Use of Quercetin for Therapeutic Purposes in COVID-19 Infections: The Opinion of the Geriatrician Doctor

 

Valerio Massimo Magro1*

 

1Department of Internal Medicine and Geriatry, University of Campania “luigi Vanvitelli”, Naples, Italy

 

*Correspondence to: Valerio Massimo Magro, PhD, Geriatrician, Department of Internal Medicine and Geriatrics, University of Campania “Luigi Vanvitelli”, Piazza L, Miraglia 2, Naples 80100, Italy; Email: valerio_magro@hotmail.com

 

DOI: 10.53964/jmbdd.2023004

 

Abstract

The COVID-19 epidemic has put health systems around the world in distress, at the same time stimulating global research in an attempt to discover new therapeutic strategies against this virus. In this opinion we analyze the characteristics of a flavonoid, quercetin, trying to better understand its usefulness in the treatment of coronavirus infection.

 

Keywords: quercetin, elderly patient, COVID-19, infection, receptors

 

1 INTRODUCTION

The COVID-19 epidemic has affected the Italian healthcare system on various levels, including the organization of hospital and territorial systems[1], the costs of diagnosis and follow-up (tampons)[2] as well as curative strategies (monoclonal and antiviral drugs)[3] and preventive (vaccines)[4]. In order to have the widest possible, accessible and low-cost therapeutic armament, clinical research has moved in various fields and together with the traditional pharmacopeia other molecules and active ingredients have been investigated that could be used in the fight against the virus and that could be therefore used alongside drugs and vaccines already tested and approved by drug regulatory bodies [Food and Drug Administration; European Medicine Agency; Italian Medicine Agency (Agenzia Italiana del Farmaco)][5-7]. Recent disappointments, such as in the case of molnupinavir (which, beyond its proven safety, has not convinced regulatory bodies in terms of efficacy on symptoms and hospitalizations)[8-10] have convinced scientists to try to find new ways to fight the virus. So, nucleoside antivirals[11], ensitrelvir - a noncovalent nonpeptidic agent with potential strong broad-spectrum anticoronaviral activities[12], antioxidant polyphenolic 1,3,4-oxadiazole compounds[13], polyphenolics and 1,3,4-oxadiazoles - like Taroxaz-104[14], molecules with a potential inhibitory activities RNA polymerase (nCoV-RdRp) protein - like the teriflunomide or synthetic nitrogenous heterocyclic antivirals[15,16], analogues and derivatives of natural nucleosides / nucleotides[17], topped the scene as top options for the treatment of coronavirus. In parallel, research has turned its interest towards compounds of natural origin, which could have antiviral properties and be useful in the fight against the virus. Among several molecules (curcumin, naringenin, luteolin, hesperidin, mangiferin, and gallic acid), quercetin has aroused particular interest[18].

 

2 QUERCETIN: CHEMICAL PROPERTIES AND DIETARY INTAKE

Quercetin is a flavonoid contained in numerous plants and foods. It too has strong antioxidant and anti-inflammatory properties, and has even been studied in cancer trials. This flavonoid is one of the most common present in nature as it can be isolated from numerous plant species. In fact, it is found in capers, asparagus, onions and red grapes / red wine, tomatoes and green tea; in berries; in citrus fruits and broccoli; in blueberries; in the apple; into the celery (Figure 1)[19,20]. For these reasons, foods rich in quercetin are recommended in the diet and products used as dietary supplements of the same are regularly found on the market. The anti-inflammatory and free radical fighting properties are well known and studied in the literature; the molecule also inhibits numerous phases that lead to the release of histamine and the production of prostaglandins and leukotrienes with a pro-inflammatory action, as well as the enzymes 5-lipoxygenase and phospholipase A2[21-23]. Due to its heterogeneous and diverse beneficial properties, quercetin has been studied for a long time in order to better understand its possible uses in the clinical setting[24].

 

Figure 1. Quercetin content.

