1. Cunha CB, Opal SM. Middle East respiratory syndrome (MERS): a new zoonotic viral pneumonia. Virulence 2014;5(6):650–654. https://doi.org/10.4161/viru.32077
2. De Groot RJ, Baker SC, Baric RS et al. Middle east Rrespiratory yndrome coronavirus (MERS-CoV): announcement of the Coronovirus Study. Group. JVirol 2013;87(14):7790-7792. https://doi.org/10.1128/JVI.01244-13
3. Velavan TP, Meyer CG. The COVID-19 epidemic. Trop Med Int Health 2020;25(3):278-280.
https://doi.org/10.1111/tmi.13383.
4. WHO Director-General's opening remarks at the media briefing on COVID-19. 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
5. Channappanavar R., Zhao J., Perlman S. T cell-mediated immune response to respiratory coronaviruses. Journal. 2014;59:118–128. https://doi.org/10.1007/s12026-014-8534-z
6. Bosch, B. J., van der Zee, R., de Haan, C. A., & Rottier, P. J. (2003). The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. Journal of virology, 77(16), 8801–8811. https://doi.org/10.1128/jvi.77.16.8801-8811.2003
7. Chen Y., Guo Y., Pan Y., Zhao Z.J. Structure analysis of the receptor binding of 2019-nCoV. Journal. 2020 https://doi.org/10.1016/j.bbrc.2020.02.071.
8. Hao X, Liang Z, Jiaxin , Jiakuan P, Hongxia D et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 12, 8 (2020). https://doi.org/10.1038/s41368-020-0074-x
9. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020. 382:1708-1720 https://doi.org/10.1056/NEJMoa2002032
10. Hamming I., Timens W., Bulthuis M.L., Lely A.T., Navis G., van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. Journal. Pathol 2004;203:631–637. https://doi.org/10.1002/path.1570.
11. Jia, H. P., Look, D. C., Shi, L., Hickey, M., Pewe, L., Netland, J., Farzan, M., Wohlford-Lenane, C., Perlman, S., & McCray, P. B., Jr (2005). ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. Journal of virology, 79(23), 14614–14621. https://doi.org/10.1128/JVI.79.23.14614-14621.2005
12. Burak M & Imen Y (1999) Flavonoids and their antioxidant properties. Turkiye Klin Tip Bil Derg 19, 296–304.
13. Cavalcante G.M., da Silva Cabral A.E., Silva C.C. Leishmanicidal Activity of Flavonoids Natural and Synthetic: A Minireview. Mintage J. Pharm. Med. Sci. (ISSN: 2320-3315), 2018;7:25–34. Retrieved from http://mjpms.in/index.php/ mjpms/article/view/317.
14. Takahashi, A., & Ohnishi, T. (2004). The significance of the study about the biological effects of solar ultraviolet radiation using the Exposed Facility on the International Space Station. Uchu Seibutsu Kagaku, 18(4), 255–260. https://doi.org/10.2187/bss.18.255
15. Dewick PM (2009) The shikimate pathway: aromatic amino acids and phenylpropanoids. In Medicinal Natural Products: a Biosynthetic Approach, 2nd ed., pp. 137–186. https://doi.org/10.1002/9780470742761.ch4
16. Shan X., Cheng J., Chen K.l., Liu Y.M., Juan L. Comparison of Lipoxygenase, Cyclooxygenase, Xanthine Oxidase Inhibitory Effects and Cytotoxic Activities of Selected Flavonoids. DEStech Trans. Environ. Energy Earth Sci. 2017 https://doi.org/10.12783/dteees/gmee2017/16624.
17. Kozłowska, A., Szostak-Wegierek, D. Flavonoids-food sources and health benefits. Rocz. Panstw. Zakl. Hig. (2014). 65(2), 79–85.
18. Ullah, A., Munir, S., Badshah, S. L., Khan, N., Ghani, L., Poulson, B. G., Emwas, A. H., & Jaremko, M. (2020). Important Flavonoids and Their Role as a Therapeutic Agent. Molecules (Basel, Switzerland), 25(22), 5243. https://doi.org/10.3390/molecules25225243
19. Ovando C, Hernandez D, Hernandez E, et al. (2009) Chemical studies of anthocyanins: a review. Food Chem 113, 859–871. http://dx.doi.org/10.1016/j.foodchem.2008.09.001
20. Lee, Y. K., Yuk, D. Y., Lee, J. W., Lee, S. Y., Ha, T. Y., Oh, K. W., Yun, Y. P., & Hong, J. T. (2009). (-)-Epigallocatechin-3-gallate prevents lipopolysaccharide-induced elevation of beta-amyloid generation and memory deficiency. Brain research, 1250, 164–174. https://doi.org/10.1016/j.brainres.2008.10.012
21. Zhao L., Yuan X., Wang J., Feng Y., Ji F., Li Z., Bian J. A review on flavones targeting serine/threonine protein kinases for potential anticancer drugs. Bioorganic Med. Chem. 2019;27:677–685. https://doi.org/10.1016/j.bmc.2019.01.027
22. Zhao K., Yuan Y., Lin B., Miao Z., Li Z., Guo Q., Lu N. LW-215, a newly synthesized flavonoid, exhibits potent anti-angiogenic activity in vitro and in vivo. Gene. 2018;642:533–541. https://doi.org/10.1016/j.gene.2017.11.065.
23. Metodiewa, D., Kochman, A., & Karolczak, S. (1997). Evidence for antiradical and antioxidant properties of four biologically active N,N-diethylaminoethyl ethers of flavanone oximes: a comparison with natural polyphenolic flavonoid (rutin) action. Biochemistry and molecular biology international, 41(5), 1067–1075. https://doi.org/10.1080/15216549700202141
24. Walker, E. H., Pacold, M. E., Perisic, O., Stephens, L., Hawkins, P. T., Wymann, M. P., & Williams, R. L. (2000). Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Molecular cell, 6(4), 909–919. https://doi.org/10.1016/s1097-2765(05)00089-4
25. Camero C.M., Germanò M.P., Rapisarda A., D’Angelo V., Amira S., Benchikh F., Braca A., De Leo M. Anti-angiogenic activity of iridoids from Galium tunetanum. Rev. Bras. de Farmacogn. 2018;28:374–377. https://doi.org/10.1016/j.bjp.2018.03.010
26. Mazidi M., Katsiki N., Banach M. A higher flavonoid intake is associated with less likelihood of nonalcoholic fatty liver disease: Results from a multiethnic study. J. Nutr. Biochem. 2019;65:66–71. https://doi.org/10.1016/j.jnutbio.2018.10.001.
27. Aguiar L.M., Geraldi M.V., Cazarin C.B.B., Junior M.R.M. Functional Food Consumption and Its Physiological Effects. Bioactive Compounds. Health Benefits and Potential Applications 2019, Pages 205-225. https://doi.org/10.1016/B978-0-12-814774-0.00011-6
28. Panche A., Diwan A., Chandra S. Flavonoids: An overview. J. Nutr. Sci. 2016;5:e47. https://doi.org/10.1017/jns.2016.41
29. Khan M.K., Zill E.H., Dangles O. A comprehensive review on flavanones, the major citrus polyphenols. J. Food Compos. Anal. 2014;33:85–104. https://doi.org/10.1016/j.jfca.2013.11.004.
