PROTECTIVE ACTIVITY OF ASCORBIC ACID AT INFLUENZA INFECTION

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Abstract

Abstract. Ascorbic acid (vitamin C, AA) is an essential nutrient of the human diet due to its participation on numerous regulatory and enzymatic processes. AA takes part in such vital physiological processes as hormone production, collagen synthesis, stimulation of the immune system, etc. In the present review the activities of AA are considered that provide its protective effect at influenza infection. This effect can be result of direct virus-inhibiting activity of AA as well as of anti-inflammatory and antioxidant properties. Oxidative stress during influenza infection leads to nonspecific damage of the pulmonary tissue and subsequent inflammation of the lungs. The antioxidant activity of AA results in alleviation of infection due to suppression of tissue damage as well as in inhibition of reactive oxygen species-mediated signal transduction and regulatory reactions. After oxidation by ROS, AA is converted to dehydroascorbic acid (DAA) and inhibits the key enzymes of NF-κB pathway, such as kinases IKKα and IKKβ. AA itself blocks the activity of another component of the NF-kB pathway, kinase IKKβ(SS/EE), whose activity is directed to the phosphorylation of the factor IκBα. As a result, activation of NF-κB and its transport to the nucleus does not occur. Thus, AA performs a dual function: first, it neutralizes free radicals, preventing them from activating NF-κB, and secondly, the product of its oxidation, DAA, further blocks the activation of this pathway. In addition, in some cases AA results in the decrease in the infectious activity of influenza virus that is not due to the antioxidant activity of AA, but to direct virus-inhibiting activity. Taken together, the presented data suggests that the use of drugs with antiviral and antioxidant activity, as a combination of individual drugs or, as in the case of AA, as a single drug with complex activity, for treatment of influenza has advantages over the etiotropic drug monotherapy scheme.

 

About the authors

V. V. Zarubaev

St. Petersburg Pasteur Institute, St. Petersburg

Author for correspondence.
Email: zarubaev@gmail.com
PhD (Biology), Senior Researcher, Laboratory of Experimental Virology Russian Federation

A. V. Slita

St. Petersburg Pasteur Institute, St. Petersburg

Email: zarubaev@gmail.com
PhD (Biology), Senior Researcher, Laboratory of Experimental Virology Russian Federation

I. N. Lavrentyeva

St. Petersburg Pasteur Institute, St. Petersburg

Email: zarubaev@gmail.com
PhD, MD (Medicine), Head of the Laboratory of Experimental Virology Russian Federation

V. S. Smirnov

Cytomed, Ltd., St. Petersburg

Email: zarubaev@gmail.com
PhD, MD (Medicine), Professor, Head Researcher Russian Federation

