Kawabata M, Higuchi I, Kubota H, et al. . Therapeutic trials in 200 patients with HTLV-I-associated myelopathy/ tropical spastic paraparesis. J Neurovirol. (1996) 2:345–55. 10.3109/13550289609146899
    1. Stantic-Pavlinic M, Banic S, Marin J, Klemenc P. Vitamin C–a challenge in management of rabies. Swiss Med Weekly. (2004) 134:326–7.
    1. Siegel BV. Enhanced interferon response to murine leukemia virus by ascorbic acid. Infect Immun. (1974) 10:409–10. 10.1128/IAI.10.2.409-410.1974
    1. Siegel BV. Enhancement of interferon production by poly(rI)-poly(rC) in mouse cell cultures by ascorbic acid. Nature. (1975) 254:531–2. 10.1038/254531a0
    1. Horvath CM. The Jak-STAT pathway stimulated by interferon gamma. Sci STKE. (2004) 2004:tr8. 10.1126/stke.2602004tr8
    1. Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. . Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. (2004) 78:11334. 10.1128/JVI.78.20.11334-11339.2004
    1. Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, et al. . Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. (2003) 300:1394–9. 10.1126/science.1085952
    1. Marra MA, Jones SJ, Astell CR, Holt RA, Brooks-Wilson A, Butterfield YS, et al. . The genome sequence of the SARS-associated coronavirus. Science. (2003) 300:1399–404. 10.1126/science.1085953
    1. Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LLM, et al. . Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol. (2003) 331:991–1004. 10.1016/S0022-2836(03)00865-9
    1. Chen L, Li J, Luo C, Liu H, Xu W, Chen G, et al. . Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features. Bioorg Med Chem. (2006) 14:8295–306. 10.1016/j.bmc.2006.09.014
    1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. (2020) 579:270–3. 10.1038/s41586-020-2012-7
    1. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. . Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. (2020) 395:565–74. 10.1016/S0140-6736(20)30251-8
    1. Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, et al. . Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. (2020) 368:409–12. 10.3410/f.737592020.793572879
    1. Atherton JG, Kratzing CC, Fisher A. The effect of ascorbic acid on infection chick-embryo ciliated tracheal organ cultures by coronavirus. Arch Virol. (1978) 56:195–9. 10.1007/BF01317848
    1. Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. (2008) 585:325–37. 10.1016/j.ejphar.2008.03.008
    1. Guo Y, Bruno RS. Endogenous and exogenous mediators of quercetin bioavailability. J Nutr Biochem. (2015) 26:201–10. 10.1016/j.jnutbio.2014.10.008
    1. Murota K, Terao J. Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism. Arch Biochem Biophys. (2003) 417:12–7. 10.1016/S0003-9861(03)00284-4
    1. Graefe EU, Derendorf H, Veit M. Pharmacokinetics and bioavailability of the flavonol quercetin in humans. Int J Clin Pharmacol Ther. (1999) 37:219–33.
    1. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. (2007) 45:2179–205. 10.1016/j.fct.2007.05.015
    1. Andrea J, Day JAR, Morgan RA. Characterization of polyphenols metabolites. In: Bao Y, Fenwick R. editors. Phytochemicals in Health and Disease. New York, NY: Marcel Dekker, Inc; (2005). p. 50.
    1. de Boer VC, Dihal AA, van der Woude H, Arts IC, Wolffram S. Tissue distribution of quercetin in rats and pigs. J Nutr. (2005) 135:1718–25. 10.1093/jn/135.7.1718
    1. Moon YJ, Wang L, DiCenzo R, Morris ME. Quercetin pharmacokinetics in humans. Biopharm Drug Dispos. (2008) 29:205–17. 10.1002/bdd.605
    1. Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial. Urology. (1999) 54:960–3. 10.1016/S0090-4295(99)00358-1
    1. Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, et al. . Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. (1996) 2:659–68.