30. Khalifa I., Zhu W., Li K.-k., Li C.-m. Polyphenols of mulberry fruits as multifaceted compounds: Compositions, metabolism, health benefits, and stability—A structural review. J. Funct. Foods. 2018;40:28–43. https://doi.org/10.1016/j.jff.2017.10.041
31. Iwashina T (2013) Flavonoid properties of five families newly incorporated into the order Caryophyllales (Review). Bull Natl Mus Nat Sci 39, 25–51. http://ci.nii.ac.jp/vol_issue/nels/AA12231458_en.html
32. Kawabata, K., Mukai, R., Ishisaka, A. Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability. Food Funct. 2015;6(5):1399-1417. https://doi.org/10.1039/C4FO01178C
33. Chun, OK., Chung, S-J., Claycombe, KJ., Song, WO. Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults. J Nutr. 2008;138(4):753-760. https://doi.org/10.1093/jn/138.4.753
34. Wang, W., Sun, C., Mao, L et al. The biological activities, chemical stability, metabolism and delivery systems of quercetin: a review. Trends in Food Sci Technol. 2016;56:21-38. https://doi.org/10.1016/j.tifs.2016.07.004
35. Kawai, Y . Understanding metabolic conversions and molecular actions of flavonoids in vivo: toward new strategies for effective utilization of natural polyphenols in human health. J Med Invest. 2018;65(3.4):162-165. https://doi.org/10.2152/jmi.65.162
36. Davis, JM., Murphy, EA., Carmichael, MD. Effects of the dietary flavonoid quercetin upon performance and health. Curr Sports Med Rep. 2009;8(4):206-213. https://doi.org/10.1249/JSR.0b013e3181ae8959
37. Dabeek, WM., Marra, MV. Dietary quercetin and kaempferol: bioavailability and potential cardiovascular-related bioactivity in humans. Nutrients. 2019;11(10):2288. https://doi.org/10.3390/nu11102288
38. Li, Y., Yao, J., Han, C et al. Quercetin, inflammation and immunity. Nutrients. 2016;8(3):167. https://doi.org/10.3390/nu8030167
39. Jafarinia, M., Sadat Hosseini, M., Kasiri, N et al. Quercetin with the potential effect on allergic diseases. Allergy Asthma Clin Immunol. 2020;16(1):36. https://doi.org/10.1186/s13223-020-00434-0
40. Brito, AF., Ribeiro, M., Abrantes, AM et al. Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Curr Med Chem. 2015;22(26):3025-3039. https://doi.org/10.2174/0929867322666150812145435
41. Dhiman, P., Malik, N., Sobarzo-Sánchez, E., Uriarte, E., Khatkar, A. Quercetin and related chromenone derivatives as monoamine oxidase inhibitors: targeting neurological and mental disorders. Molecules. 2019;24(3):418. https://doi.org/10.3390/molecules24030418
42. Chen, S., Jiang, H., Wu, X., Fang, J. Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes. Mediators Inflamm. 2016;2016(3):1-5. https://doi.org/10.1155/2016/9340637
43. Veckenstedt, A., Güttner, J., Béládi, I. Synergistic action of quercetin and murine alpha/beta interferon in the treatment of Mengo virus infection in mice. Antiviral Res. 1987;7(3):169-178. https://doi.org/10.1016/0166-3542(87)90005-2
44. Agrawal PK, Agrawal C, Blunden G. Quercetin: Antiviral Significance and Possible COVID-19 Integrative Considerations https://doi.org/10.1177/1934578X20976293
45. De Palma, AM., Vliegen, I., De Clercq, E., Neyts, J. Selective inhibitors of picornavirus replication. Med Res Rev. 2008;28(6):823-884. https://doi.org/10.1002/med.20125
47. Ganesan, S., Faris, AN., Comstock, AT et al. Quercetin inhibits rhinovirus replication in vitro and in vivo. Antiviral Res. 2012;94(3):258-271. https://doi.org/10.1016/j.antiviral.2012.03.005
48. Heinz, SA., Henson, DA., Austin, MD., Jin, F., Nieman, DC. Quercetin supplementation and upper respiratory tract infection: a randomized community clinical trial. Pharmacol Res. 2010;62(3):237-242. https://doi.org/10.1016/j.phrs.2010.05.001
49. Hung, P-Y., Ho, B-C., Lee, S-Y et al. Houttuynia cordata targets the beginning stage of herpes simplex virus infection. PLoS One. 2015;10(2):e0115475. https://doi.org/10.1371/journal.pone.0115475
50. El-Toumy, SA., Salib, JY., El-Kashak, WA et al. Antiviral effect of polyphenol rich plant extracts on herpes simplex virus type 1. Food Sci Hum Wellness. https://doi.org/10.1016/j.fshw.2018.01.001
51. Nieman, DC., Henson, DA., Gross, SJ et al. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc. 2007;39(9):1561-1569. https://doi.org/10.1249/mss.0b013e318076b566
52. Chaabi, M . Antiviral effects of quercetin and related compounds. Naturopathic Currents, Special Edition, April 2020, Antiviral effects of quercetin and related compounds. https://naturopathiccurrents.com/sites/default/files/AntiviralEffectsofQuercetinandRelatedCompounds_0.pdf
53. Shinozuka, K., Kikuchi, Y., Nishino, C., Mori, A., Tawata, S. Inhibitory effect of flavonoids on DNA-dependent DNA and RNA polymerases. Experientia. 1988;44(10):882-885. https://doi.org/10.1007/BF01941188
54. Spedding, G., Ratty, A., Middleton, E. Inhibition of reverse transcriptases by flavonoids. Antiviral Res. 1989;12(2):99-110. https://doi.org/10.1016/0166-3542(89)90073-9
55. Colunga Biancatelli, RML., Berrill, M., Catravas, JD., Marik, PE. Quercetin and vitamin C: an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol. 2020;11:1451. https://doi.org/10.3389/fimmu.2020.01451
56. Debiaggi, M., Tateo, F., Pagani, L., Luini, M., & Romero, E. (1990). Effects of propolis flavonoids on virus infectivity and replication. Microbiologica, 13(3), 207–213.
57. Yi, L., Li, Z., Yuan, K et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78(20):11334-11339. https://doi.org/10.1128/JVI.78.20.11334-11339.2004
58. Marra, MA., Jones, SJ., Astell, CR et al. The genome sequence of the SARS-associated coronavirus. Science. 2003;300(5624):1399-1404. https://doi.org/10.1126/science.1085953
59. Snijder, EJ., Bredenbeek, PJ., Dobbe, JC 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(5):991-1004. https://doi.org/10.1016/S0022-2836(03)00865-9
60. Chen, L., Li, J., Luo, C et al. Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features. Bioorg Med Chem. 2006;14(24):8295-8306. https://doi.org/10.1016/j.bmc.2006.09.014
61. Zhang, L., Lin, D., Sun, X et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409-412. https://doi.org/10.1126/science.abb3405
62. Huang, F., Li, Y., Leung, E. L., Liu, X., Liu, K., Wang, Q., Lan, Y., Li, X., Yu, H., Cui, L., Luo, H., & Luo, L. (2020). A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19). Pharmacological research, 158, 104929. https://doi.org/10.1016/j.phrs.2020.104929
63. Polansky, H., Lori, G., disease, C. Coronavirus disease 2019 (COVID-19): first indication of efficacy of Gene-Eden-VIR/Novirin in SARS-CoV-2 infection. Int J Antimicrob Agents. 2020;55(6):105971. https://doi.org/10.1016/j.ijantimicag.2020.105971
65. Han, Y-S., Chang, G-G., Juo, C-G et al. Papain-Like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition. Biochemistry. 2005;44(30):10349-10359. https://doi.org/10.1021/bi0504761
66. Dabbagh-Bazarbachi, H., Clergeaud, G., Quesada, IM., Ortiz, M., O’Sullivan, CK., Fernández-Larrea, JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem. 2014;62(32):8085-8093. https://doi.org/10.1021/jf5014633
67. Alschuler, L., Weil, A., Horwitz, R et al. Integrative considerations during the COVID-19 pandemic. Explore. 2020;16(6):354-356. https://doi.org/10.1016/j.explore.2020.03.007
68. jo, S., Kim, H., Kim, S., Shin, DH., Kim, M-S. Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors. Chem Biol Drug Des. 2019;94(6):2023-2030. https://doi.org/10.1111/cbdd.13604 31436895
69. Smith, M., Smith, JC. Repurposing therapeutics for COVID-19: Supercomputer-based docking to the SARS-CoV-2 viral spike protein and viral spike protein-human ACE2 interface. ChemRxiv. 2020.
70. Nguyen, TTH., Woo, H-J., Kang, H-K et al. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris. Biotechnol Lett. 2012;34(5):831-838. https://doi.org/10.1007/s10529-011-0845-8
71. Hui, DS., Azhar, EI., Madani, TA et al. The continuing 2019‐nCoV epidemic threat of novel coronaviruses to global health – the latest 2019 novel coronavirus outbreak in Wuhan, China. International J. of Infect Dis. 2020;2020(91):264-266. https://doi.org/10.1016/j.ijid.2020.01.009
72. Glinsky G. V. (2020). Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells. Biomedicines, 8(5), 129. https://doi.org/10.3390/biomedicines8050129
73. Ahmed, AK., Albalawi, YS., Shora, HA et al. Effects of quadruple therapy: zinc, quercetin, bromelain and vitamin C on the clinical outcomes of patients infected with COVID-19. Rea Int J of End and Diabe. 2020;1(1):018-021. https://doi.org/10.37179/rijed.000005
74. Chojnacka, K., Witek-Krowiak, A., Skrzypczak, D., Mikula, K., Młynarz, P. Phytochemicals containing biologically active polyphenols as an effective agent against Covid-19-inducing coronavirus. J Funct Foods. 2020;73:104146. https://doi.org/10.1016/j.jff.2020.104146
75. Williamson, G., Kerimi, A. Testing of natural products in clinical trials targeting the SARS-CoV-2 (Covid-19) viral spike protein-angiotensin converting enzyme-2 (ACE2) interaction. Biochem Pharmacol. 2020;178:114123. https://doi.org/10.1016/j.bcp.2020.114123
76. Yoshikawa, T., Hill, T., Li, K., Peters, C. J., & Tseng, C. T. (2009). Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. Journal of virology, 83(7), 3039–3048. https://doi.org/10.1128/JVI.01792-08
77. Yuki, K., Fujiogi, M., & Koutsogiannaki, S. (2020). COVID-19 pathophysiology: A review. Clinical immunology (Orlando, Fla.), 215, 108427. Advance online publication. https://doi.org/10.1016/j.clim.2020.108427
78. Huang C, Wang Y, Li X, Ren L, Zhao J et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 2020; 395 (10223): 497-506. https://doi.org/10.1016/s0140-6736(20)30183-5
79. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Frontiers in Immunology 2019; 10: 119. https://doi.org/10.3389/fimmu.2019.00119
80. Wang W, He J, Lie p, Huang l, Wu S et al. The definition and risks of cytokine release syndrome-like in 11 COVID19-infected pneumonia critically ill patients: disease characteristics and retrospective analysis. MedRxiv 2020. https://doi.org/10.1101/2020.02.26.20026989
81. Read M. A. (1995). Flavonoids: naturally occurring anti-inflammatory agents. The American journal of pathology, 147(2), 235–237.