 

3 CLINICAL EVIDENCE OF THE BENEFICIAL EFFECTS OF QUERCETIN IN THE MEDICAL FIELD

As highlighted in a work by Jafarinia et al.[25], quercetin modulates the immune system in various ways: It decreased allergic airway inflammation and hyperresponsiveness due to the alteration of Th1/Th2 differentiation, it reduced the increased levels of IL-4, increased interferon (IFN)-ɣ, reduced the eosinophil recruitment, IL-4 and IL-5 levels in the bronchoalveolar lavage fluid, as well as, inhibited the nuclear transcription factor-kappa B activation, P-selectin expression and the mucus production in the lung. Such actions can be useful not only in allergic pathologies but also in the case of COVID or when there is an overlap between allergies, asthmatic disease and coronavirus infection. Quercetin shows, as evidenced in the work of Deng et al.[26] number actions on inflammatory mediators that underlie atherosclerotic plaque imbalance [the production of tumor necrosis factor alpha, interleukin 1 beta, IL-6, prostaglandin E2, mitogen-activated protein kinase, Janus kinase / signal transducers and activators of transcription decreases while 5' AMP-activated protein kinase, Cathepsin production increases, just as it increases that of superoxide dismutase, glutathione and nuclear factor erythroid-derived 2-like 2(Nrf2)]. It has also been seen that quercetin can increase the activity of the Na-K-Cl cotransporter 1, by modifying the concentration of chloride ions[27]. This event, by first modifying the expression of chloride channels at the gene level and then at the protein level, leads to a reduced reabsorption of sodium, for which has a reduced blood volume and therefore a consequent drop in blood pressure. All these actions not only make quercetin a good pharmacological agent that can be used in cardiovascular pathology, but they can also be of great help in the COVID phase, whose increase in deaths is both greater in the general population due to cardiovascular causes and in cardiovascular patients[28,29]. In the same way[30], similar benefits can be obtained by using quercetin in patients with diabetes, infected with COVID: Together with the cardiovascular effects already mentioned, quercetin stimulates glucose uptake through the mechanism of insulin-dependent MAPK, with translocation of the glucose transporter type 4 in skeletal muscle. In the treatment of dyslipidemia, Talirevic et al.[31], quercetin with its antioxidant effects has been shown to contribute both to a reduction in lipid levels but above all to an intervention in the oxidation mechanisms of LDL, therefore with an anti-atherogenic profile[32]. Based on the available evidence, it is recommended by a panel of experts that safe but stringent control of blood glucose, blood pressure, and lipids be carried out in patients with type 2 diabetes, measures that could potentially serve to decrease the severity of COVID-19 should these patients contract the viral infection[33]. So the use of quercetin can be useful for this purpose. Multiple effects of quercetin, investigated in the literature, have concerned other pathologies causing fragility and vulnerability both taken individually and in the case of COVID-19 infection, such as tumors, osteoporosis, urinary obstruction and cognitive impairment[34-38], pathologies often present, individually or not, in the elderly patient.

 

4 USE OF QUERCETIN IN THE FIELD OF INFECTIOUS DISEASES: BACTERIA, FUNGI AND PARASITES

Quercetin has been seen to exert numerous actions both in vitro and in vivo against various infectious agents, both bacterial and fungal: it inhibits the synthesis of nucleic acid with interference with the plasma membranes of various bacteria (Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, Enterococcus faecalis)[39,40]. It has also potential anti-biofilm properties[41]. At the fungal level, it has been seen that at different concentrations of the drug there is an ability to inhibit the crestica of various fungal species as well as a synergy of the molecule with antifungal pharmacological agents such as fluconazole and amphotericin against Candida albicans, parapsilosis and Tropicalis, Aspergillus flavus and Cryptococcus neoformans[42,43]. Quercetin has been shown to be important in the fight against parasites and has been demonstrated in different clinical trials, such as those against Leishmania, Trypanosoma, and Plasmodium[44,45].

 

