Open access peer-reviewed chapter

Reappraisal of Dietary Phytochemicals for Coronavirus Infection: Focus on Hesperidin and Quercetin

Written By

Paolo Bellavite

Submitted: 11 December 2020 Reviewed: 17 December 2020 Published: 25 January 2021

DOI: 10.5772/intechopen.95529

From the Edited Volume

Antioxidants - Benefits, Sources, Mechanisms of Action

Edited by Viduranga Waisundara

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Abstract

Food polyphenols constitute a large family of substances with beneficial properties in a large group of communicable and non-communicable diseases. These compounds support and improve the body’s defences against oxidative stress and are helpful in the prevention of pathologies related to metabolic syndrome. Furthermore, they exhibit anti-inflammatory, antiviral, and antimicrobial properties. This chapter draws attention to certain nutritional components such as hesperidin and quercetin, which are emerging as good candidates for a complementary beneficial effect in the case of diseases caused by viruses, including COVID-19. These nutraceuticals have a complex mechanism of action, which involves both cellular defence against oxidative stress and the modulation of inflammation, which although normally is a defence, repair and activation mechanism of the immune system, it can elude its controls and become a systemic and destructive pathology (cytokine storm, respiratory distress syndrome). Furthermore, recent in silico simulation tests suggest that both hesperidin and quercetin may interfere with SARS-CoV-2 by binding to cell receptors and the proteolytic enzymes involved in its replication. In addition to the inhibitory effects on the virus at cellular level, the two flavonoids can have indirect effects in respiratory infectious diseases as they prevent or improve metabolic and vascular comorbidities that can complicate the clinical course. This brief review focuses on biochemical and pharmacological mechanisms of action of polyphenols in the context of the revaluation of dietary approaches to the prevention and treatment of infectious diseases caused by viruses, with a special application to COVID-19.

Keywords

  • hesperidin
  • quercetin
  • citrus flavanones
  • functional food
  • nutraceuticals
  • respiratory virus
  • oxidative stress
  • SARS-CoV-2
  • COVID-19
  • metabolic syndrome
  • Nrf2

1. Introduction

In modern medicine and chiefly in the approach infectious diseases, nutrition seems to be a neglected or at least underestimated aspect, although it is recognised that it often plays an important role in the prevention of various diseases, including infectious ones [1, 2]. Flavonoids are abundant functional substances in plants with potential health benefits and are used as valuable food components or as supplements. Some of these substances may have an antiviral action or in any case be important in modulating the immune system and defending cells from the oxidative stress associated with infection.

Flavonoids are hydroxylated polyphenolic compounds based on the structure of the 15-carbon backbone of the parent flavone (2-phenyl-1,4-benzopyrone), which consists of two phenyl rings (A and B) and a heterocyclic ring (C) (Figure 1A). They can be divided into various classes based on their molecular structure and according to the C-ring replacements scheme: flavones, flavonols, isoflavones, anthocyanins, flavanols and flavanones. More than 4,000 varieties of flavonoids have been identified.

Figure 1.

Molecular structure of flavone (A), quercetin (B), hesperetin (C) and hesperidin (D).

In the human diet, flavonols are widespread with quercetin standing out among them (Figure 1B). The most represented flavanone is hesperetin (Figure 1C) which is found in citrus fruits in glycosylated form as hesperidin (Figure 1D). Flavanones lack a double bond between C2 and C3 and this makes them chiral in the C2 position. Chirality implies that the B ring is not planar like in flavonols and is twisted with respect to the A-C rings. Such a difference in molecular orientation is relevant because it can affect the way the different flavonoids interact with their biological targets and therefore their bioactive properties.

Quercetin [International Union of Pure and Applied Chemistry (IUPAC) name: 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one, with a molecular weight of 302.23 g/Mol] contains five hydroxyl groups linked in position 3,5,7,3′ and 4′ to the basic flavonol skeleton. In plants and as a consequence of biotransformation by the intestinal bacterial flora, some of these hydroxyl groups are glycosylated and constitute the main derivatives of quercetin. Hesperidin (with a molecular weight 610.6 g/Mol) is a glycosylated derivative of hesperetin [IUPAC name: (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydrochromen-4-one, with a molecular weight of 302.28 g/Mol], with a 6-O-(alpha-L-rhamnopyranosyl) -beta-D-glucopyranosyl disaccharide in position 7 via a glycosidic bond.