References

  1. Akaike T. Role of free radicals in viral pathogenesis and mutation. Rev. Med. Virol., 2001, vol. 11, iss. 2, pp. 87–101. doi: 10.1002/rmv.303
  2. Akaike T., Noguchi Y., Ijiri S., Setoguchi K., Suga M., Zheng Y.M., Dietzschold B., Maeda H. Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc. Natl. Acad. Sci. USA, 1996, vol. 93, no. 6, pp. 2448–2453.
  3. Bae S., Cho C.H., Kim H., Kim Y., Kim H.R., Hwang Y.I., Yoon J.H., Kang J.S., Lee W.J. In vivo consequence of vitamin C insufficiency in liver injury: vitamin C ameliorates T-cell-mediated acute liver injury in Gulo (-/-) mice. Antioxid. Redox Signal., 2013, vol. 19, iss. 17, pp. 2040–2053. doi: 10.1089/ars.2012.4756
  4. Baeuerle P.A., Henkel T. Function and activation of NF-kB in the immune system. Annu. Rev. Immunol., 1994, vol. 12, pp. 141–179. doi: 10.1146/annurev.iy.12.040194.001041
  5. Bowie A.G., O’Neill L.A. Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. J. Immunol., 2000, vol. 165, iss. 12, pp. 7180–7188. doi: https://doi.org/10.4049/jimmunol.165.12.7180
  6. Boyera N., Galey I., Bernard B.A. Effect of vitamin C and its derivatives on collagen synthesis and cross-linking by normal human fibroblasts. Int. J. Cosmet. Sci., 1998, vol. 20, iss. 3, pp. 151–158. doi: 10.1046/j.1467-2494.1998.171747.x
  7. Buffinton G.D., Christen S., Peterhans E., Stocker R. Oxidative stress in lungs of mice infected with influenza A virus. Free Radic. Res. Commun., 1992, vol. 16, iss. 2, pp. 99–110. doi: 10.3109/10715769209049163
  8. Cai J., Chen Y., Seth S., Furukawa S., Compans R.W., Jones D.P. Inhibition of influenza infection by glutathione. Free Radic. Biol. Med., 2003, vol. 34, iss. 7, pp. 928–936. doi: 10.1016/S0891-5849(03)00023-6
  9. Cai Y., Li Y.F., Tang L.P., Tsoi B., Chen M., Chen H., Chen X.M., Tan R.R., Kurihara H., He R.R. A new mechanism of vitamin C effects on A/FM/1/47(H1N1) virus-induced pneumonia in restraint-stressed mice. Biomed Res. Int., 2015, vol. 2015, 12 p. doi: 10.1155/2015/675149
  10. Camarena V., Wang G. The epigenetic role of vitamin C in health and disease. Cell. Mol. Life Sci., 2016, vol. 73, iss. 8, pp. 1645–1658. doi: 10.1007/s00018-016-2145-x
  11. Camini F.C., da Silva Caetano C.C., Almeida L.T., de Brito Magalhães C.L. Implications of oxidative stress on viral pathogenesis. Arch. Virol., 2017, vol. 162, iss. 4, pp. 907–917. doi: 10.1007/s00705-016-3187-y
  12. Cárcamo J.M., Pedraza A., Bórquez-Ojeda O., Zhang B., Sanchez R., Golde D.W. Vitamin C is a kinase inhibitor: dehydroascorbic acid inhibits IB kinase . Mol. Cell. Biol., 2004, vol. 24, no. 15, pp. 6645–6652. doi: 10.1128/mcb.24.15.6645-6652.2004
  13. Choi A.M., Knobil K., Otterbein S.L., Eastman D.A., Jacoby D.B. Oxidant stress responses in influenza virus pneumonia: gene expression and transcription factor activation. Am. J. Physiol., 1996, vol. 271, no. 3, pp. L383–L391.
  14. Coates B.M., Staricha K.L., Wiese K.M., Ridge K.M. Influenza A virus infection, innate immunity, and childhood. JAMA Pediatr., 2015, vol. 169, no. 10, pp. 956–963. doi: 10.1001/jamapediatrics.2015.1387
  15. Hemilä H., Chalker E., Douglas B. Vitamin C for preventing and treating the common cold. Cochrane Database Syst. Rev., 2007, no. 3, CD000980. doi: 10.1002/14651858.CD000980.pub3
  16. Englard S., Seifter S. The biochemical functions of ascorbic acid. Ann. Rev. Nutr., 1986, vol. 6, pp. 365–406. doi: 10.1146/annurev. nu.06.070186.002053
