Anti-SARS-CoV-2, antioxidant and immunomodulatory potential of dietary flavonol quercetin: Focus on molecular targets and clinical efficacy
Biswanath Dinda, Manikarna Dinda, Subhajit Dinda, Partha Sarathi Ghosh, Saroj Kumar Das
European Journal of Medicinal Chemistry Reports, doi:10.1016/j.ejmcr.2023.100125
The current coronavirus disease 2019 (COVID-19) outbreak, caused by the infection of SARS-CoV-2, seems to be a tough global challenge because of its highly contagious nature and rapid evolution of the virus strain. As no effective clinical drugs are available for the treatment of this disease in the early phase till to date, scientists are hunting for drugs from natural sources for its treatment. Quercetin, a dietary polyphenolic flavonoid found in fruits and vegetables, has been reported to exhibit various health-benefit pharmacological properties including antioxidant, anti-inflammatory, antimicrobial, antiviral and anticancer properties. In silico and in vitro studies demonstrated that quercetin potently inhibits the infections of SARS-CoV-2 and other coronaviruses by interfering with viral entry and replication via inhibiting the activity of host ACE2 receptor, and viral S-, 3CL-, PL-, RdRpand Nsp13 -proteases. Moreover, quercetin is able to suppress oxidative stress, cytokine storm, thrombosis, sepsis and lung fibrosis, and thereby very likely is able to mitigate COVID-19 infection. In this review article, we elaborately discussed the antiviral, immunomodulatory, antioxidant properties of quercetin against viral infections and other diseases, as well as on its nanoformulations for enhancement of oral bioavailability and clinical efficacy in COVID-19 infection for its development as clinical drug for COVID-19.
Author contributions BD: Conceptualization, Methodology, Data curation, Resources, Validation, Writing-original draft, Writing-Review & editing, Visualization, Supervision.
Declaration of competing interest The authors declare that they have no competing interests.
References
Abian, Ortega-Alarcon, Jimenez-Alesanco, Ceballos-Laita, Vega et al., Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening, Int. J. Biol. Macromol
Agostini, Pruijssers, Chappell, Gribble, Lu et al., Small molecule antiviral β-D-N 4hydroxycytidine inhibits a proofreading intact coronavirus with a high genetic barrier to resistance, J. Virol
Agrawal, Agrawal, Bluden, Quercetin: antiviral significance and possible COVID-19 integrative considerations, Nat. Prod. Commun
Akaike, Ando, Oda, Doi, Ijiri et al., Dependence on O 2 .generation by xanthine oxidase of pathogenesis of influenza virus infection in mice, J. Clin. Invest
Akiyama, Washino, Yamada, Koda, Mattani, Constituents of enzymatically modified isoquercitrin and enzymatically modified rutin (extract), J. Food Hyg. Soc. Japan
Alaqeel, Alsheikh, Al-Harini, Quercetin nanoemulsion ameliorates neuronal dysfunction in experimental Alzheimer's disease model, Antioxidants (Basel)
Alon, Sportiello, Kozlovski, Kumar, Reilly et al., Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19, Nat. Rev. Immunol
Araf, Akter, Tang, Fatemi, Parvez et al., Omicron variant of SARS-CoV-2: genomics, transmissibility, and responses to current COVID-19 vaccines, J. Med. Virol
Auvigne, Vaux, Strat, Schaeffer, Fournier et al., Severe hospital events following J o u r n a l P r e -p r o o f symptomatic infection with Sars-CoV-2 Omicron and Delta variants in France, December 2021-January 2022: a retrospective, population based, matched cohort study, eClinMed
Bahun, Jukic, Oblak, Kranjc, Bajc et al., Inhibition of the SARS-coV-2 3CLpro main protease by plant polyphenols, Food Chem
Baird, Yamamoto, The molecular mechanisms regulating the KEAP-NRF2 pathway, Mol. Cell. Biol
Balakrishna, Satyanarayan, Kondapi, Involment of human topoisomerase II isoforms in HIV-1 reverse transcription, Arch. Biochem. Biophys
Balegamire, Mcclymont, Croteau, Dodin, Gantt et al., Prevalence, incidence, and risk factors associated with cytomegalovirus infection in healthcare and childcare worker: a systematic review and metaanalysis, Syst. Rev
Banerjee, Sarkar, Mukherjee, Miyoshi, Kitahara et al., Quercetin, a flavonoid, combats rotavirus infection by deactivating rotavirusinduced pro-survival NF-κB pathway, Front. Microbiol
Bhagwat, Haytowitz, Holden, USDA database for flavonoid content of selected foods, release 3
Boesch-Saadatmandi, Loboda, Wagner, Stachurska, Jozkowicz et al., Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression: role of miR-155, J. Nutr. Biochem