82. Manjeet K, R., & Ghosh, B. (1999). Quercetin inhibits LPS-induced nitric oxide and tumor necrosis factor-alpha production in murine macrophages. International journal of immunopharmacology, 21(7), 435–443. https://doi.org/10.1016/s0192-0561(99)00024-7
83. Geraets, L., Moonen, H. J., Brauers, K., Wouters, E. F., Bast, A., & Hageman, G. J. (2007). Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells. The Journal of nutrition, 137(10), 2190–2195. https://doi.org/10.1093/jn/137.10.2190
84. Bureau, G., Longpré, F., & Martinoli, M. G. (2008). Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. Journal of neuroscience research, 86(2), 403–410. https://doi.org/10.1002/jnr.21503
85. Kim, H. P., Mani, I., Iversen, L., & Ziboh, V. A. (1998). Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostaglandins, leukotrienes, and essential fatty acids, 58(1), 17–24. https://doi.org/10.1016/s0952-3278(98)90125-9
86. Lee, K. M., Hwang, M. K., Lee, D. E., Lee, K. W., & Lee, H. J. (2010). Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells. Journal of agricultural and food chemistry, 58(9), 5815–5820. https://doi.org/10.1021/jf903698s
87. Chirumbolo S. (2010). The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflammation & allergy drug targets, 9(4), 263–285. https://doi.org/10.2174/187152810793358741
88. Yang, D., Liu, X., Liu, M., Chi, H., Liu, J., & Han, H. (2015). Protective effects of quercetin and taraxasterol against H2O2-induced human umbilical vein endothelial cell injury in vitro. Experimental and therapeutic medicine, 10(4), 1253–1260. https://doi.org/10.3892/etm.2015.2713
89. Huang, R.Y.; Yu, Y.L.; Cheng, W.C.; OuYang, C.N.; Fu, E.; Chu, C.L. Immunosuppressive effect of quercetin on dendritic cell activation and function. J Immunol June 15, 2010, 184 (12) 6815-6821. https://doi.org/10.4049/jimmunol.0903991
90. Cheng, S-C., Huang, W-C., S. Pang, J-H., Wu, Y-H., Cheng, C-Y et al. Quercetin inhibits the production of IL-1β-induced inflammatory cytokines and chemokines in ARPE-19 cells via the MAPK and NF-κB signaling pathways. Int J Mol Sci. 2019;20(12):2957. https://doi.org/10.3390/ijms20122957
91. Nair, M. P., Kandaswami, C., Mahajan, S., Chadha, K. C., Chawda, R., Nair, H., Kumar, N., Nair, R. E., & Schwartz, S. A. (2002). The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells. Biochimica et biophysica acta, 1593(1), 29–36. https://doi.org/10.1016/s0167-4889(02)00328-2
93. Mehta, P., McAuley, DF., Brown, M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. https://doi.org/10.1016/S0140-6736(20)30628-0
94. Ding, S., Xu, S., Ma, Y., Liu, G., Jang, H., Fang, J. Modulatory mechanisms of the NLRP3 inflammasomes in diabetes. Biomolecules. 2019;9(12):E850. https://doi.org/10.3390/biom9120850
95. Chen, I-Y., Moriyama, M., Chang, M-F., Ichinohe, T. Severe acute respiratory syndrome coronavirus viroporin 3A activates the NLRP3 inflammasome. Front Microbiol. 2019;10:50. https://doi.org/10.3389/fmicb.2019.00050
96. Lim, H., Min, DS., Park, H., Kim, HP. Flavonoids interfere with NLRP3 inflammasome activation. Toxicol Appl Pharmacol. 2018;355:93-102. https://doi.org/10.1016/j.taap.2018.06.022
97. Cialdella-Kam, L., Nieman, D., Knab, A et al. A mixed Flavonoid-Fish oil supplement induces immune-enhancing and anti-inflammatory transcriptomic changes in adult obese and overweight women—A randomized controlled trial. Nutrients. 2016;8(5):pii: E277. https://doi.org/10.3390/nu8050277
98. Nedoborenko, V. M., Kaidashev, I., Lavrenko, A., Vesnina, L., & Mamontova, T. (2017). Inclusion of Quercetin in Treatment Reduces the Level of Interleukin 6 in Women with Iron Deficiency Anemia and Obesity. The Medical and Ecological Problems, 21(5-6), 37-39. Retrieved from https://ecomed-journal.org/index.php/journal/article/view/100
99. Kritas, SK., Ronconi, G., Caraffa, A et al. Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy. J Biol Regul Homeost Agents. 2020;34(1):9-14. https://doi.org/10.23812/20-Editorial-Kritas
100. Weng, Z., Zhang, B., Asadi, S., Zuyi, W., Bodi, Z., Shahrzad, A et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One. 2012;7(3):e33805. https://doi.org/10.1371/journal.pone.0033805
101. Shaik, Y., Caraffa, A., Ronconi, G., Lessiani, G., Conti, P. Impact of polyphenols on mast cells with special emphasis on the effect of quercetin and luteolin. Cent Eur J Immunol. 2018;43(4):476-481. https://doi.org/10.5114/ceji.2018.81347
102. Choudhary, S., Sharma, K., & Silakari, O. (2020). The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options. Microbial pathogenesis, 150, 104673. Advance online publication. https://doi.org/10.1016/j.micpath.2020.104673
103. Schofield, J. H., & Schafer, Z. T. (2021). Mitochondrial Reactive Oxygen Species and Mitophagy: A Complex and Nuanced Relationship. Antioxidants & redox signaling, 34(7), 517–530. https://doi.org/10.1089/ars.2020.8058
104. Picca, A., Calvani, R., Coelho-Junior, H. J., Landi, F., Bernabei, R., & Marzetti, E. (2020). Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration. Antioxidants (Basel, Switzerland), 9(8), 647. https://doi.org/10.3390/antiox9080647
105. Saleh, J., Peyssonnaux, C., Singh, K. K., & Edeas, M. (2020). Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion, 54. https://doi.org/10.1016/j.mito.2020.06.008
106. Zhang, Z., Rong, L., & Li, Y. P. (2019). Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis. Oxidative medicine and cellular longevity, 2019, 1409582. https://doi.org/10.1155/2019/1409582
107. Ivanov, A. V., Valuev-Elliston, V. T., Ivanova, O. N., Kochetkov, S. N., Starodubova, E. S., Bartosch, B., & Isaguliants, M. G. (2016). Oxidative Stress during HIV Infection: Mechanisms and Consequences. Oxidative medicine and cellular longevity, 2016, 8910396.
108. Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., Liu, S., Zhao, P., Liu, H., Zhu, L., Tai, Y., Bai, C., Gao, T., Song, J., Xia, P., Dong, J., Zhao, J., & Wang, F. S. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet. Respiratory medicine, 8(4), 420–422. https://doi.org/10.1016/S2213-2600(20)30076-X
109. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054–1062. https://doi.org/10.1016/S0140-6736(20)30566-3
110. Miripour, Z. S., Sarrami-Forooshani, R., Sanati, H., Makarem, J., Taheri, M. S., Shojaeian, F. (2020). Real-time diagnosis of reactive oxygen species (ROS) in fresh sputum by electrochemical tracing; correlation between COVID-19 and viral-induced ROS in lung/respiratory epithelium during this pandemic. Biosensors and Bioelectronics, 112435. https://doi.org/10.1016/j.bios.2020.112435
111. Ntyonga-Pono M. P. (2020). COVID-19 infection and oxidative stress: an under-explored approach for prevention and treatment?. The Pan African medical journal, 35(Suppl 2), 12. https://doi.org/10.11604/pamj.2020.35.2.22877
112. Tsujimoto, M., Yokota, S., Vilcek, J., & Weissmann, G. (1986). Tumor necrosis factor provokes superoxide anion generation from neutrophils. Biochemical and biophysical research communications, 137(3), 1094–1100. https://doi.org/10.1016/0006-291x(86)90337-2
113. Kharazmi, A., Nielsen, H., Rechnitzer, C., & Bendtzen, K. (1989). Interleukin 6 primes human neutrophil and monocyte oxidative burst response. Immunology letters, 21(2), 177–184. https://doi.org/10.1016/0165-2478(89)90056-4
114. Colston, J. T., Chandrasekar, B., & Freeman, G. L. (2002). A novel peroxide-induced calcium transient regulates interleukin-6 expression in cardiac-derived fibroblasts. The Journal of biological chemistry, 277(26), 23477–23483. https://doi.org/10.1074/jbc.M108676200
115. J. Wu, Tackle the free radicals damage in COVID-19, Nitric Oxide, https:// doi.org/10.1016/j.niox.2020.06.002.
116. Prochazkova D., Bousova I., Wilhelmova N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011;82:513–523. https://doi.org/10.1016/j.fitote.2011.01.018.
117. Terao J. Factors modulating bioavailability of quercetin-related flavonoids and the consequences of their vascular function. Biochem. Pharmacol. 2017;139:15–23. https://doi.org/10.1016/j.bcp.2017.03.021.
118. Shu Z., Yang Y., Yang L., Jiang H., Yu X., Wang Y. Cardioprotective effects of dihydroquercetin against ischemia reperfusion injury by inhibiting oxidative stress and endoplasmic reticulum stress-induced apoptosis via the PI3K/Akt pathway. Food Funct. 2019;10:203–215. https://doi.org/10.1039/C8FO01256C.
119. Terao J. (1999). Dietary flavonoids as antioxidants in vivo: conjugated metabolites of (-)-epicatechin and quercetin participate in antioxidative defense in blood plasma. The journal of medical investigation : JMI, 46(3-4), 159–168. http://www.ncbi.nlm.nih.gov/pubmed/10687310
121. Kumar, P., Khanna, M., Srivastava, V et al. Effect of quercetin supplementation on lung antioxidants after experimental influenza virus infection. Exp Lung Res. 2005;31(5):449-459. https://doi.org/10.1080/019021490927088
122. Milea Ș.-A., Aprodu I., Vasile A.M., Barbu V., Râpeanu G., Bahrim G.E., Stănciuc N. Widen the functionality of flavonoids from yellow onion skins through extraction and microencapsulation in whey proteins hydrolysates and different polymers. J. Food Eng. 2019;251:29–35. https://doi.org/10.1016/j.jfoodeng.2019.02.003.