The structure–activity studies show that the antioxidant and anti-free radical properties of flavonoids are due to the ketone group, the double bond between the 2 and 3 carbons, the 3′, 4′-catechol and the 3-hydroxyl moiety in the flavonoid skeleton (the latter two are present in quercetin but not in hesperidin) [3]. The C2-C3 double bond extends the π conjugation to the carbonyl group in the C ring, so the radical elimination capacity of unsaturated flavonoids is greater than saturated structures, such as flavanones [4]. The antiradical capacity of flavonols in aqueous solvents is mainly exerted by the mechanism of electron transfer with sequential proton loss, associated with the C3 hydroxyl group, or of electron-proton transfer in the catechol component. Therefore, the type of substitution of the B ring is also considered as a determinant of the antiradical potency of flavonoids [4].

Many of the biological effects of flavonoids appear to be related to their ability to modulate receptors, enzymes, cell signalling cascades, rather than to a direct antioxidant effect. In fact, the maximum concentrations of flavonoids that can be reached in the blood with very high intakes (~ 2 μmol/L) are much lower than the concentrations of other antioxidants, such as ascorbic acid (~50 μmol/L) uric acid (200–400 μmol/L) and glutathione (700–1500 μmol/L). The functional interaction between flavonoids and enzymes or receptors occurs through hydrogen bonds and hydrophobic interactions with key amino acids of targeted proteins. For example, an inhibition of the activity of the enzyme xanthine oxidase by quercetin is exerted thanks to hydroxyl groups of C5 and C4 [5], and the anti-inflammatory activity depends not only on the number of free hydroxyl groups, but also on the methyl group [6]. Here the binding capacity of quercetin and hesperidin to some important proteins of the SARS-CoV-2 virus will be described in more detail.

In fresh orange juice the hesperidin content represents about 30 mg per 100 ml [7], but it is found in greater quantities in the white part of the peel [8]. Quercetin is widely present in the plant kingdom [9, 10] with an average daily consumption of 25–50 milligrams [11], up to about 250 mg per day in “high-consumers” of fruit and vegetables [12].

Both hesperidin and quercetin have long been known for their antioxidant, anti-inflammatory and anti-lipemic properties. This review will focus on their effects in viral infections, with special prominence on the recently exploded COVID-19 pandemic and its SARS-CoV-2 responsible virus. With the outbreak of COVID-19 and the scientific world’s focus on the search for preventive, antiviral and immunomodulatory substances, other particularly interesting characteristics of dietary phytochemicals have emerged. Many studies have highlighted the importance of the intracellular redox state as a new target for natural or synthetic drugs aimed at blocking both viral replication and excess inflammation [13, 14]. It has therefore been suggested that early flavonoid treatment may be a way to restore redox balance, prevent cell damage and the resulting inflammatory storm that causes lung damage with respiratory dysfunction [15, 16, 17, 18].

Although there is still no clinical evidence of efficacy for COVID-19, the two flavonoids are emerging as some of the most capable substances of specifically inhibiting binding to cellular receptors of the SARS-CoV-2 virus and its replication [8, 14, 19, 20, 21]. A recent randomised study, which appeared in as a preprint version, suggests that quercetin, administered together with vitamin C, could help health care workers in the prevention of SARS-CoV-2 infection [22].

Here we will examine the known mechanisms of action of hesperidin and quercetin, taking SARS-CoV-2 as a paradigm, and without neglecting to mention the important properties of these natural substances for health care in general. Following a logical order, the various passages of the disease will be dealt with starting from cellular infection to clinical consequences, specifying the points where these flavonoids could act.

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2. Effects at cellular level

Tests on laboratory animals have shown the ability of flavonoids to inhibit infection by various viruses such as herpes simplex-1, parainfluenza and respiratory syncytial virus [23, 24], poliomyelitis-1 [25], rhinovirus [26, 27], hepatitis C [28], rotavirus [29], influenza [30, 31, 32, 33, 34, 35, 36], SARS-coronavirus-1 [37]. Here we will examine recent evidence regarding the SARS-CoV-2 virus in more detail.

