1Division of Pulmonary and Important Care Medication, Japanese Virginia Medical College, Norfolk, VA, United States
2Frank Reidy Analysis Middle for Bioelectrics, Outdated Dominion College, Norfolk, VA, United States
3Policlinico Umberto I, La Sapienza College of Rome, Rome, Italy
4Department of Respiratory Medication, St. Peter’s Hospital, Surrey, United Kingdom
1Division of Pulmonary and Important Care Medication, Japanese Virginia Medical College, Norfolk, VA, United States
2Frank Reidy Analysis Middle for Bioelectrics, Outdated Dominion College, Norfolk, VA, United States
5School of Medical Diagnostic & Translational Sciences, Faculty of Well being Sciences, Outdated Dominion College, Norfolk, VA, United States
1Division of Pulmonary and Important Care Medication, Japanese Virginia Medical College, Norfolk, VA, United States
Summary
Introduction
It’s serendipitous (or maybe indicative of arduous work) that the Nobel prize winner Szent-Gyorgyi found each ascorbic acid (vitamin C) and the flavonoid quercetin (on the time labeled vitamin P) (1). Ascorbic acid is an important vitamin with recognized antiviral properties (2) which is beneath investigation for its helpful results in the course of the stress response in sepsis and critically unwell sufferers (3).
Vitamin C exerts its antiviral properties by supporting lymphocyte exercise, rising interferon-α manufacturing, modulating cytokines, lowering irritation, bettering endothelial dysfunction, and restoring mitochondrial operate (4–6). There are additionally options that vitamin C could also be instantly viricidal (7). These in vitro results, as we beforehand mentioned (2), represent a mirrored image of each the supra-physiological concentrations of ascorbate and the interplay between vitamin C and metal-containing tradition media—each of that are pro-oxidant, producing reactive oxygen species.
Quercetin (also referred to as 3,3′,4′5,7-pentahydroxyflavone) is a broadly distributed plant flavonoid, present in a number of greens, leaves, seeds, and grains, the place it’s conjugated with residual sugars to kind quercetin glycosides (8). Research recommend that quercetin supplementation might promote antioxidant (9), anti-inflammatory, antiviral (10), and immunoprotective results (11). Quercetin has been studied in varied varieties and fashions of viral an infection resulting from its promising antiviral results in inhibiting polymerases (12), proteases (13), reverse transcriptase (14), suppressing DNA gyrase, and binding viral capsid proteins (15, 16).
On this evaluation we collate the proof of the antiviral properties of quercetin, describe its biologic motion and pharmacokinetics profile, increase on our earlier evaluation of vitamin C, focus on their synergistic actions, and suggest this experimental multi-drug strategy for the prevention and therapy of SARS-CoV-2/COVID-19 pandemic.
Chemistry of Quercetin
In vegetation, quercetin is produced from the phenylpropanoid pathway and is finally derived from phenylalanine. It’s transformed to 4-coumaroyl-CoA, through phenylalanine ammonia-lysate, to cinnamate-4-hydroxylase and 4-coumaroyl-CoA-ligase. That is mixed with malonyl-CoA in a 1:3 ratio by 7,2′-dihydroxy-4′methoxyisoflavanol synthase to kind tetrahydroxy chalcone. This in flip is transformed to naringenin and to eriodyctiol via flavonoid 3′-hydroxylase. Lastly, eriodyctiol is hydroxylated and transformed to quercetin (Determine 1) utilizing flavanol synthase (17).
Biology of Quercetin
Flavonoid compounds, equivalent to quercetin, have been initially studied for his or her organic exercise in affecting capillary wall resistance (19) and proceed to be investigated for his or her results on vascular stress (20). Dietary dietary supplements differ, however typically include the free type of quercetin—quercetin aglycone—beneath the FDA nationwide drug code numbers 65448-3085, 65448-3005 (21). As soon as consumed, quercetin passes predominantly unaltered into the big gut (22). Quercetin acts as a free radical scavenger, donating two electrons through o-quinone/quinone methide (23); each in vitro and in vivo (24, 25) research implicate quercetin as a potent antioxidant. This antioxidant exercise can also be potentiated by vitamin C (26), as can be mentioned beneath. There’s additionally important longstanding curiosity within the anti-inflammatory exercise of quercetin, because it has been recommended to be a key mediator within the cardiovascular protecting aspect of the “Mediterranean” weight-reduction plan (27). This organic rationale is secondary to quercetin’s free radical scavenging capability, alongside numerous roles recognized in in vitro and in vivo fashions together with: inhibition of platelet aggregation (28), inhibition of lipid peroxidation (29), and its inhibitory results on pro-inflammatory mediators equivalent to lipoxygenase (30) and phospholipase A2 (31). This anti-inflammatory impact is primarily mediated by flavonoid exercise on arachidonic acid metabolism and the related leukotriene/prostaglandin pathways. Moreover, 3-methyl-quercetin, a quercetin metabolite, shows stimulatory results on nasal epithelial cell ciliary beat frequency, each in vitro and in vivo, when administered both alone or with absorption enhancer HP-β-CD (32). Quercetin additionally impacts the operate of a number of lipids, protein tyrosine, and serine/threonine kinases (33, 34), equivalent to phosphatidylinositol (PI)-3-kinase and inducible nitric oxide synthase (NOS2) (35, 36).