5 ANTIVIRAL ACTIONS OF QUERCETIN

An interesting and recent meta-analysis by Brito et al.[46] well describes the action of quercetin in the lung affected by a virus that has caused inflammation: the use of the flavonoid in various forms of administration leads to a decrease in the activation of the viru-related pro-inflammatory cytokine and chemokine cascade, to a lower production of mucus, with reduction of airway resistance and increase in vital capacity. The final effect is clinical improvement and reduction of mortality in animals. It is known that the effect of the vaccine in the human body is to generate an immune response that causes the formation of neutralizing antibodies directed against the spike protein of the coronavirus. The spike protein covers the external surface of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with protuberances and is precisely one of the peculiar characteristics of the family to which this virus belongs, the coronaviruses, which thanks to the protuberances of the spike proteins on their surface, when viewed under an electron microscope, resemble crowns. The spike protein of SARS-CoV-2 is the main mechanism that the virus uses to infect target cells. The spike protein of SARS-CoV-2 is one of the most studied drug targets. In fact, blocking its functioning quercetin was identified as being between the top scoring ligands for the spike protein: Angiotensin-converting enzyme 2 (ACE2) receptor interface would mean preventing the virus from infecting target cells, thus making it harmless[47]. Spike protein of SARS-CoV-2 binds with human ACE2 protein, a component of renin-angiotensin-aldosterone system involved in regulation of blood pressure. It also plays an important role in the initiation of pulmonary hypertension-like complications in COVID-19 patients. The major druggable targets of SARS-CoV-2, in addition to the spike protein mentioned above, include the 3-chymotrypsin-like protease (3CLpro) and the papain-like protease (PLpro), RNA-dependent RNA polymerase. So, quercetin can target ACE2 expression by interfering with Spike-ACE2 binding and interacting with PLpro. Among all the potential protein targets within coronaviruses, the main protease (Mpro or 3CLpro) stands out as a highly conserved gene, making 3CLpro a good target for developing effective drugs against SARS-CoV-2. Together with PLpro, 3CLpro is responsible for the processing of the viral polyproteins synthesized from the viral RNA after infection, rendering the individual viral proteins active and functional. Quercetin binds to SARS-CoV-2 3CLpro active site. Several studies showed a significant inhibition by quercetin of 3CLpro and PLpro[48-50]. An italian 2-week, randomized, open-label and controlled clinical study, that had enrolled only 42 COVID-19 outpatients: in this study, quercetin in phytosomal form was able not only to accelerate the negativity of patients but was also able to intervene favorably on various blood parameters, decreasing many inflammatory and pro-thrombotic indices, such as C-reactive protein and D-dimer[51]. An equal prospective study on a much greater number of patients (over 400) confirmed the benefits in terms of improvement of various laboratory parameters, although there was great uncertainty about the dose of quercetin capable of giving these benefits[52]. Saeedi-Boroujeni et al.[53] have seen that this effect on inflammatory parameters is mediated by the action that quercetin has on inflammasomes. Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Inflammasome activation (for example the cytoplasmic nod-like receptor, family pyrin domain containing 3 - NLP3) and assembly promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines, generating active forms of cytokines (IL-1β and IL-18). The activation or inhibition of the inflammasome NLRP3 is affected by regulators such as Nrf2 cited in this article: affecting the regulator Nrf2, quercetin suppresses the NLRP3 inflammasome. The Nfr2 agonists abrogate replication of SARS-CoV-2 in lung cells; quercetin has been shown to be an agonist of Nfr2 and several experimental evidences have shown that this results in a lower production of reactive oxygen species[54,55]. It transduces with anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance[56]. These characteristics are important since there is not only acute damage caused by the virus, through an inflammatory response, but there are also consequences that are felt even after some time and damage that anatomically remains in the lung, even once the infection is finished. An anti-fibrotic action of quercetin is therefore of extreme interest. Since the harmful action of the coronavirus infection takes place at the level of the circulation, with a virus-induced pro-thrombotic effect[57], the anti-thrombotic properties of quercetin have been highlighted both in vitro and in animal models[58,59]. An high percentage of hospitalized patients with COVID-19 have hematologic changes in coagulation tests (elevated D-dimer, prolonged prothrombin time, thrombocytopenia and / or low fibrinogen levels) with a procoagulant response of the infection itself[60]. Quercetin inhibits agonists (ADP, collagen, and thrombin) of the platelet aggregation and granule secretion, it inhibits platelet activation by inhibiting various components, like the collagen; it also inhibits fibrin production in several histopathological and mouse experimental models[50], through inhibition of the activation of factor X (inactive) to factor Xa (active). Zhang et al.[61] reviewed ongoing clinical trials in which quercetin is used alone or in association with other drugs / dietary supplements against COVID-19: the results of these and other studies will allow us to better understand the practical extent of the properties of quercetin and its possible real applications in the therapeutic field against this virus.

 

6 CONCLUSION

The need to find new weapons to use in the fight against the coronavirus has prompted research to deal with the properties of medicinal substances present in nature. Among these, quercetin appears very promising and its effects in patients both suffering from comorbidities and infected with coronavirus have prompted the launch of several researches and clinical trials. Recent scientific works published up to 2023 and a very recent meta-analysis continue to confirm its beneficial properties and possible implications as a therapeutic agent against COVID[62-65]. Many questions currently remain to explain about the dose to be used, the significance in practice of the clinical and laboratory effects already highlighted on models and guinea pigs as well as the best therapeutic scheme (alone, together with other substances, together with other drugs already in use) to guarantee maximum benefit to patients. There are still few studies in humans to be able to infer clinically significant effects and hospitalizations. At the same time, from the literature consulted, the molecule up to now would appear to be quite safe, as no significant toxic effects on humans at the doses used and important interactions with other drugs would have been seen, so as to increase adverse events. Further studies on the subject, clarifying these points, will certainly contribute to the progress of treatments and the fight against this terrible virus.

 

Acknowledgements

Not applicable.

 

Conflicts of Interest

The author declared no conflict of interest.

 

Author Contribution

Magro VM was the primary researcher and wrote the manuscript. Magro VM provided research and editing assistance to the manuscript. Magro VM contributed to overall article design, data collection as well as revising and approving the manuscript.

 

Abbreviation List

3CLpro, 3‐chymotrypsin‐like protease

ACE2, Angiotensin‐converting enzyme 2

Nrf2, Nuclear factor erythroid-derived 2-like 2

PLpro, Papain‐like protease

 

References

[1] Magro VM. The defeat of general medicine as a role and ability to protect itself and its patients in the coronavirus pandemic era. Fam Pract, 2022; 39: 1187-1189. DOI: 10.1093/fampra/cmac028

[2] Kevill JL, Lambert-Slosarska K, Pellett C et al. Assessment of two types of passive sampler for the efficient recovery of SARS-CoV-2 and other viruses from wastewater. Sci Total Environ, 2022; 838: 156580. DOI: 10.1016/j.scitotenv.2022.156580

[3] Parums DV. Editorial: Current status of oral antiviral drug treatments for SARS-CoV-2 infection in non-hospitalized patients. Med Sci Monit, 2022; 28: 935952. DOI: 10.12659/MSM.935952

[4] Padula WV, Malaviya S, Reid NM et al. Economic value of vaccines to address the COVID-19 pandemic: A U.S. cost-effectiveness and budget impact analysis. J Med Econ, 2021; 24: 1060-1069. DOI: 10.1080/13696998.2021.1965732

[5] Shahinozzaman M, Basak B, Emran R et al. Artepillin C: A comprehensive review of its chemistry, bioavailability, and pharmacological properties. Fitoterapia, 2020; 147: 104775. DOI: 10.1016/j.fitote.2020.104775

[6] Xiong Y, Zhu G, Wang H et al. Discovery of naturally occurring inhibitors against SARS-CoV-2 3CLpro from Ginkgo biloba leaves via large-scale screening. Fitoterapia, 2021; 152: 104909. DOI: 10.1016/j.fitote.2021.104909

[7] Boccalone E, Lanni VM, Magro VM. Role of natural drugs in severe acute respiratory syndrome coronavirus 2: Potential beneficial effects in prevention or prior treatment in elderly and cancer patients. Geriatric Care, 2020; 6: 9016. DOI: 10.4081/gc.2020.9016

[8] Nappi F, Iervolino A, Singh SSA. Molecular insights of SARS-CoV-2 antivirals administration: A balance between safety profiles and impact on cardiovascular phenotypes. Biomedicines, 2022; 10: 437. DOI: 10.3390/biomedicines10020437

[9] Wen W, Chen C, Tang J et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: A meta-analysis. Ann Med, 2022; 54: 516-523. DOI: 10.1080/07853890.2022.2034936

[10] Scioscia G, Pace CC, Giganti G et al. Real life experience of molnupiravir as a treatment of SARS-CoV-2 infection in vaccinated and unvaccinated patients: A letter on its effectiveness at preventing hospitalization. Ir J Med Sci, 2022; 1: 1-3. DOI: 10.1007/s11845-022-03241-1

[11] Rabie AM, Abdalla M. Forodesine and Riboprine exhibit strong anti-SARS-CoV‑2 repurposing potential: In silico and in vitro studies. ACS Bio Med Chem Au, 2022; 2: 565-585. DOI: 10.1021/acsbiomedchemau.2c00039