Coronaviruses are a group of single-stranded RNA viruses with a corona-like morphology, mainly causing enteric and respiratory diseases of varying extents. Once the first mucosal barriers and possible intervention of the immune system have been overcome, the viruses enter the cell via specific receptors, the nucleic acid is then expressed causing various intracellular changes, including replication into multiple copies and various types of damage to the host cell. In each of these steps it is possible to imagine the action of compounds that tend to block entry or slow down replication and its pathological consequences (Figure 2).

Figure 2.

Intracellular cycle of the SARS-CoV-2 virus. Green asterisks and numbers indicate the points of the flavonoid actions described in the text.

2.1 Receptor binding and entry

The internalisation of SARS-CoV-2 in human cells is mediated by the binding of the virus’ spike glycoprotein (S) to its receptor on cell membranes, which is the angiotensin converting enzyme 2 (ACE2) [38, 39]. ACE2 is expressed in many tissues including the lung, liver, heart, colon, oesophagus, intestine, kidney, and even the brain, which is consistent with the variety of cell types that can be infected, and the variety of symptoms reported in COVID-19 patients [40, 41, 42, 43, 44, 45]. The S protein has two subunits, the first of which contains a receptor binding domain (RBD), which is responsible for binding to ACE2. Binding and entry are also favoured by the presence of a polybasic cleavage site between the two subunits of the spike and by proteolytic enzymes attached to the receptor, of which trans membrane serine protease-2 (TMPRSS2) is particularly important.

The discovery that the hesperidin molecule has a chemical–physical structure suitable for binding to the spike of the SARS-CoV-2 virus (* 1 in Figure 2) has recently aroused scientific interest [14, 46, 47, 48, 49, 50, 51]. Wu et al. [46] used in silico simulation techniques to screen 1066 natural substances with a potential antiviral effect, plus 78 antiviral drugs already known in the literature. Of all of them, hesperidin was the most suitable for binding to the SARS-CoV-2 spike, wedging into the shallow middle sulcus of the RBD, where some hydrophobic amino acids, including Tyr436, Try440, Leu442, Phe443, Phe476, Try475, Try481 and Tyr49 form a hydrophobic pocket to contain the compound.

Various authors have confirmed the affinity of hesperidin for the RBD fragment of the spike protein and its ability to hinder the binding with ACE2 or to make the interaction unstable (Figure 3) [52, 53]. The anchoring of hesperidin is stabilised by two hydrogen bonds (shown with green lines in Figure 3) with the amino acids Phe457 and Glu455 on the spike protein. According to other in silico screening studies, hesperidin also has an affinity for TMPRSS2 protease, which is involved in the functioning of the receptor when the vesicle is internalised with the virus [54, 55].

Figure 3.

Binding of the ACE2 protein with the spike in the presence of hesperidin. The RBD fragment of the spike protein (331–524) is shown in red, and the hesperidin molecule in the stick model and human ACE2 is shown in blue. Figure created using a diagram component from the cited work [52] with authorisation from Creative Commons.

Molecular dynamics simulations and energy landscape studies revealed that other flavonoids such as fisetin, quercetin and kaempferol bind to the ACE2-spike complex with favourable free energy [56]. Another group reported studies showing that quercetin has a high affinity for viral spikes, blocking the sites of interaction with cellular receptors [19]. According to other authors who followed a gene expression approach [57], quercetin is identifiable as one of the highest scoring natural substances, altering the expression of numerous human genes that encode SARS-CoV-2 protein targets, including ACE2.

2.2 Proteolysis and assembly

A second theoretical site of flavonoid action is the main protease that allows the processing of the first proteins transferred from the viral genome (point *2 in Figure 1).

After interacting with membrane receptors and their associated proteases, the viral particle is internalised by means of a vesicle formed by the same membrane, the shell of which is then removed, allowing the release of the genomic RNA into the cytoplasm. The coding sequences of the genomic RNA are translated into pp1a and pp1ab proteins, which are then broken down by a proteolytic process for a total of 16 non-structural proteins. The main enzyme that carries out this transformation is called 3-chymotrypsin-like protease (3Clpro) or major protease (Mpro) by various authors and is in fact the target of many chemical antiviral drugs.