Boots, Veith, Albrecht, Bartholome, Drittij et al., The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice, BMC Pulm. Med
Braga, Forni, Correa-Costa, Ramos, Barbuto et al., Soluble uric acid activates the NLRP3 inflammasome, Sci. Rep
Cai, Duan, Liu, Yu, Tang et al., Uric acid induces endothelial dysfunction by activating the HMGB1/RAGE signaling pathway, BioMed. Res. Int
Cao, Pauff, Hille, X-ray crystal structure of a xanthine oxidase complex with the flavonoid inhibitor quercetin, J. Nat. Prod
Catalin Mot, Coman, Miron, Damian, Sarbu et al., An assay for pro-oxidant reactivity based on phenoxyl radicals generated by laccase, Food Chem
Chan, Kok, Zhu, Chu, To et al., Genomic characterization of the 2019 novel human pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan, Emerg. Microbe Infect
Chaniad, Wattanapiromsakul, Pianwanit, Tewtrakul, Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study, Pharm. Biol
Chaves, Fintelman-Rodrigues, Wang, Sacramento, Temerozo et al., Commercially available flavonols are better SARS-CoV-2 inhibitors than isoflavones and flavones, Viruses
Chaves, Lima, Fintelman-Rodrigues, Sacramento, De Freitas et al., Agathisflavone, a natural biflavonoid that inhibits SARS-CoV-2 replication by targeting its proteases, Int. J. Biol. Macromol
Chen, Chen, Su, Hong, Ho et al., Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing J o u r n a l P r e -p r o o f quercetin in cancer treatment and in vivo pharmacokinetic study, Int. J. Nanomedicine
Chen, Liu, Wang, Liu, Zhao et al., SARS-CoV-2 activates lung epithelial cell proinflammatory signaling and leads to immune dysregulation in COVID-19 patents, eBioMed
Chen, Yin, Zuo, Chow, Pharmacokinetics and modelling of quercetin and metabolites, Pharm. Res
Chen, Zheng, Jia, Ju, Flavonoids as superoxide scavengers and antioxidants, Free Radic. Biol. Med
Cheng, Sun, Guo, Huang, Sun et al., Inhibition of hepatitis B virus replication by quercetin in human hepatoma cell lines, Virol. Sin
Cherrak, Merzouk, Mokhtari-Soulimane, Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: a molecular docking and simulation studies, PLoS One
Chiang, Chiang, Liu, Lin, In vitro antiviral activities of Caesalpinia pulcherrima and its related flavonoids, J. Antimicrob. Chemother
Choe, Kim, Quercetin and ascorbic acid suppress fructose-induced NLRP3 inflammasome activation by blocking intracellular shuttling of TXNIP in human macrophage cell lines, Inflammation
Choi, Kim, Lee, Ahn, Song et al., Antiviral activity of quercetin 7-rhamnoside against porcine epidemic diarrhea virus, Antiviral Res
Clark, Black, Tate, Roose, Kotioff et al., Estimated global, regional and national rotavirus deaths in children aged <5 years: current approaches, new analyses and proposed improvements, PLoS One
Cohen, Lavu, Bitterman, Hekking, Imahiyerobo et al., Acetylation of the C-terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis, Mol. Cell
Corona, Wycisk, Talarico, Manelfi, Milia et al., Natural compounds inhibit SARS-CoV-2 nsp13 unwinding and ATPase enzyme activities, ACS Pharmacol. Transl. Sci
Cos, Ying, Calomme, Hu, Cimanga et al., Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers, J. Nat. Prod
Cui, Zhao, Amevor, Du, Wang et al., Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism, Front. Immunol
Dabeek, Kovinich, Walsh, Marra, Characterization and quantification of major flavonol glycosides in ramps (Allium tricoccum), Molecules
Dabeek, Marra, Dietary quercetin and kaempferol:bioavailability and potential cardiovascular-related bioactivity in humans, Nutrients
David, Arulmoli, Parasuraman, Overviews of biological importance of quercetin: a bioactive flavonoid, Pharmacogn. Rev
De Barros, Santos, Reed, Fonseca, Oliva, Design of quercetinloaded natural oil-based nanostructured lipid carriers for the treatment of bacterial skin infections, Molecules
De Groot, Baker, Baric, Brown, Drosten et al., Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the coronavirus study group, J. Virol
Derosa, Maffioli, D'angelo, Pierro, A role for quercetin in coronavirus disease 2019 (COVID-19), Phytother. Res
Di Petrillo, Orru, Fais, Fantini, Quercetin and its derivatives as antiviral potentials: a comprehensive review, Phytother. Res
Di Pierro, Derosa, Maffioli, Bertuccioli, Togni et al., Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study, Int. J. Gen. Med
Di Pierro, Iqtadar, Khan, Mumtaz, Chaudhry et al., Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial, Int. J. Gen. Med