123. Pucciarini L., Ianni F., Petesse V., Pellati F., Brighenti V., Volpi C., Gargaro M., Natalini B., Clementi C., Sardella R. Onion (Allium cepa L.) Skin: A Rich Resource of Biomolecules for the Sustainable Production of Colored Biofunctional Textiles. Molecules. 2019;24:634. https://doi.org/10.3390/molecules24030634.
124. Yang S.J., Paudel P., Shrestha S., Seong S.H., Jung H.A., Choi J.S. In vitro protein tyrosine phosphatase 1B inhibition and antioxidant property of different onion peel cultivars: A comparative study. Food Sci. Nutr. 2019;7:205–215. https://doi.org/10.1002/fsn3.863.
125. Ozolina, A., Sarkele, M., Sabelnikovs, O., Skesters, A., Jaunalksne, I., Serova, J., Ievins, T., Bjertnaes, L. J., & Vanags, I. (2016). Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study. Frontiers in medicine, 3, 64. https://doi.org/10.3389/fmed.2016.00064
126. Idell S. (2003). Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Critical care medicine, 31(4 Suppl), S213–S220. https://doi.org/10.1097/01.CCM.0000057846.21303.AB
127. Gaertner, F., & Massberg, S. (2016). Blood coagulation in immunothrombosis-At the frontline of intravascular immunity. Seminars in immunology, 28(6), 561–569. https://doi.org/10.1016/j.smim.2016.10.010
128. Ranucci, M., Ballotta, A., Di Dedda, U., Bayshnikova, E., Dei Poli, M., Resta, M., Falco, M., Albano, G., & Menicanti, L. (2020). The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. Journal of thrombosis and haemostasis : JTH, 18(7), 1747–1751. https://doi.org/10.1111/jth.14854
129. Hanff, T. C., Mohareb, A. M., Giri, J., Cohen, J. B., & Chirinos, J. A. (2020). Thrombosis in COVID ‐19. American Journal of Hematology. https://doi.org/10.1002/ajh.25982
130. . Grimes, Z., Bryce, C., Sordillo, E. M., Gordon, R. E., Reidy, J., Paniz Mondolfi, A. E., & Fowkes, M. (2020). Fatal Pulmonary Thromboembolism in SARS-CoV-2-Infection. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 48, 107227. https://doi.org/10.1016/j.carpath.2020.107227
131. Ng, L. F., Hibberd, M. L., Ooi, E. E., Tang, K. F., Neo, S. Y., Tan, J., Murthy, K. R., Vega, V. B., Chia, J. M., Liu, E. T., & Ren, E. C. (2004). A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection. BMC infectious diseases, 4, 34. https://doi.org/10.1186/1471-2334-4-34
132. Poon, T. C., Pang, R. T., Chan, K. C., Lee, N. L., Chiu, R. W., Tong, Y. K., Chim, S. S., Ngai, S. M., Sung, J. J., & Lo, Y. M. (2012). Proteomic analysis reveals platelet factor 4 and beta-thromboglobulin as prognostic markers in severe acute respiratory syndrome. Electrophoresis, 33(12), 1894–1900. https://doi.org/10.1002/elps.201200002
133. Subramaniam, S., & Scharrer, I. (2018). Procoagulant activity during viral infections. Frontiers in bioscience (Landmark edition), 23, 1060–1081. https://doi.org/10.2741/4633
134. Lupu, F., Keshari, R. S., Lambris, J. D., & Coggeshall, K. M. (2014). Crosstalk between the coagulation and complement systems in sepsis. Thrombosis research, 133 Suppl 1(0 1), S28–S31. https://doi.org/10.1016/j.thromres.2014.03.014
135. Gragnano, F., Sperlongano, S., Golia, E., Natale, F., Bianchi, R., Crisci, M., Fimiani, F., Pariggiano, I., Diana, V., Carbone, A., Cesaro, A., Concilio, C., Limongelli, G., Russo, M., & Calabrò, P. (2017). The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy. Mediators of inflammation, 2017, 5620314. https://doi.org/10.1155/2017/5620314
136. Gryglewski, R. J., Korbut, R., Robak, J., & Świȩs, J. (1987). On the mechanism of antithrombotic action of flavonoids. Biochemical Pharmacology, 36(3), 317–322. doi:10.1016/0006-2952(87)90288-7
137. Guglielmone, H. A., Nuñez-Montoya, S. C., Agnese, A. M., Pellizas, C. G., Cabrera, J. L., & Donadio, A. C. (2012). Quercetin 3,7,3′,4′-tetrasulphated isolated from Flaveria bidentis inhibits tissue factor expression in human monocyte. Phytomedicine, 19(12), 1068–1071. doi:10.1016/j.phymed.2012.06.013
138. Guglielmone, H. A., Agnese, A. M., Nuñez-Montoya, S. G., Cabrera, J. L., & Cuadra, G. R. (2020). Antithrombotic “in vivo” effects of quercetin 3,7,3′,4′-tetrasulfate isolated from Flaveria bidentis in an experimental thrombosis model in mice. Thrombosis Research. doi:10.1016/j.thromres.2020.07.040
139. Stainer, A. R., Sasikumar, P., Bye, A. P., Unsworth, A. J., Holbrook, L. M., Tindall, M., Lovegrove, J. A., & Gibbins, J. M. (2019). The Metabolites of the Dietary Flavonoid Quercetin Possess Potent Antithrombotic Activity, and Interact with Aspirin to Enhance Antiplatelet Effects. TH open : companion journal to thrombosis and haemostasis, 3(3), e244–e258. https://doi.org/10.1055/s-0039-1694028
140. Oh, W. J., Endale, M., Park, S. C., Cho, J. Y., & Rhee, M. H. (2012). Dual Roles of Quercetin in Platelets: Phosphoinositide-3-Kinase and MAP Kinases Inhibition, and cAMP-Dependent Vasodilator-Stimulated Phosphoprotein Stimulation. Evidence-based complementary and alternative medicine : eCAM, 2012, 485262. https://doi.org/10.1155/2012/485262
141. Rivera, J., Lozano, M. L., Navarro-Núñez, L., & Vicente, V. (2009). Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica, 94(5), 700–711. https://doi.org/10.3324/haematol.2008.003178
142. Liu, L., Ma, H., Yang, N., Tang, Y., Guo, J., Tao, W., & Duan, J. (2010). A Series of Natural Flavonoids as Thrombin Inhibitors: Structure-activity relationships. Thrombosis Research, 126(5), e365–e378. Rivera, J., Lozano, M. L., Navarro-Núñez, L., & Vicente, V. (2009). Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica, 94(5), 700–711. https://doi.org/10.3324/haematol.2008.00317810.1016/j.thromres.2010.08.006
143. Smyth, S. S., Woulfe, D. S., Weitz, J. I., Gachet, C., Conley, P. B., … Goodman, S. G. (2008). G-Protein-Coupled Receptors as Signaling Targets for Antiplatelet Therapy. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(4), 449–457. doi:10.1161/atvbaha.108.176388
144. Wang J, Li F, Wei H, Lian ZX, Sun R et al. (2014). Respiratory influenza virus infection induces intestinal immune injury via microbiotamediated Th17 cell-dependent inflammation. Journal of Experimental Medicine 211 (12): 2397-2410. https://doi.org/10.1084/jem.20140625
145. Dickson RP, Singer BH, Newstead MW, Falkowski NR, ErbDownward JR et al. (2017). Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nature Microbiology 1 (10): 16113. https://doi.org/10.1038/ nmicrobiol.2016.113
146. Fanos V, Pintus MC, Pintus R, Marcialis MA (2020). Lung microbiota in the acute respiratory disease: from coronavirus to metabolomics. Journal of Pediatric and Neonatal Individualized Medicine 9 (1): 90139. https://doi.org/10.7363/090139
147. Wu Y, Guo C, Tang L, Hong Z, Zhou J et al. (2020). Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterology and Hepatology 5 (5): 434-435. https://doi.org/10.1016/ S2468-1253(20)30083-2
148. Aktas, B., & Aslim, B. (2020). Gut-lung axis and dysbiosis in COVID-19. Turkish journal of biology = Turk biyoloji dergisi, 44(3), 265–272. https://doi.org/10.3906/biy-2005-102
149. Pei, R., Liu, X., & Bolling, B. (2020). Flavonoids and gut health. Current Opinion in Biotechnology, 61, 153–159. https://doi.org/10.1016/j.copbio.2019.12.018
150. Shi T, Bian X, Yao Z, et al. Quercetin improves gut dysbiosis in antibiotic-treated mice. Food & Function. 2020 Sep;11(9):8003-8013. https://doi.org/10.1039/d0fo01439g.
151. Etxeberria, U., Arias, N., Boqué, N., Macarulla, M. T., Portillo, M. P., Martínez, J. A., & Milagro, F. I. (2015). Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. The Journal of Nutritional Biochemistry, 26(6), 651–660. https://doi.org/10.1016/j.jnutbio.2015.01.002
Quercetin in the treatment and prevention of COVID-19
Coronavirus Disease-19 ( COVID-19) is a disease that started at the end of 2019 and continues to affect all the world as a pandemic. There is no definitive cure for COVID-19 yet. The disease is characterized by excessive immune activity, inflammation and coagulopathy. Many agents have been tried for treatment and prevention. Flavonoids are valuable natural food components with antioxidant, anti-inflammatory and anticoagulant properties. Quercetin, the best known flavonoid, is one of the most studied and beneficial one. Quercetin, which has been shown to be effective in many viral diseases, is mainly used in diseases such as cardiovascular disease and diabetes, which are associated with chronic inflammation. it is an important candidate for the treatment and prophylaxis of COVID-19, thanks to its powerful anti-inflammatory, antioxidant and immune-modulating effects.