Some non-structural proteins then form a replication complex that uses genomic (+) RNA as a template. Eventually, the subgenomic RNAs produced through transcription are translated into structural proteins that will form new viral particles. For this purpose, structural proteins are incorporated into the membrane and the nucleocapsid N protein combines with the RNA produced through the replication process to become a nucleoprotein complex. The various components fuse into the complete viral particle in the Golgi endoplasmic reticulum apparatus, which is finally excreted in the extracellular region.

A strong affinity of hesperidin to Mpro has been discovered by various authors [46, 47, 50] in the screening of thousands of potential molecules using molecular docking techniques. Hesperidin binds with hydrogen bonds to various amino acids, mainly Thr24, Thr25, Thr45, His4, Ser46, Cys145 [50]. An important precedent exists when the authors investigated natural compounds capable of inhibiting Mpro of the SARS virus [37], using cell-based proteolytic cleavage assays. Out of seven phenolic compounds tested, hesperetin inhibited proteolytic activity efficiently with an IC50 of 8.3 μmol/L. Since the coronavirus main protease structure and active site conformation are preserved despite sequence variations [51], it is conceivable that the inhibitory effect of hesperidin, previously observed in the SARS virus, could also be exploited in SARS-CoV-2. Furthermore, hesperidin binds to structural protein 16 (nsp16) of the coronavirus, which is a methyltransferase dependent on S-adenosyl methionine [58]. This protein plays an important role in viral replication and prevents recognition by the innate immune system.

Quercetin has also been shown to inhibit the Mpro of the SARS-CoV [59], MERS-CoV [60] and SARS-CoV-2 [61] coronaviruses. The binding points of quercetin and hesperetin on SARS-CoV-2 Mpro are partially different [19]: the first in fact binds to Glu288, Asp289 and Glu290, while the second to Glu290, Asp289, Lys5. Furthermore, hesperetin, naringenin and kaempferol bind to the regulatory site Leu286, which quercetin does not do. All this suggests that the different molecules do not overlap as a pharmacological activity on the Mpro, but can synergise.

An even more recent study [62] confirms the affinity of quercetin to Mpro using the measurement of the enzymatic activity. Evidence of its inhibitory effect was obtained with a fairly low dose of quercetin (7.7 μmol/L). Figure 4 shows the molecular complex formed by quercetin bound in the cavity that constitutes the active site of Mpro (in blue), in the most favourable position to inhibit the protein enzymatic activity in order to block the replication of the coronavirus.

Figure 4.

Representation of the quercetin molecule (in orange) within the active site of the Mpro of the SARS-CoV-2 virus. Developed by Bruno Rizzuti on the basis of the study of which he is co-author [62]. Reproduction authorised by the author.

Da Silva et al. [63] have expanded the search for molecules interacting with Mpro to a series of flavonoid glycosides using a molecular docking approach. The interactions and binding affinity with the protease by quercetin and even more by its glycosidic derivatives quercetin-3-O-rutinoside (rutin), quercetin-3-O-glucuronide, quercetin-3′- O-sulphate, quercetin-7-O-glucuronide, quercetin-7-O-sulfate were thus predicted. It should be noted that the absorbed flavonoids normally undergo extensive metabolism in the epithelial cells of the small intestine and in the liver. Metabolites conjugated with the methyl, glucuronate and sulphate groups are the predominant forms present in plasma [64, 65, 66]. Quercetin has also been indicated as one of the substances capable of binding and thus inhibiting RNA-dependent RNA polymerase, an essential enzyme in the replication of viral RNA in the host cell [63].

Russo et al. [20] further confirmed the ability of known flavonoids (e.g. quercetin, baicalin, luteolin, hesperetin, gallocatechin gallate, epigallocatechin gallate) to inhibit the key proteins involved in the infectious cycle of SARS-CoV-2. They suggested that flavonoids and their derivatives, due to their pleiotropic activities and lack of systemic toxicity, may represent target compounds to be tested in future clinical trials to enrich the arsenal of drugs against coronavirus infections.