Di Pierro, Khan, Iqtadar, Mumtaz, Akbar-Chaudhry et al., Quercetin as a possible complementary agent for early-stage COVID-19: concluding results of a randomized clinical trial, Front. Pharmacol
Dombrowski, Peric, Koglin, Kammerbauer, Goss et al., Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions, Sci. Transl. Med
Domiciano, Wakita, Jones, Crother, Vern et al., Quercetin inhibits inflammasome activation by interfering the ASC oligomerization and prevents interleukin-1 mediated mouse vasculitis, Sci. Rep
Dong, Chen, Xu, Yao, Zhang et al., Quercetin attenuates myocardial ischemia-reperfusion injury via downregulation of the HMGB1-TLR4-NF-κB signaling pathway, Am. J. Transl. Res
Du, Hou, Miao, Huang, Liu, Traditional Chinese Medicine: an effective treatment for 2019 novel coronavirus pneumonia (NCP), Chinese J. Nat. Med
Duan, Xu, Li, Bao, An et al., Molecular characteristics of human Adinovirus type 3 circulating in parts of China during 2014-2018, Front. Microbiol
Ebihara, Takada, Kobasa, Jones, Neumann et al., Molecular determinants of Ebola virus virulence in mice, PLoS Pathog
Engelman, Cherepanov, The structural biology of HIV-1: mechanistic and therapeutic insights, Nat. Rev. Microbiol
Evers, Chao, Wang, Zhang, Huang et al., Human cytomegalovirus-inhibitory flavonoids: studies on antiviral activity and mechanism of action, Antiviral Res
Fang, Dou, Liang, Hou, Ma et al., Quercetin reduces oxidative stress and apoptosis by inhibiting HMGB1 and its translation, thereby alleviating liver injury in ACLF rats, Evid. Based Complement. Alternat. Med
Fang, Liang, Jiang, Fang, Wu et al., Quercetin attenuates D-GaLN-induced LO2 cell damage by suppressing oxidative stress and mitochondrial apoptosis via inhibition of HMGB1, Front. Pharmacol
Fanunza, Iampietro, Distinto, Corona, Quartu et al., Quercetin blocks Ebola virus infection by counteracting the VP24 interferoninhibitory function, Antimicrob. Agents Chemother
Fesen, Kohn, Leteurtre, Pommier, Inhibitors of human immunodeficiency virus integrase, Proc. Natl. Acad. Sci
Filippi, Sarton, Facci, Trentin, Armani et al., Pulmonary embolism in patients with COVID-19 pneumonia: when we have to search for it?, Thromb. Res
Finzi, Hermankova, Pierson, Carruth, Buck et al., Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy, Science
Foretz, Carling, Guichard, Ferre, Foufelle, AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes, J. Biol. Chem
Formica, Regelson, Review of the biology of quercetin and related bioflavonoids, Food Chem. Toxicol
Ganesan, Faris, Comstock, Wang, Nanua et al., Quercetin inhibits rhinovirus replication in vitro and in vivo, Antiviral Res
Garten, Davis, Russell, Shu, Lindstrom et al., Antigenic and genetic characteristics of swine origin 2009 A (H1N1) influenza viruses circulating in humans, Science
Gasmi, Mujawdiya, Lysiuk, Shanaida, Peana et al., Quercetin in the prevention and treatment of coronavirus infections: a focus on SARS-CoV-2, Pharmaceuticals (Basel)
Gaunt, Hardie, Claas, Simmonds, Templeton, Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63 and OC43 detected over 3 years using a novel multiplex real-time PCR method, J. Clin. Microbiol
Gonzalez, Fontanes, Raychaudhuri, Loo, Loo et al., The heat shock protein inhibitor quercetin attenuates hepatitis C virus production, Hepatology
Graefe, Wittig, Mueller, Riethling, Uehleke et al., Pharmacokinetics and bioavailability of quercetin glycosides in humans, J. Clin. Pharmacol
Grein, Ohmagari, Shin, Diaz, Asperges et al., Compassionate use of remdesivir for patients with severe Covid-19, N. Engl. J. Med
Grit, Crommelin, Chemical stability of liposomes: implications for their physical stability, Chem. Phys. Lipids
Guerrero, Castillo, Quinones, Garcia-Vallve, Arola et al., Inhibition of angiotensin-converting enzyme activity by flavonoids: structureactivity relationship studies, PLoS One
Hao, Guo, Yu, Zhang, Zhang et al., Encapsulation of the flavonoid quercetin with chitosan-coated nano-liposomes, LWT
He, Ma, Redox regulation by nuclear factor erythroid 2-related factor 2: gatekeeping for the basal and diabetes-induced expression of thioredoxin-interacting protein, Mol. Pharmacol
He, Wan, Hu, Chen, Wang et al., Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion, Cell Res
Heinz, Henson, Austin, Jin, Nieman, Quercetin supplementation and upper respiratory tract infection: a randomized community clinical trial, Pharmacol. Res
Herengt, Thyrsted, Holm, NRF2 in viral infection, Antioxidants (Basel)