1. Cunha CB, Opal SM. Middle East respiratory syndrome (MERS): a new zoonotic viral pneumonia. Virulence 2014;5(6):650–654. https://doi.org/10.4161/viru.32077
2. De Groot RJ, Baker SC, Baric RS et al. Middle east Rrespiratory yndrome coronavirus (MERS-CoV): announcement of the Coronovirus Study. Group. JVirol 2013;87(14):7790-7792. https://doi.org/10.1128/JVI.01244-13
3. Velavan TP, Meyer CG. The COVID-19 epidemic. Trop Med Int Health 2020;25(3):278-280.
https://doi.org/10.1111/tmi.13383.
4. WHO Director-General's opening remarks at the media briefing on COVID-19. 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
5. Channappanavar R., Zhao J., Perlman S. T cell-mediated immune response to respiratory coronaviruses. Journal. 2014;59:118–128. https://doi.org/10.1007/s12026-014-8534-z
6. Bosch, B. J., van der Zee, R., de Haan, C. A., & Rottier, P. J. (2003). The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. Journal of virology, 77(16), 8801–8811. https://doi.org/10.1128/jvi.77.16.8801-8811.2003
7. Chen Y., Guo Y., Pan Y., Zhao Z.J. Structure analysis of the receptor binding of 2019-nCoV. Journal. 2020 https://doi.org/10.1016/j.bbrc.2020.02.071.
8. Hao X, Liang Z, Jiaxin , Jiakuan P, Hongxia D et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 12, 8 (2020). https://doi.org/10.1038/s41368-020-0074-x
9. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020. 382:1708-1720 https://doi.org/10.1056/NEJMoa2002032
10. Hamming I., Timens W., Bulthuis M.L., Lely A.T., Navis G., van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. Journal. Pathol 2004;203:631–637. https://doi.org/10.1002/path.1570.
11. Jia, H. P., Look, D. C., Shi, L., Hickey, M., Pewe, L., Netland, J., Farzan, M., Wohlford-Lenane, C., Perlman, S., & McCray, P. B., Jr (2005). ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. Journal of virology, 79(23), 14614–14621. https://doi.org/10.1128/JVI.79.23.14614-14621.2005
12. Burak M & Imen Y (1999) Flavonoids and their antioxidant properties. Turkiye Klin Tip Bil Derg 19, 296–304.
13. Cavalcante G.M., da Silva Cabral A.E., Silva C.C. Leishmanicidal Activity of Flavonoids Natural and Synthetic: A Minireview. Mintage J. Pharm. Med. Sci. (ISSN: 2320-3315), 2018;7:25–34. Retrieved from http://mjpms.in/index.php/ mjpms/article/view/317.
14. Takahashi, A., & Ohnishi, T. (2004). The significance of the study about the biological effects of solar ultraviolet radiation using the Exposed Facility on the International Space Station. Uchu Seibutsu Kagaku, 18(4), 255–260. https://doi.org/10.2187/bss.18.255
15. Dewick PM (2009) The shikimate pathway: aromatic amino acids and phenylpropanoids. In Medicinal Natural Products: a Biosynthetic Approach, 2nd ed., pp. 137–186. https://doi.org/10.1002/9780470742761.ch4
16. Shan X., Cheng J., Chen K.l., Liu Y.M., Juan L. Comparison of Lipoxygenase, Cyclooxygenase, Xanthine Oxidase Inhibitory Effects and Cytotoxic Activities of Selected Flavonoids. DEStech Trans. Environ. Energy Earth Sci. 2017 https://doi.org/10.12783/dteees/gmee2017/16624.
17. Kozłowska, A., Szostak-Wegierek, D. Flavonoids-food sources and health benefits. Rocz. Panstw. Zakl. Hig. (2014). 65(2), 79–85.
18. Ullah, A., Munir, S., Badshah, S. L., Khan, N., Ghani, L., Poulson, B. G., Emwas, A. H., & Jaremko, M. (2020). Important Flavonoids and Their Role as a Therapeutic Agent. Molecules (Basel, Switzerland), 25(22), 5243. https://doi.org/10.3390/molecules25225243
19. Ovando C, Hernandez D, Hernandez E, et al. (2009) Chemical studies of anthocyanins: a review. Food Chem 113, 859–871. http://dx.doi.org/10.1016/j.foodchem.2008.09.001
20. Lee, Y. K., Yuk, D. Y., Lee, J. W., Lee, S. Y., Ha, T. Y., Oh, K. W., Yun, Y. P., & Hong, J. T. (2009). (-)-Epigallocatechin-3-gallate prevents lipopolysaccharide-induced elevation of beta-amyloid generation and memory deficiency. Brain research, 1250, 164–174. https://doi.org/10.1016/j.brainres.2008.10.012
21. Zhao L., Yuan X., Wang J., Feng Y., Ji F., Li Z., Bian J. A review on flavones targeting serine/threonine protein kinases for potential anticancer drugs. Bioorganic Med. Chem. 2019;27:677–685. https://doi.org/10.1016/j.bmc.2019.01.027
22. Zhao K., Yuan Y., Lin B., Miao Z., Li Z., Guo Q., Lu N. LW-215, a newly synthesized flavonoid, exhibits potent anti-angiogenic activity in vitro and in vivo. Gene. 2018;642:533–541. https://doi.org/10.1016/j.gene.2017.11.065.
23. Metodiewa, D., Kochman, A., & Karolczak, S. (1997). Evidence for antiradical and antioxidant properties of four biologically active N,N-diethylaminoethyl ethers of flavanone oximes: a comparison with natural polyphenolic flavonoid (rutin) action. Biochemistry and molecular biology international, 41(5), 1067–1075. https://doi.org/10.1080/15216549700202141
24. Walker, E. H., Pacold, M. E., Perisic, O., Stephens, L., Hawkins, P. T., Wymann, M. P., & Williams, R. L. (2000). Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Molecular cell, 6(4), 909–919. https://doi.org/10.1016/s1097-2765(05)00089-4
25. Camero C.M., Germanò M.P., Rapisarda A., D’Angelo V., Amira S., Benchikh F., Braca A., De Leo M. Anti-angiogenic activity of iridoids from Galium tunetanum. Rev. Bras. de Farmacogn. 2018;28:374–377. https://doi.org/10.1016/j.bjp.2018.03.010
26. Mazidi M., Katsiki N., Banach M. A higher flavonoid intake is associated with less likelihood of nonalcoholic fatty liver disease: Results from a multiethnic study. J. Nutr. Biochem. 2019;65:66–71. https://doi.org/10.1016/j.jnutbio.2018.10.001.
27. Aguiar L.M., Geraldi M.V., Cazarin C.B.B., Junior M.R.M. Functional Food Consumption and Its Physiological Effects. Bioactive Compounds. Health Benefits and Potential Applications 2019, Pages 205-225. https://doi.org/10.1016/B978-0-12-814774-0.00011-6
28. Panche A., Diwan A., Chandra S. Flavonoids: An overview. J. Nutr. Sci. 2016;5:e47. https://doi.org/10.1017/jns.2016.41
29. Khan M.K., Zill E.H., Dangles O. A comprehensive review on flavanones, the major citrus polyphenols. J. Food Compos. Anal. 2014;33:85–104. https://doi.org/10.1016/j.jfca.2013.11.004.