2.3 Oxidative stress

Oxidative stress is an important cell pathology mechanism which is involved in many diseases, including those caused by viruses. Viral respiratory infections are generally associated with the production of cytokines, inflammation, cell death and other pathophysiological processes, which could be linked to increased production of reactive oxygen species (ROS), redox imbalance and oxidative stress.

Many lines of evidence suggest that viral infections are accompanied by signs of increased production of ROS, presence of oxidation products in blood plasma and urine, and reduced antioxidant capacity [67]. This pathological and pathogenic phenomenon has been observed in the infection of viruses such as hepatitis B [68], hepatitis C [69], influenza [70] and SARS-CoV-2 [71]. In the latter, ROS could also determine an unfavourable evolution in elderly subjects with low antioxidant capacity [72, 73], perhaps because the intracellular redox environment alters the presentation of antigens [74] and the expression of ACE2 [75, 76]. In fact, the severity and mortality risk of SARS-CoV-2 or COVID-19 have been associated with age [73].

Studies have shown that the ability of viral envelope glycoproteins to fuse to the surface of a cell membrane depends on the disulphide-thiol balance of the cell, even if the binding of coronaviruses to cell receptors seems rather insensitive to these parameters [77]. It seems possible that the oxidation of thiols to disulphides, under an oxidative stress mechanism, increases the affinity of spike proteins for the ACE2 receptor and, therefore, increases the severity of COVID-19 [75]. In this regard, reduced glutathione (GSH) may also have direct anti-SARS-CoV-2 potential: in fact, a computational study indicates that the binding of the spike protein to ACE2 is at its highest when the ACE2-sulfur groups are in the form of disulphides and are altered when they are fully reduced to thiols: therefore a pro-oxidant environment with low levels of GSH would favour the cellular entry of viruses [75, 78].

In the course of viral diseases, analgesic and antipyretic drugs are widely used, and of these one of the most common is paracetamol (acetaminophen). However, the fact that this drug depletes glutathione reserves and can worsen oxidative stress is not always taken into account [78, 79]. This type of biochemical modifications can decrease the antiviral defences [80] or complicate the course especially in patients with abnormal liver tests or liver failure [81, 82].

As described in the Introduction, flavonoids have a molecular structure capable of participating in redox reactions and free radical scavenging, which are involved in the biochemical phenomena described here and in the cellular pathology resulting from viral infection (point * 3 in Figure 2). Hesperidin contributes significantly to antioxidant defence systems and has been reported to act as an effective agent against superoxide and hydroxyl radicals [83], while hesperetin inhibits the production of nitric oxide by lipopolysaccharide (LPS)-stimulated microglial cells [84].

Quercetin also acts as a free radical scavenger, donating two electrons to oxidised species which are reduced. When this occurs with the transfer of one electron at a time, a semiquinonic intermediate molecule is formed. This antioxidant activity of quercetin is exploited in synergy with vitamin C, thanks to the ability of ascorbate to recycle the flavonol molecule, protecting it from oxidation and recycling its oxidised quinonic form after the scavenger action on free radicals [85]. In addition to ascorbic acid, glutathione is also important for maintaining quercetin in its reduced and therefore functional form and preventing the risk that quercetin quinone, in turn, may oxidise the thiol groups of proteins [86, 87].

Various in vitro and in vivo studies have shown that the antioxidant activity of hesperidin and quercetin is not limited to their scavenger activity, but actually increases cellular defences against oxidative stress through the signalling path Nrf2/ARE [88, 89, 90, 91, 92, 93, 94, 95] (Figure 5).

Figure 5.

Oxidative stress induced by several pathogenic factors (top part) and cellular defensive effects of flavonoids, functioning as direct free radicals scavengers in synergy with ascorbate and other liposoluble vitamins (A, E) and as stimulants of the Nrf2/ARE pathway. O2-: Superoxide anion; H2O2: hydrogen peroxide; °OH: hydroxyl radical; LO2H: Lipid hydroperoxide; LPS: lipopolysaccharide; Keap1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factor erythroid 2–related factor 2; Maf: musculoaponeurotic fibrosarcoma element; ARE: antioxidant response element.