Herker, Harris, Hernandez, Carpentier, Kaehlcke et al., Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase 1 (DGAT1), Nat. Med
Hille, Nishino, Xanthine oxidase and xanthine dehydrogenase, FASEB J
Hoffmann, Kleine-Weber, Pohlmann, A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells, Mol. Cell
Hoffmann, Kleine-Weber, Schroeder, Kruger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Hu, Wang, Li, Zhang, Kong, Allopurinol, rutin and quercetin attenuate hyperuricemia and renal dysfunction in rats induced by fructose intake: renal organic ion transporter involvement, Am. J. Physiol. Renal Physiol
Hu, Zhang, Pan, Li, Kong, Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats, Biochem. Pharmacol
Huang, Nguyen, Pickett, Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription, J. Biol. Chem
Hull, Mclean, Wong, Duriez, Karsan, Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH 2 -terminal kinase, J. Immunol
Hung, Ho, Lee, Chang, Kao et al., Houttuynia cordata targets the beginning stage of herpes simplex virus infection, PLoS One
Iba, Levy, Levi, Thachil, Coagulopathy in COVID-19, J. Thromb. Haemost
Imran, Thabet, Alaqel, Alzahrani, Abida et al., The therapeutic and prophylactic potential of quercetin against COVID-19: an outlook on the clinical studies, inventive compositions, and patent literature, Antioxidants
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
J O U R N A L P R E, None
Jacobs, Damania, NLRs, inflammasomes, and viral infection, J. Leukoc. Biol
Jiang, Huang, Han, He, Li et al., Quercetin suppresses NLRP3 inflammasome activation and attenuates histopathology in a rat model of spinal cord injury, Spinal Cord
Jiang, Yamashita, Nakamura, Croft, Ashida, Quercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes, Sci. Rep
Jing, Wu, Chen, Xiao, Zhang et al., Quercetin encapsulated in folic acid-modified liposomes is therapeutic against osteosarcoma by non-covalent binding to the JH2 domain of JAK2 via the JAK2-STAT3-PDL1, Pharm. Res
Johari, Kianmehr, Mustafa, Abubakar, Zandi, Antiviral activity of baicalein and quercetin against Japanese encephalitis virus, Int. J. Mol. Sci
Joosten, Netea, Mylona, Koenders, Subbarao Malireddi et al., Fatty acids engagement with TLR2 drive IL-1β production via ASC-Caspase-1 pathway by urate crystals in gouty arthritis, Arthritis Rheum
Jung, Saif, Wang, Porcine epidemic diarrhea virus (PEDV): an update on etiology, transmission, and prevention and control, Virus Res
Kaspar, Niture, Nrf2: INrf2 (Keap1) signaling in oxidative stress, Free Radic, Biol. Med
Kelley, Jeltema, Duan, Ye, The NLRP3 inflammasome: an overview of mechanisms of activation and regulation, Int. J. Mol. Sci
Kim, Choi, Yi, Lee, Won et al., Relative antioxidant activities of quercetin and its structurally related substances and their effects on NF-κB/CRE/AP-1 signaling in murine macrophages, Mol. Cells
Kim, Oh, Youn, Lee, pH-Sensitive twin liposomes containing quercetin and laccase for tumor therapy, Biomacromolecules
Kobayashi, Kang, Okawa, Ohtsuji, Zenke et al., Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2, Mol. Cell Biol
Komaravelli, Tian, Ivanciuc, Mautemps, Brasier et al., Respiratory syncytial virus infection downregulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of NRF2, Free Radic, Biol. Med
Kozlov, Maattanen, Schrag, Hura, Gabrielli et al., Structure of the noncatalytic domains and global fold of the protein disulfide isomerase ERp72, Structure
Kumar, Sharma, Khanna, Raj, Effect of quercetin on lipid peroxidation and changes in lung morphology in experimental influenza virus infection, Int. J. Exp. Pathol
Kupferschmidt, Cohen, Race to find COVID-19 treatment accelerates, Science
Kupila, Vuorinen, Vainionpaa, Hukkanen, Marttila et al., Etiology of aseptic meningitis and encephalitis in an adult population, Neurology
Kuwabata, Zhang, Schuiki, Curi, Volchuk et al., NADPH oxidase-dependent production of reactive oxygen species induces endoplasmatic reticulum stress in neutrophil-like HL60 cells, PLoS One
Lanaspa, Cicerchi, Garcia, Li, Roncal-Jimenez et al., Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver, PLoS One
Lee, Kang, Yun, Lee, Quercetin inhibits the poly (dA:dT)-induced secretion of IL-18 via down-regulation of the expression of AIM2 and pro-caspase-1 by inhibiting the JAK2/STAT1 pathway in IFN-γ-primed human keratinocytes, Biochem. Biophys. Res. Commun
Lee, Karki, Wang, Nguyen, Kalathur et al., AIM2 forms a complex with pyrin and ZBPI to drive PANoptosis and host defense, Nature
Lee, Mitchell, Pharmacokinetics of quercetin absorption from apples and onions in healthy humans, J. Agric. Food Chem