    1. Marik PE. Vitamin C for the treatment of sepsis: the scientific rationale. Pharmacol Ther. (2018) 189:63–70. 10.1016/j.pharmthera.2018.04.007
    1. Awad HM, Boersma MG, Boeren S, van der Woude H, van Zanden J, van Bladeren PJ, et al. . Identification of o-quinone/quinone methide metabolites of quercetin in a cellular in vitro system. FEBS Lett. (2002) 520:30–34. 10.1016/S0014-5793(02)02754-0
    1. Boots AW, Li H, Schins RP, Duffin R, Heemskerk JW, Bast A, et al. . The quercetin paradox. Toxicol Appl Pharmacol. (2007) 222:89–96. 10.1016/j.taap.2007.04.004
    1. Askari G, Ghiasvand R, Feizi A, Ghanadian SM, Karimian J. The effect of quercetin supplementation on selected markers of inflammation and oxidative stress. J Res Med Sci. (2012) 17:637–41.
    1. Boots AW, Kubben N, Haenen GR, Bast A. Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation. Biochem Biophys Res Commun. (2003) 308:560–5. 10.1016/S0006-291X(03)01438-4
    1. Bors W, Michel C, Schikora S. Interaction of flavonoids with ascorbate and determination of their univalent redox potentials: a pulse radiolysis study. Free Radic Biol Med. (1995) 19:45–52. 10.1016/0891-5849(95)00011-L
    1. Moalin M, van Strijdonck GPF, Bast A, Haenen GRMM. Competition between ascorbate and glutathione for the oxidized form of methylated quercetin metabolites and analogues: tamarixetin, 4′o-methylquercetin, has the lowest thiol reactivity. J Agric Food Chem. (2012) 60:9292–7. 10.1021/jf302068v
    1. Boots AW, Balk JM, Bast A, Haenen GR. The reversibility of the glutathionyl-quercetin adduct spreads oxidized quercetin-induced toxicity. Biochem Biophys Res Commun. (2005) 338:923–9. 10.1016/j.bbrc.2005.10.031
    1. Awad HM, Boersma MG, Boeren S, Van Bladeren PJ, Vervoort J, Rietjens IM. Quenching of quercetin quinone/quinone methides by different thiolate scavengers: stability and reversibility of conjugate formation. Chem Res Toxicol. (2003) 16:822–31. 10.1021/tx020079g
    1. Roubalová L, Purchartová K, Papoušková B, Vacek J, Kren V, Ulrichová J, et al. . Sulfation modulates the cell uptake, antiradical activity and biological effects of flavonoids in vitro: an examination of quercetin, isoquercitrin and taxifolin. Bioorg Med Chem. (2015) 23:5402–9. 10.1016/j.bmc.2015.07.055
    1. Ruotolo R, Calani L, Brighenti F, Crozier A, Ottonello S, Del Rio D. Glucuronidation does not suppress the estrogenic activity of quercetin in yeast and human breast cancer cell model systems. Arch Biochem Biophys. (2014) 559:62–7. 10.1016/j.abb.2014.03.003
    1. Terao J, Murota K, Kawai Y. Conjugated quercetin glucuronides as bioactive metabolites and precursors of aglycone in vivo. Food Funct. (2011) 2:11–7. 10.1039/C0FO00106F
    1. Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, 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) 34:1. 10.23812/CONTI-E
    1. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. (2020) 5 10.1172/jci.insight.138999
    1. Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng L, et al. . Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis. (2020) 221:1762–9. 10.1093/infdis/jiaa150
    1. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. . Remdesivir for the treatment of Covid-19 — preliminary report. N Engl J Med. (2020) 10.1056/NEJMoa2007764
    1. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. . Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma. JAMA. (2020) 323:1582–9. 10.1001/jama.2020.4783
    1. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. . Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. (2020). [Epub ahead of print]. 10.1002/jmv.25882
    1. Carr AC, Lykkesfeldt J. Discrepancies in global vitamin C recommendations: a review of RDA criteria and underlying health perspectives. Crit Rev Food Sci Nutr. (2020) 1–14. 10.1080/10408398.2020.1744513

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir