Discussion
Quercetin, as a common component of many fruits and vegetables such as high capers, lovage, and tea (Camellia sinensis), is a flavonoid.[6] There is a wealth of literature supporting the anti-viral properties of quercetin in both in vitro and in vivo experiments. Quercetin is proven to inhibit several respiratory viruses in cell cultures.[7, 8] Viral S-protein of SARS-CoV-2 is known to infect the human cell via binding angiotensin-converting enzyme-2 (ACE-2) receptor. This mechanism of the virus emerged as a target for several anti-viral therapies. Hence, in silico studies demonstrated that a variety of small molecules which bind to either the isolated SARS-CoV-2 Viral S-protein at its host receptor region or to the S protein-human ACE-2 interface.[9] Quercetin is pointed one of those top five small molecules. Having that advantage of sharing the same receptor (ACE-2) and the accessory protease FURIN with SARS-CoV to bind the cell, quercetin is suggested to be an effective drug against COVID-19.[11,12] Besides, quercetin, due to its similar biochemical structure, was reported as a competitive inhibitor of SARS-CoV-2 for entry into human cells like luteolin It, therefore, has the ability to prevent SARS-CoV-2 infection.[10] Several natural polyphenolic compounds like quercetin and kaempferol are revealed as anti-viral in virtual studies.[13]
Shukor et al. (1999) showed that flavonoids which include a catechol group, enact better inhibitory capacity on ACE.[14] Thus, quercetin seems to be the most effective inhibitory flavonoid against ACE. Elimination of quercetin in humans is relatively low, with a half-life ranging from 11 to 28 hrs.[13] In parallel with this data, the bioavailability of oral quercetin widely varies, ranging from 0 to 50%.[14] Mostly depending on the individual features, an average terminal half-life of 3.5 hrs is defined for 500 mg oral quercetin.[17] Isoquercetin (glycosylated quercetin) is reported to be more absorbable than quercetin in the aglycone form, and the concomitant ingestion of quercetin with vitamin C, folate and additional flavonoids improves bioavailability.[13,15] Quercetin has the ability of spontaneous oxidation to O-semiquinone (antioxidant) or O-quinone/quinone methide (QQ; prooxidant), and this can result in the process of ”quercetin paradox.”[18] Consequently, inadequate ascorbate or glutathione levels may cause quercetin to convert to QQ, which has prooxidant effects. Since its co-administration with vitamin C is crucial.[19,20] Therefore, a combination of quercetin and vitamin C would not only provide a viral blockade of SARS-CoV-2 but also strengthen the immune response.
US Food and Drug Administration described quercetin as GRAS status (generally recognised as safe).[6] Besides, the European Food Safety Authority (EFSA) claimed several beneficial physiological effects of quercetin, including the protection of DNA, proteins and lipids from oxidative damage (EFSA, 2011). Bromelain is a crude extract of the pineapple that is considered as a food supplement and is freely available to the general public in health food stores and pharmacies around the world.[22] Bromelain is also demonstrated to improve oral bioavailability of quercetin up to 80% similar to vitamin C.[22]
Oral supplementation with quercetin up to 1 g/day for 3 months has not resulted in significant adverse effects.[15] The safety of quercetin-based oral supplementation during pregnancy and breastfeeding has not been established. None of the adverse effects related to QCB supplement was observed in participants. SARS CoV2 can affect many other systems along with the lung, and its effect may last after the acute period of infection resolves. It can cause endothelial dysfunction, hypercoagulability and cytokine storm.[24] In the case of significant blood levels achieved for quercetin, the adverse effects of SARS CoV2, in both acute and chronic periods, can be overcome. Inhibitory effect of quercetin on the xanthine dehydrogenase/xanthine oxidase system is another mechanism to decrease oxidative injury due to the pathological conditions.[24,25] As the most potent scavenger of reactive oxygen species, quercetin also reduces ischemia reperfusion injury in experimental models.[25,26] Moreover, quercetin provides antihypertensive effects and improves endothelial function by inhibiting endothelin-1.[27,28] Depending on its structural relation to disodium cromoglycate, quercetin is a potent antihistamine that can prevent allergic and asthma attacks.[29,30] Several studies demonstrated that quercetin causes a down-regulation of histidine decarboxylase mRNA in the human mast cell line; it also inhibits the production of leukotriene B4 in leukocytes.[33-35] Besides, it suppresses TNFa and nitric oxide release from macrophages.[31,32] Regardless of its antioxidant properties, quercetin noted to have a positive impact on endothelial function by PDE5A inhibition.[36,37] Quercetin has the ability to regulate platelet function by inhibiting thrombin-induced and collagen-induced platelet activation.[37] Possible impacts of quercetin on platelet functions may include down-regulation of CD40L on platelets and interference with adhesion molecules.[38,39] In the current study, although the lung involvement was more advanced and significantly comorbid COPD was present in the group with QCB supplement, a significant decrease was achieved in the acute phase reactants (APRs). Besides, QCB supplement is suggested to have a role on the elevation of the thrombocyte and lymphocyte count. The exaggerated release of the pro-inflammatory cytokines from ’hyper-reactive’ monocytes, thought to be the reason for the increase of APRs in COVID-19.[41] Therefore, those findings may be explained by the immune-modulatory properties of flavonoids on macrophages via contributing their transformation from pro- to anti-inflammatory phenotypes. [42] Variable bioavailability, high bio-transformations due to adsorption in the gut, and complexity of the gut microbiota make it unlikely for flavonoids and their metabolites to reach micromolar blood concentrations.[43] We tried to overcome this problem with vitamin C and bromelain supplements. Although the lung findings are more advanced in the patient group receiving QCB, it has a positive effect in terms of improvement in laboratory markers/results. We suggest that a similar event rate between groups is due to the non-optimal bioavailability of quercetin. Furthermore, the possible effect of hydroxychloroquine which is included in the standard treatment, on the bioavailability of QCB has not been well described.
Conclusion We suggest that QCB has a positive effect in addition to routine treatment against COVID-19 even for patients with more advanced lung involvement, still further studies with isoquercetin, a different form of quercetin with higher bioavailability, are needed as a light of hope.
Acknowledgement: None.