The nuclear factor erythroid 2–related factor 2 (Nrf2) is of primary importance because it regulates gene expression through a promoter sequence known as the antioxidant response element (ARE). Normally Nrf2 is attached to another protein called Kelch-like ECH-associated protein 1 (Keap1) and is rapidly degraded through the ubiquitination and proteasome system, without performing any functions. On the other hand, in the presence of ROS, Nrf2 detaches from Keap1, is phosphorylated and translocates to the nucleus, where it combines with a small musculoaponeurotic fibrosarcoma (Maf) protein to form a dimer and binds to the antioxidant response element upstream of the promoter. This ARE + Nrf2 dimer then initiates the messenger RNA transcription of a series of target genes such as those encoding antioxidant enzymes (“Antioxidant systems” in Figure 5).

The ability of hesperidin to fight damage from toxic oxygen radicals and stimulate the expression of Nrf2 has been reported by various authors in other experimental models namely in hepatocarcinogenesis [96], hepatotoxicity [97], neuroinflammation and neurodegeneration [91, 98, 99, 100, 101, 102]. The protective effects of quercetin in neurodegenerative disorders and cerebrovascular diseases, demonstrated both in in vitro and in vivo studies are also largely linked to its ability to stimulate the defences against oxidative stress [103].

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3. Organ failure and systemic pathology

Once they have reproduced in the cells of the entry tissues and overcome the first barriers of innate defences, the viruses spread to target organs and cause various types of clinical consequences in different individuals. It is known that the severity of COVID-19 as well as other viral respiratory infections is related to many different parameters (age, gender, nutritional status, comorbidities, etc.) and that people with pre-existing conditions such as diabetes, hypertension, and lung, heart and kidney diseases (all diseases in which ROS play a pathogenetic role) are at increased risk of developing severe effects. In serious cases, endothelial dysfunction, coagulopathy and pulmonary thrombosis cause hypoxia, mitochondrial chain abnormalities, mitochondrial dysfunction, oxidative stress, DNA damage [104, 105]. Another mechanism that links systemic inflammation syndrome and oxidative stress is hyperferritinemia, which often characterises COVID-19 [106, 107].

These mechanisms are involved in the extensive systemic lesions observed during severe complications associated with influenza. It has therefore been suggested that agents with antioxidant properties could be drugs of choice for the treatment of patients with such severe complications [108]. N-acetylcysteine, which supports glutathione and thus the main antioxidant defence systems [109], was used with good results in influenza syndromes [110] and acute respiratory distress syndrome (ARDS) [111], and it was suggested as a potential therapeutic agent for COVID-19 [112, 113, 114].

Figure 6 summarises the main critical points of the SARS-CoV-2 virus in the whole body and the possible interventions of the two flavonoids considered here, based on the knowledge acquired so far in other types of systemic and metabolic disorders.

Figure 6.

Diagram of the major systemic effects of COVID-19. The asterisks show the possible operation points of the flavonoids, as discussed in chapter 2 (*1, *2, *3) and in this chapter (*3, *4 and *5).

Experimental evidence showed that treatment with hesperidin safeguards the aged rat’s heart by increasing the levels of the Nrf2 factor and the activity of enzymatic antioxidants [115]. The same group showed a protective effect of hesperetin on experimental heart failure in the rat [116]. The authors conclude that it is conceivable that hesperetin could be a potential therapeutic candidate that enhances Nrf2 signalling and thereby improves cardiac remodelling. Results from another study show the beneficial effects of citrus flavanones in the liver of aged rats, where nirangerin and hesperidin prevented the age-related decrease in catalase, superoxide dismutase and glutathione reductase [117].

The mechanism of ischemia–reperfusion liver injury was studied in a murine model by measuring oxidative stress indicators, serum enzymes and inflammation indices [118]. Hesperidin (100–400 mg/kg) significantly improved liver ischemia–reperfusion injury measured by serum alanine aminotransferase levels, reduced malondialdehyde content, but it increased superoxide dismutase, catalase, glutathione peroxidase levels. Furthermore, hesperidin significantly alleviated the expression levels of TNF-α, IL 6 and IL-1β. Hesperidin (100 mg/kg) protects rats from liver damage and dyslipidaemia caused by cadmium chloride [119].