Lee, Woo, Ryu, Moon, Han et al., Glucosylation of flavonol and flavanones by Bacillus cyclodextrin glucosyltransferase to enhance their solubility and stability, Food Chem
Li, Zhang, Frei, Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction, Redox Biol
Lin, Chen, Chen, Liang, Lin, Molecular modelling of flavonoids that inhibits xanthine oxidase, Biochem. Biophys. Res. Commun
Lin, Gopal, Sharda, Passam, Bowley et al., Quercetin-3-rutinoside inhibits protein disulfide isomerase by binding to its b'x domain, J. Biol. Chem
Liu, Raghuvanshi, Ceylan, Bolling, Quercetin and its metabolites inhibit recombinant human angiotensin-converting enzyme 2 (ACE2) activity, J. Agric. Food Chem
Liu, Tang, Gao, Li, Chen et al., Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers, Colloids Surf. B: Biointerfaces
Liu, Tian, Chai, Wen, Wang, Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation, Food Funct
Liu, Xue, Li, Ao, Lu, Quercetin liposomes protect against radiationinduced pulmonary injury in a murine model, Oncol. Lett
Loniewski, Patial, Parameswaran, Sensitivity of TLR4-and -7-induced NF-κB1 p105-TPL2-ERK pathway to TNF-receptor-associated-factor-6 revealed by RNAi in mouse macrophages, Mol. Immunol
Lu, Crespi, Liu, Vu, Ahmadieh et al., A phase 1 dose escalation study demonstrates quercetin safety and explores potential for bioflavonoid antivirals in patients with chronic hepatitis C, Phytother. Res
Lu, Qiu, Luo, Liu, Sun et al., Phytophospholipid complexes (phytosomes): a novel strategy to improve the bioavailability of active constituents, Asian J. Pharm. Sci
Lu, Ross, Powers, Rasco, Determination of quercetins in onion (Allium cepa) using infrared spectroscopy, J. Agric. Food Chem
Lu, Zhao, Li, Niu, Yang et al., Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding, Lancet
Lucas, Wong, Klein, Castro, Silva et al., Longitudinal analyses reveal immunological misfiring in severe COVID-19, Nature
Luo, Nikolaev, Imai, Chen, Su et al., Negative control of p53 by Sir2α promotes cell survival under stress, Cell
Mahapatra, Donahue, Nyska, Hayashi, Koyanagi et al., alpha-Glycosylisoquercitrin (AGIQ) and its lack of carcinogenicity in rasH2 mice, Food Chem. Toxicol
Makino, Shimizu, Kanemaru, Suzuki, Moriwaki et al., Enzymatically modified isoquercitrin, α-oligoglucosyl-quercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats, Biol. Pharm. Bull
Makni-Maalej, Chiandotto, Hurtado-Nedelec, Bedouhene, Gougerot-Pocidalo et al., Zymogen induces NADPH oxidase activation in human neutrophils by inducing the phosphorylation of p47phox and the activatiob of Rac2: involvement of protein tyrosine kinases, PI3kinase, PKC, ERK1/2 and p38MAPkinase, Biochem. Pharmacol
Maldonado-Celis, Yahia, Bedoyo, Landazuri, Loango et al., Chemical composition of mango (Mangifera indica L.) fruit: nutritional and phytochemical compounds, Front. Plant Sci
Mangiavacchi, Botwina, Menichetti, Bagnoli, Rosati et al., Seleno-functionalization of quercetin improves the non-covalent inhibition of Mpro and its antiviral activity in cells against SARS-CoV-2, Int. J. Mol. Sci
Manjunathan, Periyaswami, Mitra, Rosita, Pandya et al., Molecular docking analysis reveals the functional inhibitory effect of genistein and quercetin on TMPRSS2: SARS-CoV-2 cell entry facilitator spike protein, BMC Bioinformatics
Mateo, Reid, Leung, Basler, Volchkov, Ebolavirus VP24 binding to karyopherins is required for inhibition of interferon signaling, J. Virol
Meng, Liu, Fu, Shu, Yang et al., Anti-entry activity of natural flavonoids against SARS-CoV-2 by targeting spike RBD, Viruses
Middleton, He, Denorme, Campbell, Ng et al., Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome, Blood
Moon, Wang, Dicenzo, Morris, Quercetin pharmacokinetics in humans, Biopharm. Drug Dispos
Mouffouk, Mouffouk, Mouffouk, Hambaba, Haba, Flavonols as potential antiviral drugs targeting SARS-CoV-2 proteases (3CLpro and PLpro), spike protein, RNAdependent RNA polymerase (RdRp) and angiotensin-converting enzyme II receptor (ACE2), Eur. J. Pharmacol
Munafo, Donati, Brindani, Ottonello, Armirotti et al., Quercetin and luteolin are single-digit micromolar inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase, Sci. Rep
Murota, Matsuda, Kashino, Fujikura, Nakamura et al., Alpha-oligoglucosylation of a sugar moiety enhances the bioavailability of quercetin glucosides in humans, Arch. Biochem. Biophys
Nagao, Seki, Kobayashi, Inhibition of xanthine oxidase by flavonoids, Biosci. Biotechnol. Biochem