30. Khalifa I., Zhu W., Li K.-k., Li C.-m. Polyphenols of mulberry fruits as multifaceted compounds: Compositions, metabolism, health benefits, and stability—A structural review. J. Funct. Foods. 2018;40:28–43. https://doi.org/10.1016/j.jff.2017.10.041
31. Iwashina T (2013) Flavonoid properties of five families newly incorporated into the order Caryophyllales (Review). Bull Natl Mus Nat Sci 39, 25–51. http://ci.nii.ac.jp/vol_issue/nels/AA12231458_en.html
32. Kawabata, K., Mukai, R., Ishisaka, A. Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability. Food Funct. 2015;6(5):1399-1417. https://doi.org/10.1039/C4FO01178C
33. Chun, OK., Chung, S-J., Claycombe, KJ., Song, WO. Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults. J Nutr. 2008;138(4):753-760. https://doi.org/10.1093/jn/138.4.753
34. Wang, W., Sun, C., Mao, L et al. The biological activities, chemical stability, metabolism and delivery systems of quercetin: a review. Trends in Food Sci Technol. 2016;56:21-38. https://doi.org/10.1016/j.tifs.2016.07.004
35. Kawai, Y . Understanding metabolic conversions and molecular actions of flavonoids in vivo: toward new strategies for effective utilization of natural polyphenols in human health. J Med Invest. 2018;65(3.4):162-165. https://doi.org/10.2152/jmi.65.162
36. Davis, JM., Murphy, EA., Carmichael, MD. Effects of the dietary flavonoid quercetin upon performance and health. Curr Sports Med Rep. 2009;8(4):206-213. https://doi.org/10.1249/JSR.0b013e3181ae8959
37. Dabeek, WM., Marra, MV. Dietary quercetin and kaempferol: bioavailability and potential cardiovascular-related bioactivity in humans. Nutrients. 2019;11(10):2288. https://doi.org/10.3390/nu11102288
38. Li, Y., Yao, J., Han, C et al. Quercetin, inflammation and immunity. Nutrients. 2016;8(3):167. https://doi.org/10.3390/nu8030167
39. Jafarinia, M., Sadat Hosseini, M., Kasiri, N et al. Quercetin with the potential effect on allergic diseases. Allergy Asthma Clin Immunol. 2020;16(1):36. https://doi.org/10.1186/s13223-020-00434-0
40. Brito, AF., Ribeiro, M., Abrantes, AM et al. Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Curr Med Chem. 2015;22(26):3025-3039. https://doi.org/10.2174/0929867322666150812145435
41. Dhiman, P., Malik, N., Sobarzo-Sánchez, E., Uriarte, E., Khatkar, A. Quercetin and related chromenone derivatives as monoamine oxidase inhibitors: targeting neurological and mental disorders. Molecules. 2019;24(3):418. https://doi.org/10.3390/molecules24030418
42. Chen, S., Jiang, H., Wu, X., Fang, J. Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes. Mediators Inflamm. 2016;2016(3):1-5. https://doi.org/10.1155/2016/9340637
43. Veckenstedt, A., Güttner, J., Béládi, I. Synergistic action of quercetin and murine alpha/beta interferon in the treatment of Mengo virus infection in mice. Antiviral Res. 1987;7(3):169-178. https://doi.org/10.1016/0166-3542(87)90005-2
44. Agrawal PK, Agrawal C, Blunden G. Quercetin: Antiviral Significance and Possible COVID-19 Integrative Considerations https://doi.org/10.1177/1934578X20976293
45. De Palma, AM., Vliegen, I., De Clercq, E., Neyts, J. Selective inhibitors of picornavirus replication. Med Res Rev. 2008;28(6):823-884. https://doi.org/10.1002/med.20125
47. Ganesan, S., Faris, AN., Comstock, AT et al. Quercetin inhibits rhinovirus replication in vitro and in vivo. Antiviral Res. 2012;94(3):258-271. https://doi.org/10.1016/j.antiviral.2012.03.005
48. Heinz, SA., Henson, DA., Austin, MD., Jin, F., Nieman, DC. Quercetin supplementation and upper respiratory tract infection: a randomized community clinical trial. Pharmacol Res. 2010;62(3):237-242. https://doi.org/10.1016/j.phrs.2010.05.001
49. Hung, P-Y., Ho, B-C., Lee, S-Y et al. Houttuynia cordata targets the beginning stage of herpes simplex virus infection. PLoS One. 2015;10(2):e0115475. https://doi.org/10.1371/journal.pone.0115475
50. El-Toumy, SA., Salib, JY., El-Kashak, WA et al. Antiviral effect of polyphenol rich plant extracts on herpes simplex virus type 1. Food Sci Hum Wellness. https://doi.org/10.1016/j.fshw.2018.01.001
51. Nieman, DC., Henson, DA., Gross, SJ et al. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc. 2007;39(9):1561-1569. https://doi.org/10.1249/mss.0b013e318076b566
52. Chaabi, M . Antiviral effects of quercetin and related compounds. Naturopathic Currents, Special Edition, April 2020, Antiviral effects of quercetin and related compounds. https://naturopathiccurrents.com/sites/default/files/AntiviralEffectsofQuercetinandRelatedCompounds_0.pdf
53. Shinozuka, K., Kikuchi, Y., Nishino, C., Mori, A., Tawata, S. Inhibitory effect of flavonoids on DNA-dependent DNA and RNA polymerases. Experientia. 1988;44(10):882-885. https://doi.org/10.1007/BF01941188
54. Spedding, G., Ratty, A., Middleton, E. Inhibition of reverse transcriptases by flavonoids. Antiviral Res. 1989;12(2):99-110. https://doi.org/10.1016/0166-3542(89)90073-9
55. Colunga Biancatelli, RML., Berrill, M., Catravas, JD., Marik, PE. Quercetin and vitamin C: an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol. 2020;11:1451. https://doi.org/10.3389/fimmu.2020.01451
56. Debiaggi, M., Tateo, F., Pagani, L., Luini, M., & Romero, E. (1990). Effects of propolis flavonoids on virus infectivity and replication. Microbiologica, 13(3), 207–213.
57. Yi, L., Li, Z., Yuan, K et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78(20):11334-11339. https://doi.org/10.1128/JVI.78.20.11334-11339.2004
58. Marra, MA., Jones, SJ., Astell, CR et al. The genome sequence of the SARS-associated coronavirus. Science. 2003;300(5624):1399-1404. https://doi.org/10.1126/science.1085953
59. Snijder, EJ., Bredenbeek, PJ., Dobbe, JC 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(5):991-1004. https://doi.org/10.1016/S0022-2836(03)00865-9
60. Chen, L., Li, J., Luo, C et al. Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features. Bioorg Med Chem. 2006;14(24):8295-8306. https://doi.org/10.1016/j.bmc.2006.09.014
61. Zhang, L., Lin, D., Sun, X et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409-412. https://doi.org/10.1126/science.abb3405
62. Huang, F., Li, Y., Leung, E. L., Liu, X., Liu, K., Wang, Q., Lan, Y., Li, X., Yu, H., Cui, L., Luo, H., & Luo, L. (2020). A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19). Pharmacological research, 158, 104929. https://doi.org/10.1016/j.phrs.2020.104929
63. Polansky, H., Lori, G., disease, C. Coronavirus disease 2019 (COVID-19): first indication of efficacy of Gene-Eden-VIR/Novirin in SARS-CoV-2 infection. Int J Antimicrob Agents. 2020;55(6):105971. https://doi.org/10.1016/j.ijantimicag.2020.105971
65. Han, Y-S., Chang, G-G., Juo, C-G et al. Papain-Like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition. Biochemistry. 2005;44(30):10349-10359. https://doi.org/10.1021/bi0504761
66. Dabbagh-Bazarbachi, H., Clergeaud, G., Quesada, IM., Ortiz, M., O’Sullivan, CK., Fernández-Larrea, JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem. 2014;62(32):8085-8093. https://doi.org/10.1021/jf5014633
67. Alschuler, L., Weil, A., Horwitz, R et al. Integrative considerations during the COVID-19 pandemic. Explore. 2020;16(6):354-356. https://doi.org/10.1016/j.explore.2020.03.007
68. jo, S., Kim, H., Kim, S., Shin, DH., Kim, M-S. Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors. Chem Biol Drug Des. 2019;94(6):2023-2030. https://doi.org/10.1111/cbdd.13604 31436895
69. Smith, M., Smith, JC. Repurposing therapeutics for COVID-19: Supercomputer-based docking to the SARS-CoV-2 viral spike protein and viral spike protein-human ACE2 interface. ChemRxiv. 2020.
70. Nguyen, TTH., Woo, H-J., Kang, H-K et al. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris. Biotechnol Lett. 2012;34(5):831-838. https://doi.org/10.1007/s10529-011-0845-8
71. Hui, DS., Azhar, EI., Madani, TA et al. The continuing 2019‐nCoV epidemic threat of novel coronaviruses to global health – the latest 2019 novel coronavirus outbreak in Wuhan, China. International J. of Infect Dis. 2020;2020(91):264-266. https://doi.org/10.1016/j.ijid.2020.01.009
72. Glinsky G. V. (2020). Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells. Biomedicines, 8(5), 129. https://doi.org/10.3390/biomedicines8050129
73. Ahmed, AK., Albalawi, YS., Shora, HA et al. Effects of quadruple therapy: zinc, quercetin, bromelain and vitamin C on the clinical outcomes of patients infected with COVID-19. Rea Int J of End and Diabe. 2020;1(1):018-021. https://doi.org/10.37179/rijed.000005
74. Chojnacka, K., Witek-Krowiak, A., Skrzypczak, D., Mikula, K., Młynarz, P. Phytochemicals containing biologically active polyphenols as an effective agent against Covid-19-inducing coronavirus. J Funct Foods. 2020;73:104146. https://doi.org/10.1016/j.jff.2020.104146
75. Williamson, G., Kerimi, A. Testing of natural products in clinical trials targeting the SARS-CoV-2 (Covid-19) viral spike protein-angiotensin converting enzyme-2 (ACE2) interaction. Biochem Pharmacol. 2020;178:114123. https://doi.org/10.1016/j.bcp.2020.114123
76. Yoshikawa, T., Hill, T., Li, K., Peters, C. J., & Tseng, C. T. (2009). Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. Journal of virology, 83(7), 3039–3048. https://doi.org/10.1128/JVI.01792-08
77. Yuki, K., Fujiogi, M., & Koutsogiannaki, S. (2020). COVID-19 pathophysiology: A review. Clinical immunology (Orlando, Fla.), 215, 108427. Advance online publication. https://doi.org/10.1016/j.clim.2020.108427
78. Huang C, Wang Y, Li X, Ren L, Zhao J et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 2020; 395 (10223): 497-506. https://doi.org/10.1016/s0140-6736(20)30183-5
79. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Frontiers in Immunology 2019; 10: 119. https://doi.org/10.3389/fimmu.2019.00119
80. Wang W, He J, Lie p, Huang l, Wu S et al. The definition and risks of cytokine release syndrome-like in 11 COVID19-infected pneumonia critically ill patients: disease characteristics and retrospective analysis. MedRxiv 2020. https://doi.org/10.1101/2020.02.26.20026989
81. Read M. A. (1995). Flavonoids: naturally occurring anti-inflammatory agents. The American journal of pathology, 147(2), 235–237.