[12] Eltayb WA, Abdalla M, Rabie AM. Novel investigational anti-SARS-CoV-2 agent ensitrelvir “S-217622”: A very promising potential universal broad-spectrum antiviral at the therapeutic frontline of coronavirus species. ACS Omega, 2023; 8: 5234-5246. DOI: 10.1021/acsomega.2c03881

[13] Rabie AM. Two antioxidant 2,5-disubstituted-1,3,4-oxadiazoles (CoViTris2020 and ChloViD2020): Successful repurposing against COVID-19 as the first potent multitarget anti-SARS-CoV-2 drugs. New J Chem, 2021; 45: 761-771. DOI: 10.1039/D0NJ03708G

[14] Rabie AM. Potent toxic effects of Taroxaz-104 on the replication of SARS-CoV-2 particles. Chem Biol Interact, 2021; 343: 109480. DOI: 10.1016/j.cbi.2021.109480

[15] Rabie AM. Teriflunomide: A possible effective drug for the comprehensive treatment of COVID-19. Curr Res Pharmacol Drug Discov, 2021; 2: 100055. DOI: 10.1016/j.crphar.2021.100055

[16] Rabie AM, Eltayb WA. Potent dual polymerase/exonuclease inhibitory activities of antioxidant aminothiadiazoles against the COVID-19 omicron virus: A promising in silico/in vitro repositioning research study. Mol Biotechnol, 2023; 1-20. DOI: 10.1007/s12033-022-00551-8

[17] Rabie AM. Efficacious preclinical repurposing of the nucleoside analogue didanosine against COVID-19 polymerase and exonuclease. ACS Omega,  2022; 7: 21385-21396. DOI: 10.1021/acsomega.1c07095

[18] Junior AG, Tolouei SEL, Lívero FA et al. Natural agents modulating ACE-2: A review of compounds with potential against SARS-CoV-2 infections. Curr Pharm Des, 2021; 27: 1588-1596. DOI: 10.2174/1381612827666210114150607

[19] Nishimuro H, Ohnishi H, Sato M et al. Estimated daily intake and seasonal food sources of quercetin in Japan. Nutrients, 2015; 7: 2345-2358. DOI: 10.3390/nu7042345

[20] Vida RG, Fittler A, Somogyi-Végh A et al. Dietary quercetin supplements: Assessment of online product informations and quantitation of quercetin in the products by high-performance liquid chromatography. Phytother Res, 2019; 33: 1912-1920. DOI: 10.1002/ptr.6382

[21] Li Y, Yao J, Han C et al. Quercetin, Inflammation and immunity. Nutrients, 2016; 8: 167. DOI: 10.3390/nu8030167

[22] Magar RT, Sohng JK. A review on structure, modifications and structure-activity relation of quercetin and its derivatives. J Microbiol Biotechnol, 2020; 30: 11-20. DOI: 10.4014/jmb.1907.07003

[23] Alizadeh SR, Ebrahimzadeh MA. O-glycoside quercetin derivatives: Biological activities, mechanisms of action, and structure-activity relationship for drug design, a review. Phytother Res, 2022; 36: 778-807. DOI: 10.1002/ptr.7352

[24] Yang D, Wang T, Long M et al. Quercetin: Its main pharmacological activity and potential application in clinical medicine. Oxid Med Cell Longev, 2020; 2020: 8825387. DOI: 10.1155/2020/8825387

[25] Jafarinia M, Hosseini MS, Kasiri N et al. Quercetin with the potential effect on allergic diseases. Allergy Asthma Clin Immunol, 2020; 16: 36. DOI: 10.1186/s13223-020-00434-0

[26] Deng Q, Li X, Fang Y et al. Therapeutic potential of quercetin as an antiatherosclerotic agent in atherosclerotic cardiovascular disease: A Review. Evid-based Compl Alt Med, 2020; 2020: 5926381. DOI: 10.1155/2020/5926381

[27] Marunaka Y, Marunaka R, Sun H et al. Actions of quercetin, a polyphenol, on blood pressure. Molecules, 2017; 22: 209. DOI: 10.3390/molecules22020209

[28] Patel RV, Mistry BM, Shinde SK et al. Therapeutic potential of quercetin as a cardiovascular agent. Eur J Med Chem, 2018; 155: 889-904. DOI: 10.1016/j.ejmech.2018.06.053

[29] Pasquale G, Palma R, Fortuna D et al. Effetti indiretti della pandemia COVID-19 sulla mortalità cardiovascolare. G Ital Cardiol (Rome), 2021; 22: 188-192.