Nakajima, Van Tin, Sato, Thach, Katano et al., Pathological study of archival lung tissues from five fatal cases of avian H5N1 influenza in Vietnam, Mod. Pathol
Nakamura, Matsushima, Hayashi, Shibasaki, Imaizumi et al., Attenuation of transforming growth factor-βstimulated collagen production in fibroblasts by quercetin-induced heme oxygenase-1, Am. J. Respir. Cell Mol. Biol
Ng, Yen, Liao, Lin, Protective effect of Houttuynia cordata extract on bleomycin-induced pulmonary fibrosis in rats, Am. J. Chin. Med
Nguyen, Jung, Kim, Lim, Choi et al., The inhibitory effects of plant derivate polyphenols on the main protease of SARScoronavirus 2 and their structure-activity relationship, Molecules
Ni, Sun, Zhao, Xia, Quercetin-loaded nanostructured lipid carrier for food fortification: preparation, characterization and in vitro study, J. Food Process Engineer
Nie, Liu, Zhang, Zhang, Wang et al., The effects of hyperuricemia on endothelial cells are mediated via GLUT9 and the JAK2/STAT3 pathway, Mol. Biol. Rep
Nishimura, Ohnishi, Sato, Ohnishi-Kameyama, Matsunaga et al., Estimated daily intake and seasonal food sources of quercetin in Japan, Nutrients
Nizami, Arunasalam, Green, Cook, Lawrence et al., Inhibition of the NLRP3 inflammasome by HSP90 inhibitors, Immunology
Olagnier, Farahani, Thyrsted, Blay-Cadanet, Herengt et al., SARS-CoV-2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4octyl-itaconate and dimethyl fumarate, Nat. Commun
Onal, Arslan, Ergun, Topuz, Semerci et al., Treatment of COVID-19 patients with quercetin: a prospective single-centre, randomized, controlled trial, Turk. J. Biol
Owczarek-Januszkiewicz, Magiera, Olszewska, Enzymatically modified isoquercitrin: production, metabolism, bioavailability, toxicity, pharmacology, and related molecular mechanisms, Int.J. Mol. Sci
Pan, Fang, Wang, Pan, Li et al., Quercetin: a promising drug candidate against the potential SARS-CoV-2 spike mutants with high viral infectivity, Comput. Struct. Biotechnol. J
Pan, Shen, Yu, Ge, Chen et al., SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation, Nat. Commun
Pandey, Rane, Chatterjee, Kumar, Khan et al., Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development, J. Biomol. Struct. Dyn
Pang, Jin, Ke, Man, Wang et al., The role of serotonin in Concanavalin A-induced liver injury in mice, Oxid. Med. Cell. Longev
Park, Yuk, Ryu, Lim, Kim et al., Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors, J. Enzyme Inhib. Med. Chem
Pasetto, Pardi, Murata, Anti-HIV-1 activity of flavonoid myricetin on HIV-1 infection in a dual-chamber in vitro model, PLoS One
Pauff, Hille, Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin, and curcumin, J. Nat. Prod
Pendurthi, Ghosh, Mandal, Vijaya, Rao, Tissue factor activation: is disulfide bond switching a regulatory mechanism?, Blood
Persaud, Zhou, Siliciano, Siliciano, Latency in human immunodeficiency virus type 1 infection: no easy answers, J. Virol
Pillay, Gene of the mouth: the (2019-nCoV) SARS-CoV-2 novel coronavirus spike protein, J. Clin. Pathol
Pitsillou, Liang, Ververis, Lim, Hung et al., Identification of small molecule inhibitors of the deubiquitinating activity of the SARS-CoV-2 papain-like protease: in silico molecular docking studies and in vitro enzymatic activity assay, Front. Chem
Ponce, Blanco, Molina, Garcia-Domenech, Galvez, Study of the action of flavonoids on xanthine oxidase by molecular topology, J. Chem. Inf. Comput. Sci
Pratomo, Noor, Kusmardi, Rukmana, Paramita et al., Xanthine oxidaseinduced inflammatory responses in respiratory epithelial cells: a review in immunopathology of COVID-19, Int. J. Inflam
Price, Casuscelli, Colquhoun, Rhodes, Composition and content of flavonol glycosides in broccoli florets (Brassica olearacea) and their fate during cooking, J. Sci. Food, Agric
Qui, Kroeker, He, Kozak, Audet et al., Prophylactic efficacy of quercetin 3-β-O-D-glucoside against Ebola virus infection, Antimicrob. Agents Chemother
Rahman, Tabrez, Ali, Alqahtani, Ahmed et al., Molecular docking analysis of rutin reveals possible inhibition of SARS-CoV-2 vital proteins, J. Tradit. Complement. Med
Rather, Bhagat, Quercetin as an innovative therapeutic tool for cancer chemoprevention: molecular mechanisms and implications in human health, Cancer Med
Rathinam, Jiang, Waggoner, Sharma, Cole et al., The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses, Nat. Immunol
Rathinam, Vanaja, Waggoner, Sokolovska, Becker et al., TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by Gram-negative bacteria, Cell