Useful Results of Vitamin C and Quercetin in Viral Infections – “vitamin c quercetin absorption”
There’s a super quantity of literature supporting the antiviral properties of quercetin, in each in vitro and in vivo experiments. Quercetin inhibits a number of respiratory viruses in cultured cells (16, 37). It inhibits the cytopathic results provoked by many serotypes of rhinovirus, echovirus (sort 7, 11, 12, and 19), coxsackievirus (A21 and B1), and poliovirus (sort 1 Sabin) at a minimal inhibitory focus of 0.03 to 0.5 μg/ml in Hela or WI-38 cells (38). Quercetin additionally considerably reduces plaque formation by RNA and DNA viruses [Respiratory Syncytial Virus (RSV), Polio type 1, parainfluenza type 3, and Herpes Simplex Virus-1(HSV-1)] displaying anti-infective and anti-replicative properties (39). It inhibits the replication of cytomegalovirus (CMV) inoculated HeLa cells at a half inhibitory focus (IC50) of three.2 ± 0.8 μM and with a selectivity index (SI) of twenty-two (40). Dengue virus sort 2 (DENV-2) replication in Vero cells is inhibited by quercetin at an IC50 of 35.7 μg/mL, inflicting a DENV-2 RNA discount of 67%. That is attributed to quercetin’s capacity to both block virus entry or inhibit viral replication enzymes equivalent to viral polymerases (41).
In vivo research point out that mice inoculated with meningoencephalitis virus are protected against deadly an infection by quercetin (30 or 40 mg/Kg BID, po, for 4 days) in a dose dependent method (42). These helpful results are abolished if the compound is run for <3 days, as soon as per day or through subcutaneous injection. This may occasionally recommend that the antiviral results could also be depending on a minimal inhibitory focus or from some type of metabolic drug conversion (42). Quercetin therapy additionally displayed a helpful impact in immunocompetent mice contaminated with Mengo virus, the place it lessened the severity of organ injury (43). Athletes supplemented with quercetin are protected against stress-induced susceptibility to higher respiratory tract an infection (44)—which was not associated to immunomodulation (45, 46).
Vitamin C is an important nutrient concerned in a various array of immune capabilities; its supplementation has demonstrated helpful results in several types of viral infections. Diminished ranges of ascorbate have been present in sufferers with viral infections (47), sepsis (48), sepsis-related ARDS (49), and different important sickness (50). Throughout an infection, vitamin C is critical for neutrophil killing (51), is concentrated inside macrophages (52), is accountable of T cell maturation (53), and promotes phagocytosis and apoptosis of spent neutrophils (4). It's not stunning, due to this fact, that viral infections, relying on their severity, are related to an elevated metabolism and diminished circulating ascorbate. Vitamin C has improved survival in numerous murine fashions of deadly an infection. Mice contaminated with Venezuelan encephalitis virus and handled with vitamin C (50 mg/kg) exhibit half the mortality of controls with related reductions in viral titers, lipid peroxidation merchandise, and NO content material (54). Mice incapable of synthetizing vitamin C (L-Gulono-gamma-lactone oxidase nulls) have been contaminated with influenza; mice not receiving supplemental vitamin C exhibited larger lung pathology scores regardless of no variations in viral titers (55). In restraint-stressed mice with H1N1 viral-induced pneumonia, vitamin C diminished mortality dose-dependently (100% vs. 80% vs. 50% at 0, 125, and 250 mg/kg/day) and diminished capillary-alveolar structural injury (56). Mice inoculated with Rabies+ mouse mind cells and handled with day by day 100 mg/kg IM vitamin C exhibited practically half the mortality of controls (57). The one human examine of vitamin C has been in USSR troopers with extreme viral an infection indicated vitamin C supplementation (300 mg/day) protected against influenza-associated pneumonia and was related to shorter hospital stays (58). Vitamin C administration (i.v. 5 g/day twice/week) in sufferers with herpes zoster exhibited a decrease incidence of postherpetic neuralgia (31.1% vs. 57.1%) and at examine finish (week 16) there was a decrease ache rating within the therapy group (0.64+/−0.9 vs. 1.98 +/−0.7) (59). Vitamin C administered at 1 g BID to 133 sufferers, diminished the chance (OR 0.25) of herpes simplex keratitis (HSK) recurrence (60), in accordance with earlier research indicating diminished ascorbate availability within the eye (61). It's noteworthy {that a} rising variety of case stories of virus-related acute respiratory misery syndromes (ARDS) point out profitable therapy with intravenous excessive doses of Vitamin C (62, 63). Co-administration of quercetin (12.5 mg/kg/week) and vitamin C and B3 in a murine mannequin of exercise-induced susceptibility to influenza H1N1 extended time-to-death (median time to loss of life: placebo 9.0 ± 0.33 vs. quercetin 16.5 ± 1.2) and improved survival (mortality: placebo 74% vs. quercetin 52%) when in comparison with mice receiving solely nutritional vitamins B3 and C (64). An older, small scientific trial recognized the mix of flavonoids and ascorbic acid (1:1 ratio) as helpful for respiratory an infection (200 mg TID) (65).Give attention to SARS-CoV-2