The antioxidant effect of quercetin was studied in a two-week, randomised, crossover-controlled intervention trial [120]. Fourteen individuals ingested 2 capsules (total 1 g/d) of quercetin or a placebo. Blood samples were collected before, after 2 weeks of supplementation and after a period of strenuous exercise. Quercetin significantly reduced erythrocyte lipid peroxidation levels and susceptibility to haemolysis induced by free radicals, while no differences were found in antioxidant enzyme activities and glutathione homeostasis between the two groups. After a single period of intense exercise, quercetin supplementation improved redox status as assessed by the reduced glutathione/oxidised glutathione ratio and by thiobarbituric acid reactive substances levels in both erythrocytes and plasma.

3.1 Excess inflammation

During the spread of the virus in the tissues (first of all in the lung) and systemically (lymph, blood, immune system, coagulation, kidney, liver), an inflammatory reaction develops which can be clinically very serious, especially in patients with comorbidities. Excessive and “vicious” inflammation can be mediated by a distorted activation of the cytokine network, by coagulation disorders, even by a paradoxical excess of the immune reaction (autoimmunity, cytotoxic lymphocytes) [121]. Oxidative stress and excess inflammation are linked, as shown in Figure 6 (points *3 e *4). Autoimmune phenomena are also likely to be involved in the attack on the cell infected with SARS-CoV-2, which could have implications both in the clinical course of the disease [122, 123] and in the safety of vaccines [124].

The two flavonoids which are reviewed here have a remarkable ability to modulate local and systemic inflammatory responses, through various mechanisms. Hesperidin showed antioxidant activity in rats after an intense training programme and, at the same time, alleviated cytokine secretion by stimulated macrophages [125, 126]. Furthermore, the administration of hesperetin has been shown to significantly reduce the levels of myeloperoxidase, malondialdehyde (a marker of lipid peroxidation) and inflammation in experimental models of colitis [127] and hepatic trauma [128]. A study on macrophage cells in culture induced by bacterial endotoxin (LPS) clearly highlighted the main molecular effects of hesperetin capable of modulating inflammation [129].

One of the most frequently used experimental models is LPS-induced pneumonia in mice, which somewhat mimics ARDS. Three separate studies have shown that hesperidin (in doses between 10 and 200 mg/kg) significantly reduces the accumulation of fluid in the lung and proinflammatory cytokines [130, 131, 132]. The protective and anti-inflammatory effect of hesperidin or hesperetin was also demonstrated in rats with acute lung injury induced by mechanical ventilation [133] and lung infection with the H1N1 influenza virus [36]. Finally, hesperidin has anti-inflammatory and antioxidant effects in chronic obstructive pulmonary disease (COPD) caused by smoking, reducing the levels of IL-6, IL-8 and malondialdehyde [134].

Quercetin is a powerful antioxidant but also acts as an enzymatic inhibitor in a series of mechanisms involved with inflammation [135]. In LPS-stimulated macrophages, quercetin treatment inhibited NF-kB activation and proinflammatory cytokines [136]. A randomised, parallel-group, controlled polycentric study showed the efficacy of a dietary supplement based on quercetin (150 mg), perilla dry extract (80 mg) and vitamin D3 (5 μg) in preventing allergic rhinitis flare-ups in children [137, 138].

The antiallergic property of quercetin has been explored in the laboratory setting by studying the secretory response of activated mast cells in both human and animal models [139, 140, 141, 142, 143], and by evaluating the release of histamine from human basophils [144, 145]. This flavonol inhibits several protein tyrosine and serine/threonine kinases involved in signal transduction in inflammatory cells [26, 103, 139, 146, 147, 148]. These inhibitory properties on the release of histamine could also be interesting for COVID-19, given that the pulmonary mast cells are involved in the phenomenon of worsening the pulmonary picture in the event of a “cytokine storm” [149].

A meta-analysis of seven randomised trials sought to quantify the effect of quercetin on inflammatory mechanisms in vivo by measuring plasma C-reactive protein (CRP) concentrations. Meta-analysis showed a significant reduction in circulating CRP levels following supplementation with quercetin, especially at doses of 500 mg /day or more and in patients with CRP <3 mg/l [150].