Rayavara, Kurosky, Susan, Garg, Brasier et al., Proinflammatory effects of respiratory syncytial virus-induced epithelial HMGB1 on human innate immune cell activation, J. Immunol
Rehermann, Nascimbeni, Immunology of hepatitis B and hepatitis C virus infection, Nat. Rev. Immunol
Reid, Leung, Hartman, Martinez, Shaw et al., Ebola virus VP24 binds karyopherin α1 and blocks STAT1 nuclear accumulation, J. Virol
Reid, Valmas, Martinez, Sanchez, Basler, Ebola virusVP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1, J. Virol
Riva, Ronchi, Petrangolini, Bosisio, Allegrini, Improved oral absorption of quercetin from quercetin phytosome ®, a new delivery system based on food grade lecithin, Eur. J. Drug Metab. Pharmacokinet
Rizzuti, Grande, Conforti, Jimenez-Alesanco, Ceballos-Laita et al., Rutin is a low micromolar inhibitor of SARS-CoV-2 main protease 3CLpro: implications for drug design of quercetin analogs, Biomedicines
Rodrigues, De Sa, Ishimoto, Becerra, Oliveira et al., Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients, J. Exp. Med
Rojas, Del Campo, Clement, Lemasson, Garcia-Valdecasas et al., Effect of quercetin on hepatitis C virus life cycle:from viral to host targets, Sci. Rep
Roman-Aguirre, Leyva-Porras, Cruz-Alcantar, Aguilar-Elguezabal, Saavedra-Leos, Comparison of polysaccharides as coatings for quercetin-loaded liposomes (QLL) and their effect as antioxidants on radical scavenging activity, Polymers
Rondanelli, Perna, Gasparri, Petrangolini, Allegrini et al., Promising effects of 3-month period of quercetin phytosome ® supplementation in prevention of symptomatic COVID-19 disease in healthcare workers: a pilot study, Life (Basel)
Roy, Ghosh, Dubey, Dubey, Benito-Leon et al., Neurological and neuropsychiatric impacts of COVID-19 pandemic, Can. J. Neurol. Sci
Saeedi-Boroujeni, Mahmoudian-Sani, Anti-inflammatory potential of quercetin in COVID-19 treatment, J. Inflamm
Scalbert, Johnson, Saltmarsh, Polyphenols: antioxidants and beyond, Am. J. Clin. Nutr
Shahhamzehei, Abdelfatah, Efferth, In silico and in vitro identification of pancoronaviral main protease inhibitors from a large Natural Product Library, Pharmaceuticals
Shang, Ye, Shi, Wan, Luo et al., Structural basis of receptor recognition by SARS-CoV-2, Nature
Shao, Yu, Yang, Li, Hang et al., A solid dispersion of quercetin shows enhanced Nrf2 activation and protective effects against oxidative injury in a mouse model of dry age-related macular degeneration, Oxid. Med. Cell. Longev
Sharma, Parikh, Shah, Gandhi, Modulation of Nrf2 by quercetin in doxorubicin-treated rats, Heliyon
Shimoi, Saka, Nozawa, Sato, Amano et al., Deglucuronidation of a flavonoid, luteolin monoglucuronide, during inflammation, Drug Metab. Dispos
Shin, Mukherjee, Grewe, Bojkova, Baek et al., Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity, Nature
Shohan, Nashibi, Mahmoudian-Sani, Abolnezhadian, Ghafourian et al., The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: a randomized controlled trial, Eur. J. Pharmacol
Sidik, The hunt for drugs for mild COVID: scientists seek to those at lower risk, Nature
Sivakorn, Dechsanga, Jamjumrus, Boonnak, Schultz et al., High mobility group box 1 and interleukin 6 at intensive care unit admission as biomarkers in critically ill COVID-19 patients, Am. J. Trop. Med. Hyg
Srinivas, King, Howard, Monrad, Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water, J. Food Engineering
Stopa, Neuberg, Puligandla, Furie, Flaumenhaft et al., Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering the platelet factor V activation, JCI Insight
Stopa, Zwicker, The intersection of protein disulfide isomerase and cancer associated thrombosis, Thromb. Res
Su, Yao, Zhao, Zhang, Liu et al., Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease, Nat. Commun
Suchankova, Nelson, Gerhart-Hines, Kelly, Gauthier et al., Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells, Biochem. Biophys. Res. Commun
Suntar, Cetinkaya, Panieri, Saha, Buttari et al., Regulatory role of Nrf2 signaling pathway in wound healing process, Molecules
Tang, Kang, Xiao, Zhang, Lotze et al., Quercetin prevents LPS-induced high-mobility group box 1 release and proinflammatory function, Am. J. Respir. Cell Mol. Biol
Tanigawa, Fujii, Hou, Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin, Free Radic, Biol. Med
Tomou, Papakyriakopoulou, Saitani, Valsami, Pippa et al., Recent advances in nanoformulations for quercetin delivery, Pharmaceutics