[30] Chen S, Jiang H, Wu X et al. Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes. Mediat Inflamm, 2016; 2016: 9340637. DOI: 10.1155/2016/9340637

[31] Talirevic E, Sehovic J. Quercetin in the treatment of dyslipidemia. Med Arh, 2012; 66: 87-88. DOI: 10.5455/medarh.2012.66.87-88

[32] Ishizawa K, Yoshizumi M, Kawai Y et al. Pharmacology in health food: Metabolism of quercetin in vivo and its protective effect against arteriosclerosis. J Pharmacol Sci, 2011; 115: 466-470. DOI: 10.1254/jphs.10R38FM

[33] Rajpal A, Rahimi L, Ismail-Beigi F. Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes. J Diabetes, 2020; 12: 895-908. DOI: 10.1111/1753-0407.13085

[34] Wong SK, Chin KY, Ima-Nirwana S. Quercetin as an agent for protecting the bone: A review of the current evidence. Int J Mol Sci, 2020; 21: 6448. DOI: 10.3390/ijms21176448

[35] Khan F, Niaz K, Maqbool F et al. Molecular targets underlying the anticancer effects of quercetin: An update. Nutrients, 2016; 8: 529. DOI: 10.3390/nu8090529

[36] Vrolijk MF, Haenen GR, Opperhuizen A et al. The supplement-drug interaction of quercetin with tamsulosin on vasorelaxation. Eur J Pharmacol, 2015; 746: 132-137. DOI: 10.1016/j.ejphar.2014.11.006

[37] Babaei F, Mirzababaei M, Nassiri-Asl M. Quercetin in food: Possible mechanisms of its effect on memory. J Food Sci, 2018; 83: 2280-2287. DOI: 10.1111/1750-3841.14317

[38] Ebrahimpour S, Zakeri M, Esmaeili A. Crosstalk between obesity, diabetes, and alzheimer's disease: Introducing quercetin as an effective triple herbal medicine. Ageing Res Rev, 2020; 62: 101095. DOI: 10.1016/j.arr.2020.101095

[39] Cushnie TP, Lamb AJ. Antimicrobial activity of flavonoids. Int J Antimicrob Agents, 2005; 26343-26356. DOI: 10.1016/j.ijantimicag.2005.09.002

[40] Nguyen TLA, Bhattacharya D. Antimicrobial activity of quercetin: An approach to its mechanistic principle. Molecules, 2022; 27: 2494. DOI: 10.3390/molecules27082494

[41] Memariani H, Memariani M, Ghasemian A. An overview on anti-biofilm properties of quercetin against bacterial pathogens. World J Microbiol Biotechnol, 2019; 35: 143. DOI: 10.1007/s11274-019-2719-5

[42] Nguyen W, Grigori L, Just E et al. The in vivo anti-Candida albicans activity of flavonoids. J Oral Biosci, 2021; 63: 120-128. DOI: 10.1016/j.job.2021.03.004

[43] Oliveira VM, Carraro E, Auler ME et al. Quercetin and rutin as potential agents antifungal against cryptococcus spp. Braz J Biol, 2016; 76: 1029-1034. DOI: 10.1590/1519-6984.07415

[44] Jean-Moreno V, Rojas R, Goyeneche D et al. Leishmania donovani: Differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays. Exp Parasitol, 2006; 112: 21-30. DOI: 10.1016/j.exppara.2005.08.014

[45] Ganesh D, Fuehrer HP, Starzengrüber P et al. Antiplasmodial activity of flavonol quercetin and its analogues in plasmodium falciparum: Evidence from clinical isolates in bangladesh and standardized parasite clones. Parasitol Res, 2012; 110: 2289-2295. DOI: 10.1007/s00436-011-2763-z

[46] Brito JCM, Lima WG, Cordeiro LPB et al. Effectiveness of supplementation with quercetin-type flavonols for treatment of viral lower respiratory tract infections: Systematic review and meta-analysis of preclinical studies. Phytother Res, 2021; 35: 4930-4942. DOI: 10.1002/ptr.7122

[47] Derosa G, Maffioli P, D'Angelo A et al. A role for quercetin in coronavirus disease 2019 (COVID-19). Phytother Res, 2021; 35: 1230-1236. DOI: 10.1002/ptr.6887