82. Manjeet K, R., & Ghosh, B. (1999). Quercetin inhibits LPS-induced nitric oxide and tumor necrosis factor-alpha production in murine macrophages. International journal of immunopharmacology, 21(7), 435–443. https://doi.org/10.1016/s0192-0561(99)00024-7
83. Geraets, L., Moonen, H. J., Brauers, K., Wouters, E. F., Bast, A., & Hageman, G. J. (2007). Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells. The Journal of nutrition, 137(10), 2190–2195. https://doi.org/10.1093/jn/137.10.2190
84. Bureau, G., Longpré, F., & Martinoli, M. G. (2008). Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. Journal of neuroscience research, 86(2), 403–410. https://doi.org/10.1002/jnr.21503
85. Kim, H. P., Mani, I., Iversen, L., & Ziboh, V. A. (1998). Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostaglandins, leukotrienes, and essential fatty acids, 58(1), 17–24. https://doi.org/10.1016/s0952-3278(98)90125-9
86. Lee, K. M., Hwang, M. K., Lee, D. E., Lee, K. W., & Lee, H. J. (2010). Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells. Journal of agricultural and food chemistry, 58(9), 5815–5820. https://doi.org/10.1021/jf903698s
87. Chirumbolo S. (2010). The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflammation & allergy drug targets, 9(4), 263–285. https://doi.org/10.2174/187152810793358741
88. Yang, D., Liu, X., Liu, M., Chi, H., Liu, J., & Han, H. (2015). Protective effects of quercetin and taraxasterol against H2O2-induced human umbilical vein endothelial cell injury in vitro. Experimental and therapeutic medicine, 10(4), 1253–1260. https://doi.org/10.3892/etm.2015.2713
89. Huang, R.Y.; Yu, Y.L.; Cheng, W.C.; OuYang, C.N.; Fu, E.; Chu, C.L. Immunosuppressive effect of quercetin on dendritic cell activation and function. J Immunol June 15, 2010, 184 (12) 6815-6821. https://doi.org/10.4049/jimmunol.0903991
90. Cheng, S-C., Huang, W-C., S. Pang, J-H., Wu, Y-H., Cheng, C-Y et al. Quercetin inhibits the production of IL-1β-induced inflammatory cytokines and chemokines in ARPE-19 cells via the MAPK and NF-κB signaling pathways. Int J Mol Sci. 2019;20(12):2957. https://doi.org/10.3390/ijms20122957
91. Nair, M. P., Kandaswami, C., Mahajan, S., Chadha, K. C., Chawda, R., Nair, H., Kumar, N., Nair, R. E., & Schwartz, S. A. (2002). The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells. Biochimica et biophysica acta, 1593(1), 29–36. https://doi.org/10.1016/s0167-4889(02)00328-2
93. Mehta, P., McAuley, DF., Brown, M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. https://doi.org/10.1016/S0140-6736(20)30628-0
94. Ding, S., Xu, S., Ma, Y., Liu, G., Jang, H., Fang, J. Modulatory mechanisms of the NLRP3 inflammasomes in diabetes. Biomolecules. 2019;9(12):E850. https://doi.org/10.3390/biom9120850
95. Chen, I-Y., Moriyama, M., Chang, M-F., Ichinohe, T. Severe acute respiratory syndrome coronavirus viroporin 3A activates the NLRP3 inflammasome. Front Microbiol. 2019;10:50. https://doi.org/10.3389/fmicb.2019.00050
96. Lim, H., Min, DS., Park, H., Kim, HP. Flavonoids interfere with NLRP3 inflammasome activation. Toxicol Appl Pharmacol. 2018;355:93-102. https://doi.org/10.1016/j.taap.2018.06.022
97. Cialdella-Kam, L., Nieman, D., Knab, A et al. A mixed Flavonoid-Fish oil supplement induces immune-enhancing and anti-inflammatory transcriptomic changes in adult obese and overweight women—A randomized controlled trial. Nutrients. 2016;8(5):pii: E277. https://doi.org/10.3390/nu8050277
98. Nedoborenko, V. M., Kaidashev, I., Lavrenko, A., Vesnina, L., & Mamontova, T. (2017). Inclusion of Quercetin in Treatment Reduces the Level of Interleukin 6 in Women with Iron Deficiency Anemia and Obesity. The Medical and Ecological Problems, 21(5-6), 37-39. Retrieved from https://ecomed-journal.org/index.php/journal/article/view/100
99. Kritas, SK., Ronconi, G., Caraffa, A et al. Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy. J Biol Regul Homeost Agents. 2020;34(1):9-14. https://doi.org/10.23812/20-Editorial-Kritas
100. Weng, Z., Zhang, B., Asadi, S., Zuyi, W., Bodi, Z., Shahrzad, A et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One. 2012;7(3):e33805. https://doi.org/10.1371/journal.pone.0033805
101. Shaik, Y., Caraffa, A., Ronconi, G., Lessiani, G., Conti, P. Impact of polyphenols on mast cells with special emphasis on the effect of quercetin and luteolin. Cent Eur J Immunol. 2018;43(4):476-481. https://doi.org/10.5114/ceji.2018.81347
102. Choudhary, S., Sharma, K., & Silakari, O. (2020). The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options. Microbial pathogenesis, 150, 104673. Advance online publication. https://doi.org/10.1016/j.micpath.2020.104673
103. Schofield, J. H., & Schafer, Z. T. (2021). Mitochondrial Reactive Oxygen Species and Mitophagy: A Complex and Nuanced Relationship. Antioxidants & redox signaling, 34(7), 517–530. https://doi.org/10.1089/ars.2020.8058
104. Picca, A., Calvani, R., Coelho-Junior, H. J., Landi, F., Bernabei, R., & Marzetti, E. (2020). Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration. Antioxidants (Basel, Switzerland), 9(8), 647. https://doi.org/10.3390/antiox9080647
105. Saleh, J., Peyssonnaux, C., Singh, K. K., & Edeas, M. (2020). Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion, 54. https://doi.org/10.1016/j.mito.2020.06.008
106. Zhang, Z., Rong, L., & Li, Y. P. (2019). Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis. Oxidative medicine and cellular longevity, 2019, 1409582. https://doi.org/10.1155/2019/1409582
107. Ivanov, A. V., Valuev-Elliston, V. T., Ivanova, O. N., Kochetkov, S. N., Starodubova, E. S., Bartosch, B., & Isaguliants, M. G. (2016). Oxidative Stress during HIV Infection: Mechanisms and Consequences. Oxidative medicine and cellular longevity, 2016, 8910396.
108. Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., Liu, S., Zhao, P., Liu, H., Zhu, L., Tai, Y., Bai, C., Gao, T., Song, J., Xia, P., Dong, J., Zhao, J., & Wang, F. S. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet. Respiratory medicine, 8(4), 420–422. https://doi.org/10.1016/S2213-2600(20)30076-X
109. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054–1062. https://doi.org/10.1016/S0140-6736(20)30566-3
110. Miripour, Z. S., Sarrami-Forooshani, R., Sanati, H., Makarem, J., Taheri, M. S., Shojaeian, F. (2020). Real-time diagnosis of reactive oxygen species (ROS) in fresh sputum by electrochemical tracing; correlation between COVID-19 and viral-induced ROS in lung/respiratory epithelium during this pandemic. Biosensors and Bioelectronics, 112435. https://doi.org/10.1016/j.bios.2020.112435
111. Ntyonga-Pono M. P. (2020). COVID-19 infection and oxidative stress: an under-explored approach for prevention and treatment?. The Pan African medical journal, 35(Suppl 2), 12. https://doi.org/10.11604/pamj.2020.35.2.22877
112. Tsujimoto, M., Yokota, S., Vilcek, J., & Weissmann, G. (1986). Tumor necrosis factor provokes superoxide anion generation from neutrophils. Biochemical and biophysical research communications, 137(3), 1094–1100. https://doi.org/10.1016/0006-291x(86)90337-2
113. Kharazmi, A., Nielsen, H., Rechnitzer, C., & Bendtzen, K. (1989). Interleukin 6 primes human neutrophil and monocyte oxidative burst response. Immunology letters, 21(2), 177–184. https://doi.org/10.1016/0165-2478(89)90056-4
114. Colston, J. T., Chandrasekar, B., & Freeman, G. L. (2002). A novel peroxide-induced calcium transient regulates interleukin-6 expression in cardiac-derived fibroblasts. The Journal of biological chemistry, 277(26), 23477–23483. https://doi.org/10.1074/jbc.M108676200
115. J. Wu, Tackle the free radicals damage in COVID-19, Nitric Oxide, https:// doi.org/10.1016/j.niox.2020.06.002.
116. Prochazkova D., Bousova I., Wilhelmova N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011;82:513–523. https://doi.org/10.1016/j.fitote.2011.01.018.
117. Terao J. Factors modulating bioavailability of quercetin-related flavonoids and the consequences of their vascular function. Biochem. Pharmacol. 2017;139:15–23. https://doi.org/10.1016/j.bcp.2017.03.021.
118. Shu Z., Yang Y., Yang L., Jiang H., Yu X., Wang Y. Cardioprotective effects of dihydroquercetin against ischemia reperfusion injury by inhibiting oxidative stress and endoplasmic reticulum stress-induced apoptosis via the PI3K/Akt pathway. Food Funct. 2019;10:203–215. https://doi.org/10.1039/C8FO01256C.