  17. Fowler III A.A., Kim C., Lepler L., Malhotra R., Debesa O., Natarajan R., Fisher B.J., Syed A., DeWilde C., Priday A., Kasirajan V. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J. Crit. Care Med., 2017, vol. 6, iss. 1, pp. 85–90. doi: 10.5492/wjccm.v6.i1.85
  18. Furuya A., Uozaki M., Yamasaki H., Arakawa T., Arita M., Koyama A.H. Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int. J. Mol. Med., 2008, vol. 22, iss. 4, pp. 541–545. doi: 10.3892/ijmm_00000053
  19. Gonzalez M.J., Miranda-Massari J.R., Berdiel M.J., Duconge J., Rodríguez-López J.L., Hunninghake R., Cobas-Rosario V.J. High dose intraveneous vitamin C and chikungunya fever: a case report. J. Orthomol. Med., 2014, vol. 29, iss. 4, pp. 154–156.
  20. Gullberg R.C., Steel J.J., Moon S.L., Soltani E., Geiss B.J. Oxidative stress influences positive strand RNA virus genome synthesis and capping. Virology, 2015, vol. 475, pp. 219–229. doi: 10.1016/j.virol.2014.10.037
  21. Hampl J.S., Taylor C.A., Johnston C.S. Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994. Am. J. Public Health, 2004, vol. 94, no. 5, pp. 870–875. doi: 10.2105/ajph.94.5.870
  22. Harakeh S., Jariwalla R.J. Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV-infected cells. Am. J. Clin. Nutr., 1991, vol. 54, suppl. 6, pp. 1231S–1235S.
  23. Hayashi T. Preventive effect of ascorbic acid against biological function of human immunodeficiency virus trans-activator of transcription. J. Intercult. Ethnopharmacol., 2016, vol. 5, iss. 2, pp. 205–209. doi: 10.5455/jice.20160316010322
  24. Hayashi T., Ueno Y., Okamoto T. Oxidoreductive regulation of nuclear factor kappa B. Involvement of a cellular reducing catalyst thioredoxin. J. Biol. Chem., 1993, vol. 268, no. 15, pp. 11380–11388.
  25. Hemilä H. Vitamin C and infections. Nutrients, 2017, vol. 9, iss. 4: 339. doi: 10.3390/nu9040339
  26. Hemilä H., Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst. Rev., 2013, iss. 1, CD000980. doi: 10.1002/14651858.CD000980.pub4
  27. Hennet T., Peterhans E., Stocker R. Alterations in antioxidant defences in lung and liver of mice infected with influenza A virus. J. Gen. Virol., 1992, no. 73, pp. 39–46. doi: 10.1099/0022-1317-73-1-39
  28. Hess A.F. Scurvy, Past and Present. Philadelphia, USA: J.B. Lippincott Company, Washington Sqvare Press, 1920, 261 p.
  29. Hosakote Y.M., Jantzi P.D., Esham D.L., Spratt H., Kurosky A., Casola A., Garofalo R.P. Viral-mediated inhibition of antioxidant enzymes contributes to the pathogenesis of severe respiratory syncytial virus bronchiolitis. Am. J. Respir. Crit. Care Med., 2011, vol. 183, no. 11, pp. 1550–1560. doi: 10.1164/rccm.201010-1755OC
  30. Huang Y.N., Lai C.C., Chiu C.T., Lin J.J., Wang J.Y. L-ascorbate attenuates the endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation and NF-B translocation in cortical neurons/glia Cocultures. PLoS One, 2014, vol. 9, iss. 7: e97276. doi: 10.1371/journal.pone.0097276
  31. Hume R., Weyers E. Changes in leucocyte ascorbic acid during the common cold. Scott. Med. J., 1973, vol. 18, iss. 1, pp. 3–7. doi: 10.1177/003693307301800102
  32. Israël N., Gougerot-Pocidalo M.A., Aillet F., Virelizier J.L. Redox status of cells influences constitutive or induced NF-kappa B translocation and HIV long terminal repeat activity in human T and monocytic cell lines. J. Immunol., 1992, vol. 149, iss. 10, pp. 3386–3393.