Quercetin has been investigated for its doable antiviral impact on a number of members of the Coronaviridae household and, as talked about by Ling Yi and colleagues, “quercetin offers great promise as a potential drug in the clinical treatment of SARS” (98). SARS-Coronavirus, described in 2003 (99), is a single-stranded RNA virus of ~29,700 nucleotides, which makes use of ribosome websites to encode two replicase glycoproteins, PP1a and PP1b, that mediate viral replication (99, 100). As soon as these precursor glycoproteins are synthesized, 3C-like protease (3CLpro) performs a important function within the lytic launch of its replicates (101). Quercetin-3β-galactoside binds SARS-Cov 3CL protease and inhibits its proteolytic exercise with an IC50 of 42.79 ± 4.95 μM (102). This inhibitory motion on 3CLpro relies on the hydroxyl group of quercetin which, as proven via molecular modeling and Q189A mutation, acknowledges Gln189 as an important web site on 3CLpro chargeable for the binding of quercetin (102). Quercetin was additionally recognized as a compound in a position to block SARS-Coronavirus entry into Vero E6 cells with a half-effective focus (EC50) of 83.4 μM and with low cytotoxicity (CC50 3.32 mM) (98).
SARS-CoV-2, the virus chargeable for the 2020 COVID-19 pandemic (103), belongs to the genus Betacoronavirus and subgenus Sarbecovirus and, resulting from its comparable receptor-binding area, it’s assumed, equally to SARS-CoV, to contaminate sort II pneumocytes getting into through the angiotensin-converting enzyme II receptor (104). SARS-Cov-2 protease 3CL maintains the identical Gln189 web site (105) of SARS-Cov 3CLpro, which beforehand was recognized because the binding web site for the hydroxyl teams of quercetin and its derivates (102).
Curiously, an in vitro examine of ascorbic acid therapy on chick-embryo ciliated tracheal organ cells (CETO) promoted resistance to Coronavirus an infection however didn’t present any impact on orthomyxovirus or paramyxovirus (106).
Regardless of the breadth and depth of anti-viral in vitro and in vivo research into the immunomodulatory results of quercetin and vitamin C administration, additional research are completely vital to verify quercetin inhibitory actions on SARS-Cov-2 virus entry, RNA polymerase, and on different vital viral life-cycle enzymes.
Pharmacokinetics of Quercetin
Orally administered quercetin glycosides are hydroxylated by β-glucosidases within the intestine (107, 108). Aglycone quercetin passively permeate the intestinal epithelial barrier whereas quercetin glycosides are absorbed through the intestinal sodium/glucose cotransporter-1 (109). The bioavailability of oral quercetin is extraordinarily variable, reaching values from 0 to 50% (110). Quercetin may be metabolized both within the enterocytes or within the hepatocytes forming glucuronidated, sulfated, or/and methylated compounds (111). Certainly, 4 out of 5 hydroxyl teams of quercetin may be glucuronidated by UDP-glucuronosyltransferase, forming its main metabolites: quercetin-3-glucuronide, 3′-methylquercetin-3-glucuronide, and quercetin-3′-sulfate (112). Rat tissue distribution of orally, long-term administered quercetin (12 weeks) exhibits the best focus within the lungs whereas pigs show the best concentrations within the liver and kidneys (113). In distinction, short-term administration reveals no marked distribution, implying that the helpful results of quercetin in stopping lung respiratory viral an infection might be maximized by long-term administration. Following 500 mg oral quercetin, most plasma focus of ~15 μg/L of aglycone quercetin (~50 nM, Tmax of three h) and 450 μg/L of quercetin non-methylated conjugates (Tmax of 4 h) have been discovered (114). Intravenous administration leads to an elimination half-life of 0.7–2.4 h with a distribution quantity at steady-state of 6.2 to 92.6 L and with a complete physique clearance of 30 h (110).
“vitamin c quercetin absorption”