119. Terao J. (1999). Dietary flavonoids as antioxidants in vivo: conjugated metabolites of (-)-epicatechin and quercetin participate in antioxidative defense in blood plasma. The journal of medical investigation : JMI, 46(3-4), 159–168. http://www.ncbi.nlm.nih.gov/pubmed/10687310
121. Kumar, P., Khanna, M., Srivastava, V et al. Effect of quercetin supplementation on lung antioxidants after experimental influenza virus infection. Exp Lung Res. 2005;31(5):449-459. https://doi.org/10.1080/019021490927088
122. Milea Ș.-A., Aprodu I., Vasile A.M., Barbu V., Râpeanu G., Bahrim G.E., Stănciuc N. Widen the functionality of flavonoids from yellow onion skins through extraction and microencapsulation in whey proteins hydrolysates and different polymers. J. Food Eng. 2019;251:29–35. https://doi.org/10.1016/j.jfoodeng.2019.02.003.
123. Pucciarini L., Ianni F., Petesse V., Pellati F., Brighenti V., Volpi C., Gargaro M., Natalini B., Clementi C., Sardella R. Onion (Allium cepa L.) Skin: A Rich Resource of Biomolecules for the Sustainable Production of Colored Biofunctional Textiles. Molecules. 2019;24:634. https://doi.org/10.3390/molecules24030634.
124. Yang S.J., Paudel P., Shrestha S., Seong S.H., Jung H.A., Choi J.S. In vitro protein tyrosine phosphatase 1B inhibition and antioxidant property of different onion peel cultivars: A comparative study. Food Sci. Nutr. 2019;7:205–215. https://doi.org/10.1002/fsn3.863.
125. Ozolina, A., Sarkele, M., Sabelnikovs, O., Skesters, A., Jaunalksne, I., Serova, J., Ievins, T., Bjertnaes, L. J., & Vanags, I. (2016). Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study. Frontiers in medicine, 3, 64. https://doi.org/10.3389/fmed.2016.00064
126. Idell S. (2003). Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Critical care medicine, 31(4 Suppl), S213–S220. https://doi.org/10.1097/01.CCM.0000057846.21303.AB
127. Gaertner, F., & Massberg, S. (2016). Blood coagulation in immunothrombosis-At the frontline of intravascular immunity. Seminars in immunology, 28(6), 561–569. https://doi.org/10.1016/j.smim.2016.10.010
128. Ranucci, M., Ballotta, A., Di Dedda, U., Bayshnikova, E., Dei Poli, M., Resta, M., Falco, M., Albano, G., & Menicanti, L. (2020). The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. Journal of thrombosis and haemostasis : JTH, 18(7), 1747–1751. https://doi.org/10.1111/jth.14854
129. Hanff, T. C., Mohareb, A. M., Giri, J., Cohen, J. B., & Chirinos, J. A. (2020). Thrombosis in COVID ‐19. American Journal of Hematology. https://doi.org/10.1002/ajh.25982
130. . Grimes, Z., Bryce, C., Sordillo, E. M., Gordon, R. E., Reidy, J., Paniz Mondolfi, A. E., & Fowkes, M. (2020). Fatal Pulmonary Thromboembolism in SARS-CoV-2-Infection. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 48, 107227. https://doi.org/10.1016/j.carpath.2020.107227
131. Ng, L. F., Hibberd, M. L., Ooi, E. E., Tang, K. F., Neo, S. Y., Tan, J., Murthy, K. R., Vega, V. B., Chia, J. M., Liu, E. T., & Ren, E. C. (2004). A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection. BMC infectious diseases, 4, 34. https://doi.org/10.1186/1471-2334-4-34
132. Poon, T. C., Pang, R. T., Chan, K. C., Lee, N. L., Chiu, R. W., Tong, Y. K., Chim, S. S., Ngai, S. M., Sung, J. J., & Lo, Y. M. (2012). Proteomic analysis reveals platelet factor 4 and beta-thromboglobulin as prognostic markers in severe acute respiratory syndrome. Electrophoresis, 33(12), 1894–1900. https://doi.org/10.1002/elps.201200002
133. Subramaniam, S., & Scharrer, I. (2018). Procoagulant activity during viral infections. Frontiers in bioscience (Landmark edition), 23, 1060–1081. https://doi.org/10.2741/4633
134. Lupu, F., Keshari, R. S., Lambris, J. D., & Coggeshall, K. M. (2014). Crosstalk between the coagulation and complement systems in sepsis. Thrombosis research, 133 Suppl 1(0 1), S28–S31. https://doi.org/10.1016/j.thromres.2014.03.014
135. Gragnano, F., Sperlongano, S., Golia, E., Natale, F., Bianchi, R., Crisci, M., Fimiani, F., Pariggiano, I., Diana, V., Carbone, A., Cesaro, A., Concilio, C., Limongelli, G., Russo, M., & Calabrò, P. (2017). The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy. Mediators of inflammation, 2017, 5620314. https://doi.org/10.1155/2017/5620314
136. Gryglewski, R. J., Korbut, R., Robak, J., & Świȩs, J. (1987). On the mechanism of antithrombotic action of flavonoids. Biochemical Pharmacology, 36(3), 317–322. doi:10.1016/0006-2952(87)90288-7
137. Guglielmone, H. A., Nuñez-Montoya, S. C., Agnese, A. M., Pellizas, C. G., Cabrera, J. L., & Donadio, A. C. (2012). Quercetin 3,7,3′,4′-tetrasulphated isolated from Flaveria bidentis inhibits tissue factor expression in human monocyte. Phytomedicine, 19(12), 1068–1071. doi:10.1016/j.phymed.2012.06.013
138. Guglielmone, H. A., Agnese, A. M., Nuñez-Montoya, S. G., Cabrera, J. L., & Cuadra, G. R. (2020). Antithrombotic “in vivo” effects of quercetin 3,7,3′,4′-tetrasulfate isolated from Flaveria bidentis in an experimental thrombosis model in mice. Thrombosis Research. doi:10.1016/j.thromres.2020.07.040
139. Stainer, A. R., Sasikumar, P., Bye, A. P., Unsworth, A. J., Holbrook, L. M., Tindall, M., Lovegrove, J. A., & Gibbins, J. M. (2019). The Metabolites of the Dietary Flavonoid Quercetin Possess Potent Antithrombotic Activity, and Interact with Aspirin to Enhance Antiplatelet Effects. TH open : companion journal to thrombosis and haemostasis, 3(3), e244–e258. https://doi.org/10.1055/s-0039-1694028
140. Oh, W. J., Endale, M., Park, S. C., Cho, J. Y., & Rhee, M. H. (2012). Dual Roles of Quercetin in Platelets: Phosphoinositide-3-Kinase and MAP Kinases Inhibition, and cAMP-Dependent Vasodilator-Stimulated Phosphoprotein Stimulation. Evidence-based complementary and alternative medicine : eCAM, 2012, 485262. https://doi.org/10.1155/2012/485262
141. Rivera, J., Lozano, M. L., Navarro-Núñez, L., & Vicente, V. (2009). Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica, 94(5), 700–711. https://doi.org/10.3324/haematol.2008.003178
142. Liu, L., Ma, H., Yang, N., Tang, Y., Guo, J., Tao, W., & Duan, J. (2010). A Series of Natural Flavonoids as Thrombin Inhibitors: Structure-activity relationships. Thrombosis Research, 126(5), e365–e378. Rivera, J., Lozano, M. L., Navarro-Núñez, L., & Vicente, V. (2009). Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica, 94(5), 700–711. https://doi.org/10.3324/haematol.2008.00317810.1016/j.thromres.2010.08.006
143. Smyth, S. S., Woulfe, D. S., Weitz, J. I., Gachet, C., Conley, P. B., … Goodman, S. G. (2008). G-Protein-Coupled Receptors as Signaling Targets for Antiplatelet Therapy. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(4), 449–457. doi:10.1161/atvbaha.108.176388
144. Wang J, Li F, Wei H, Lian ZX, Sun R et al. (2014). Respiratory influenza virus infection induces intestinal immune injury via microbiotamediated Th17 cell-dependent inflammation. Journal of Experimental Medicine 211 (12): 2397-2410. https://doi.org/10.1084/jem.20140625
145. Dickson RP, Singer BH, Newstead MW, Falkowski NR, ErbDownward JR et al. (2017). Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nature Microbiology 1 (10): 16113. https://doi.org/10.1038/ nmicrobiol.2016.113
146. Fanos V, Pintus MC, Pintus R, Marcialis MA (2020). Lung microbiota in the acute respiratory disease: from coronavirus to metabolomics. Journal of Pediatric and Neonatal Individualized Medicine 9 (1): 90139. https://doi.org/10.7363/090139
147. Wu Y, Guo C, Tang L, Hong Z, Zhou J et al. (2020). Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterology and Hepatology 5 (5): 434-435. https://doi.org/10.1016/ S2468-1253(20)30083-2
148. Aktas, B., & Aslim, B. (2020). Gut-lung axis and dysbiosis in COVID-19. Turkish journal of biology = Turk biyoloji dergisi, 44(3), 265–272. https://doi.org/10.3906/biy-2005-102
149. Pei, R., Liu, X., & Bolling, B. (2020). Flavonoids and gut health. Current Opinion in Biotechnology, 61, 153–159. https://doi.org/10.1016/j.copbio.2019.12.018
150. Shi T, Bian X, Yao Z, et al. Quercetin improves gut dysbiosis in antibiotic-treated mice. Food & Function. 2020 Sep;11(9):8003-8013. https://doi.org/10.1039/d0fo01439g.
151. Etxeberria, U., Arias, N., Boqué, N., Macarulla, M. T., Portillo, M. P., Martínez, J. A., & Milagro, F. I. (2015). Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. The Journal of Nutritional Biochemistry, 26(6), 651–660. https://doi.org/10.1016/j.jnutbio.2015.01.002