[48] Abian O, Ortega-Alarcon D, Jimenez-Alesanco A et al. Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. Int J Biol Macromol, 2020; 164: 1693-1703. DOI: 10.1016/j.ijbiomac.2020.07.235

[49] Imran M, Thabet HK, Alaqel SI et al. The therapeutic and prophylactic potential of quercetin against COVID-19: An outlook on the clinical studies, inventive compositions, and patent literature. Antioxidants (Basel), 2022; 11: 876. DOI: 10.3390/antiox11050876

[50] Bhattacharya K, Bordoloi R, Chanu NR et al. In silico discovery of 3 novel quercetin derivatives against papain-like protease, spike protein, and 3C-like protease of SARS-CoV-2. J Genet Eng Biotechnol, 2022; 20: 43. DOI: 10.1186/s43141-022-00314-7

[51] Pierro F, Iqtadar S, Khan A 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, 2021; 14: 2807-2816. DOI: 10.2147/IJGM.S318949

[52] Önal H, Arslan B, Ergun NÜ et al. Treatment of COVID-19 patients with quercetin: A prospective, single center, randomized, controlled trial. Turk J Biol, 2021; 45: 518-529. DOI: 10.3906/biy-2104-16

[53] Saeedi-Boroujeni A, Mahmoudian-Sani MR. Anti-inflammatory potential of Quercetin in COVID-19 treatment. J Inflamm (Lond), 2021; 18: 3. DOI: 10.1186/s12950-021-00268-6

[54] Jia H, Zhang Y, Si X et al. Quercetin alleviates oxidative damage by activating nuclear factor erythroid 2-related factor 2 signaling in porcine enterocytes. Nutrients, 2021; 13: 375. DOI: 10.3390/nu13020375

[55] Lee YJ, Lee DM, Lee SH. Nrf2 Expression and apoptosis in quercetin-treated malignant mesothelioma cells. Mol Cells, 2015; 38: 416-25. DOI: 10.14348/molcells.2015.2268

[56] Boots AW, Veith C, Albrecht C et al. The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice. BMC Pulm Med, 2020; 20: 112. DOI: 10.1186/s12890-020-1142-x

[57] Ali MAM, Spinler SA. COVID-19 and thrombosis: From bench to bedside. Trends Cardiovas Med, 2021; 31: 143-160. DOI: 10.1016/j.tcm.2020.12.004

[58] Hubbard GP, Wolffram S, Lovegrove JA et al. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen‐stimulated platelet activation pathway in humans. J Thromb Haemost, 2004; 2: 2138-2145. DOI: 10.1111/j.1538-7836.2004.01067.x

[59] Choi JH, Kim KJ, Kim S. Comparative effect of quercetin and quercetin‐3‐O‐β‐d‐glucoside on fibrin polymers, blood clots, and in rodent models. J Biochem Mol Toxic, 2016; 30: 548-558. DOI: 10.1002/jbt.21822

[60] Gómez-Mesa JE, Galindo-Coral S, Montes MC et al. Thrombosis and Coagulopathy in COVID-19. Curr Prob Cardiology, 2021; 46: 100742. DOI: 10.1016/j.cpcardiol.2020.100742

[61]  Zhang L, Ma J, Yang F et al. Neuroprotective effects of quercetin on ischemic stroke: A literature review. Front Pharmacol, 2022; 13: 854249. DOI: 10.3389/fphar.2022.854249

[62] Pawar A, Russo M, Rani I et al. A critical evaluation of risk to reward ratio of quercetin supplementation for COVID-19 and associated comorbid conditions. Phytother Res, 2022; 36: 2394-2415. DOI: 10.1002/ptr.7461

[63] Pierro F, Khan A, Iqtadar S et al. Quercetin as a possible complementary agent for early-stage COVID-19: Concluding results of a randomized clinical trial. Front Pharmacol, 2023; 13: 1096853. DOI: 10.3389/fphar.2022.1096853

[64] Martínez JPQ, Campos MRS. Flavonoids as a therapeutical option for the treatment of thrombotic complications associated with COVID-19. Phytother Res, 2023; 37: 1092-1114. DOI: 10.1002/ptr.7700

[65] Cheema HA, Sohail A, Fatima A et al. Quercetin for the treatment of COVID-19 patients: A systematic review and meta-analysis. Rev Med Virol, 2023; 33: 2427. DOI: 10.1002/rmv.2427

 

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