  33. Iwasaki A., Pillai P.S. Innate immunity to influenza virus infection. Nat. Rev. Immunol., 2014, vol. 14, pp. 315–328. doi: 10.1038/ nri3665
  34. Jariwalla R.J., Roomi M.W., Gangapurkar B., Kalinovsky T., Niedzwiecki A., Rath M. Suppression of influenza A virus nuclear antigen production and neuraminidase activity by a nutrient mixture containing ascorbic acid, green tea extract and amino acids. BioFactors, 2007, vol. 31, iss. 1, pp. 1–15. doi: 10.1002/biof.5520310101
  35. Kim H., Jang M., Kim Y., Choi J., Jeon J., Kim J., Hwang Y.I., Kang J.S., Lee W.J. Red ginseng and vitamin C increase immune cell activity and decrease lung inflammation induced by influenza A virus/H1N1 infection. J. Pharm. Pharmacol., 2016, vol. 68, iss. 3, pp. 406–420. doi: 10.1111/jphp.12529
  36. Kim Y., Kim H., Bae S., Choi J., Lim S.Y., Lee N., Kong J.M., Hwang Y.I., Kang J.S., Lee W.J. Vitamin C is an essential factor on the anti-viral immune responses through the production of interferon-/ at the initial stage of influenza a virus (H3N2) infection. Immune Netw., 2013, vol. 13, no. 2, pp. 70–74. doi: 10.4110/in.2013.13.2.70
  37. Kojo S. Vitamin C: basic metabolism and its function as an index of oxidative stress. Curr. Med. Chem., 2004, vol. 11, iss. 8, pp. 1041–1064. doi: 10.2174/0929867043455567
  38. Li W., Maeda N., Beck M.A. Vitamin C deficiency increases the lung pathology of influenza virus-infected Gulo-/- mice. J. Nutr., 2006, vol. 136, no. 10, pp. 2611–2616.
  39. Liang T., Chen X., Su M., Chen H., Lu G., Liang K. Vitamin C exerts beneficial hepatoprotection against Concanavalin A-induced immunological hepatic injury in mice through inhibition of NF-B signal pathway. Food Funct., 2014, vol. 5, iss. 9, pp. 2175–2182. doi: 10.1039/c4fo00224e
  40. Lykkesfeldt J., Michels A.J., Frei B. Vitamin C. Adv. Nutr., 2014, vol. 5, pp. 16–18. doi: 10.3945/an.113.005157
  41. Meyer M., Pahl H.L., Baeuerle P.A. Regulation of the transcription factors NF-kappa B and AP-1 by redox changes. Chem. Biol. Interact., 1994, vol. 91, no. 2–3, pp. 91–100.
  42. Mlkirova N., Hunninghake R. Effect of high dose vitamin C on Epstein–Barr viral infection. Med. Sci. Monit., 2014, vol. 20, pp. 725–732. doi: 10.12659/msm.890423
  43. Mohammed B.M., Fisher B.J., Kraskauskas D., Farkas D., Brophy D.F., Fowler A.A., Natarajan R. Vitamin C: a novel regulator of neutrophil extracellular trap formation. Nutrients, 2013, vol. 5, iss. 8, pp. 3131–3151. doi: 10.3390/nu5083131
  44. Muller F. Reactive oxygen intermediates and human immunodeficiency virus (HIV) infection. Free Radic. Biol. Med., 1992, vol. 13, iss. 6, pp. 651–657. doi: 10.1016/0891-5849(92)90039-J
  45. Noh K., Lim H., Moon S.-K., Kang J.S., Lee W.J., Lee D., Hwang Y.I. Mega-dose Vitamin Cmodulates T cell functions in Balb/c mice only when administered during T cell activation. Immunol. Lett., 2005, vol. 98, no. 1, pp. 63–72. doi: 10.1016/j.imlet.2004.10.012
  46. Padayatty S.J., Katz A., Wang Y., Eck P., Kwon O., Lee J.H., Shenglin C., Corpe C., Dutta A., Dutta S.K., Levine M. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J. Am. Coll. Nutr., 2003, vol. 22, iss. 1, pp. 18–35. doi: 10.1080/0731 5724.2003.10719272
  47. Pauling L. Vitamin C and the Common Cold. San Francisco, CA: W.H. Freeman and Company, 1970, 122 p.
  48. Peterhans E. Oxidants and antioxidants in viral diseases: disease mechanisms and metabolic regulation. J. Nutr., 1997, vol. 127, no. 5, pp. 962S–965S.