Tuculeanu, Barbu, Lazar, Chitu-Tisu, Moisa et al., Coagulation disorders in sepsis and COVID-19-two sides of the same coin? a review of inflammation-coagulation crosstalk in bacterial sepsis and COVID-19, J. Clin. Med
V'kovski, Kratzel, Steiner, Stalder, Thiel, Coronavirus biology and replication: implications for SARS-CoV-2, Nat. Rev. Microbiol
Vafadar, Shabaninejad, Movahedpour, Fallahi, Taghavipour et al., Quercetin and cancer: new insights into its therapeutic effects on ovarian cancer cells, Cell Biosci
Van Der Woude, Boersma, Vervoort, Rietjens, Identification of 14 quercetin phase II mono-and mixed conjugates and their formation by rat and human phase II in vitro model systems, Chem. Res. Toxicol
Vaziri, Dessain, Eaton, Imai, Frye et al., hSIR (SIRT1) functions as an NAD-dependent p53 deacetylase, Cell
Verma, Kushwah, Gohel, Patel, Marvania et al., Evaluating the ameliorative potential of quercetin against the bleomycin-induced pulmonary fibrosis in Wistar rats, Pulm. Med
Wang, Bloom, Zhang, Vishnubhakat, Ombrellino et al., HMG-1 as a late mediator of endotoxin lethality in mice, Science
Wang, Pan, Zhang, Wang, Kong, Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation, PLoS One
Wang, Wang, Ding, Pan, Gu et al., Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats, Br. J. Pharmacol
Wang, Ward, Fan, Sama, Li, Potential role of high mobility group box 1 in viral infectious diseases, Viral Immunol
Wang, Xue, Song, Xu, Chen et al., Molecular basis of rutin inhibition of protein disulfide isomerase (PDI) by combined in silico and experimental methods, RSC Adv
Wang, Zhang, Du, Du, Zhao et al., Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Lancet
White, Lin, Cheng, Discovery of COVID-19 inhibitors targeting the SARS-CoV-2 nsp13 helicase, J. Phys. Chem. Lett
Wu, Li, Li, He, Jiang et al., Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry, Viruses
Wu, Liu, Yang, Zhang, Zhong et al., Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods, Acta Pharm. Sin. B
Wu, Peng, Huang, Ding, Wang et al., Genome composition and divergence of the novel coronavirus (2019-nCOV) originating in China, Cell Host Microbe
Wu, Wang, Li, Li, Feng et al., Hepatoprotective effect of quercetin via TRAF6/JNK pathway in acute hepatitis, Biomed. Pharmacother
Wulandari, Hartono, Wibawa, The role of HMGB1 in COVID-19-induced cytokine storm and its potential therapeutic targets, Immunology
Xue, Du, Zhu, Quercetin suppresses NLRP3 inflammasome activation in epithelial cells triggered by Escherichia coli, Free Radic, Boil. Med
Yang, Islam, Wang, Li, Chen, Traditional Chinese Medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective, Int. J. Biol. Sci
Yang, Zhu, Ji, Deng, Lu et al., Quercetin synergistically reactivates human immunodeficiency virus type 1 latency by activating nuclear factor-κB, Mol. Med. Rep
Yap, Craddock, Yang, Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription, Int. J. Biol. Sci
Yeung, Hoberg, Ramsey, Keller, Jones et al., Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase, EMBO J
Yi, Li, Yuan, Qu, Chen et al., Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells, J. Virol
Zandi, Teoh, Sam, Wong, Mustafa et al., Antiviral activity of bioflavonoid against dengue virus type 2, Virol. J
Zhan, Ta, Tang, Hua, Wang et al., Potential antiviral activity of isorhamnetin against SARS-CoV-2 spike pseudotyped virus in vitro, Drug Dev. Res
Zhang, Pan, Wang, Kang, Xue et al., Quercetin inhibits AMPK/TXNIP activation and reduces inflammatory lesions to improve insulin signaling defect in the hypothalamus of high fructose-fed rats, J. Nutr. Biochem
Zhang, Qu, Gao, Zhai, Tao et al., Quercetin attenuates NLRP3 inflammasome activation and apoptosis to protect INH-induced liver injury via regulating STAT1 pathway, Int. Immunopharmacol
Zhao, Zhang, Wang, Liu, Lei et al., Quinoline and quinazoline derivatives inhibit viral RNA synthesis by SARS-CoV-2 RdRp, ACS Infect. Dis
Zheng, Liwinski, Elinav, Inflammasome activation and regulation: toward a better understanding of complex mechanisms, Cell Dis
Zhong, Zheng, Li, Poon, Xie et al., Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, Lancet
Zhou, Xu, Xing, Wang, Jiang, A harmless-harmful switchable and uninterrupted laccase-instructed killer for activatable chemodynamic therapy, Adv. Mat
Zhu, Scholle, Kisthardt, Xie, Flavonols and dihydroflavonols inhibit the main protease activity of SARS-CoV-2 and the replication of human coronavirus 229E, Virology
Zwicker, Schlechter, Stopa, Liebman, Aggarwal et al., Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer, JCI Insight