  49. Peterhans E. Sendai virus stimulates chemiluminescence in mouse spleen cells. Biochem. Biophys. Res. Commun., 1979, vol. 91, pp. 383–392. doi: 10.1016/0006-291X(79)90630-2
  50. Peterhans E., Grob M., Burge T., Zanoni R. Virus-induced formation of reactive oxygen intermediates in phagocytic cells. Free Radic. Res. Commun., 1987, vol. 3, iss. 1–5, pp. 39–46. doi: 10.3109/10715768709069768
  51. Qiao H., May J.M. Macrophage differentiation increases expression of the ascorbate transporter (SVCT2). Free Radic. Biol. Med., 2009, vol. 46, iss. 8, pp. 1221–1232. doi: 10.1016/j.freeradbiomed.2009.02.004
  52. Reshi M.L., Su Y.-C., Hong J.-R. RNA viruses: ROS-mediated cell death. Int. J. Cell. Biol., 2014, 16 p. doi: 10.1155/2014/467452
  53. Roederer M., Staal F.J., Raju P.A., Ela S.W., Herzenberg L.A., Herzenberg L.A. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. Proc. Natl. Acad. Sci. USA, 1990, vol. 87, no. 12, pp. 4884–4888. doi: 10.1073/ pnas.87.12.4884
  54. Sasazuki S., Sasaki S., Tsubono Y., Okubo S., Hayashi M., Tsugane S. Effect of vitamin C on common cold: randomized controlled trial. Eur. J. Clin. Nutr., 2006, vol. 60, pp. 9–17. doi: 10.1038/sj.ejcn.1602261
  55. Schwarz K.B. Oxidative stress during viral infection: a review. Free Radic. Biol. Med., 1996, vol. 21, iss. 5, pp. 641–649.
  56. Shi X., Shi Z., Huang H., Zhu H., Zhou P., Zhu H., Ju P. Ability of recombinant human catalase to suppress inflammation of the murine lung induced by influenza A. Inflammation, 2014, vol. 37, iss. 3, pp. 809–817. doi: 10.1007/s10753-013-9800-2
  57. Son E.W., Mo S.J., Rhee D.K., Pyo S. Vitamin C blocks TNF-alpha-induced NF-kappaB activation and ICAM-1 expression in human neuroblastoma cells. Arch. Pharm. Res., 2004, vol. 27, iss. 10: 1073.
  58. Tan P.H., Sagoo P., Chan C., Yates J.B., Campbell J., Beutelspacher S.C., Foxwell B.M., Lombardi G., George A.J. Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells. J. Immunol., 2005, vol. 174, iss. 12, pp. 7633–7644. doi: 10.4049/jimmunol.174.12.7633
  59. Terezhalmy G.T., Bottomley W.K., Pelleu G.B. The use of water-soluble bioflavonoid-ascorbic acid complex in the treatment of recurrent herpes labialis. Oral Surg. Oral Med. Oral Pathol., 1978, vol. 45, iss. 1, pp. 56–62.
  60. Uchide N., Toyoda H. Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules, 2011, vol. 16, iss. 3, pp. 2032–2052. doi: 10.3390/molecules16032032
  61. Wang H., Xu R., Shi Y., Si L., Jiao P., Fan Z., Han X., Wu X., Zhou X., Yu F., Zhang Y., Zhang L., Zhang L., Zhou D., Xiao S. Design, synthesis and biological evaluation of novel L-ascorbic acid-conjugated pentacyclic triterpene derivatives as potential influenza virus entry inhibitors. Eur. J. Med. Chem., 2016, vol. 110, pp. 376–388. doi: 10.1016/j.ejmech.2016.01.005
  62. Williams V.M., Filippova M., Soto U., Duerksen-Hughes P.J. HPV-DNA integration and carcinogenesis: putative roles for inflammation and oxidative stress. Future Virol., 2011, vol. 6, no. 1, pp. 45–57. doi: 10.2217/fvl.10.73
  63. Wintergerst E.S., Maggini S., Hornig D.H. Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann. Nutr. Metab., 2006, vol. 50, suppl. 2, pp. 85–94. doi: 10.1159/000090495
  64. Yuan S. Drugs to cure avian influenza infection-multiple ways to prevent cell death. Cell Death Dis., 2013, 4: e835. doi: 10.1038/ cddis.2013.367

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