3.2 Comorbidities

Since COVID-19 is a multi-organ disease and has more serious clinical consequences in patients with pulmonary, intestinal, hepatic and cardiovascular comorbidities, it is conceivable that its clinical course may profit from the multiple beneficial effects of hesperidin and quercetin in systemic pathologies of this type (point * 5 in Figure 6). Epidemiological studies have reported an inverse relationship between citrus flavonoid intake and the risk of cardiovascular disease [151, 152]. From a careful review of the literature [153], the use of natural antioxidant polyphenols seems to be an excellent approach as they have strong antioxidant and anti-inflammatory properties.

A constellation of risk factors for cardiovascular disease is called metabolic syndrome (MetS), whose determining factors are, in order of importance: weight, genetics, ageing and lifestyle [154]. The criteria for defining MetS are based on the presence of 3 out of 5 factors, including obesity, elevated triglycerides, reduced HDL-C, elevated blood pressure and elevated fasting glucose [155]. It has been shown that individuals with these characteristics are also commonly prone to a chronic, low-grade inflammatory states. Oxidative stress phenomena are also involved in MetS, probably due to the disturbance of the nutrient metabolism at the mitochondrial level [154].

In this context, it is interesting to note that good results have been obtained in clinical studies with the integration of orange juice, polyphenols and particularly with both hesperidin and quercetin, with antioxidant and antihypertensive effects, and by regulating glucose metabolism and lipid profiles. A recent experimental study showed that hesperidin (15 or 30 mg/kg) improved biochemical alterations and cardiac dysfunction in a high-fat diet-induced MetS model in rats [156].

Soy isoflavones, citrus products, hesperidin and quercetin improved lipid metabolism [157]. Rizza et al. [158] performed a randomised, placebo-controlled study to investigate whether oral administration of hesperidin (500 mg once daily for 3 weeks) improves endothelial function in individuals with MetS. As a measure of efficacy, they measured the difference in flow-mediated dilation of the brachial artery between subjects receiving placebo or hesperidin. In the clinical study, hesperidin treatment increased flow-mediated dilation and decreased the circulating inflammatory biomarkers (highly sensitive C-reactive protein, serum amyloid A protein, soluble E-selectin). The authors concluded that hesperidin recovers endothelial dysfunction and reduces circulating markers of inflammation. Such vasculoprotective actions may explain the beneficial cardiovascular effects of citrus fruit consumption.

A double-blind study documented the beneficial effects of hesperidin supplementation (500 mg/day) on blood pressure and inflammatory markers in type 2 diabetes [159]. The mechanisms by which hesperidin could contribute to blood pressure control are associated with improvements in endothelial function, oxidative stress and inflammation [160]. In a study with a parallel group design, 49 patients with MetS received either 500 mg of hesperidin or a placebo, twice daily for 12 weeks [155]. Hesperidin led to a significant decrease in serum levels of glucose, insulin, triglycerides, total cholesterol, low density lipoprotein cholesterol, TNF-α and high sensitive-CRP. The data on the antihypertensive effect of hesperidin is more uncertain but recently Valls et al. published a study on healthy volunteers in which they actually showed an antihypertensive effect of orange juice enriched with hesperidin [152].

A systematic review has highlighted the potential antidiabetic action of citrus flavonoids and their molecular mechanisms based on in vitro and in vivo studies [161]. The research identified 38 articles, mostly on experimental animals, which reported that citrus flavonoids regulate glycaemic control biomarkers, lipid profiles, kidney function, liver enzymes and antioxidant enzymes, and modulated signalling pathways related to glucose uptake and insulin sensitivity that are involved in the pathogenesis of diabetes and its related complications. Citrus flavonoids, therefore, are promising antidiabetic candidates, while their antidiabetic effects have yet to be verified in upcoming human studies.

Quercetin supplementation also may have positive effects among patients with MetS and related disorders [162]. A meta-analysis identified 9 studies on this topic, which showed overall that quercetin supplementation did not affect fasting plasma glucose or insulin resistance. However, in the subgroup analysis, quercetin supplementation slightly but significantly reduced fasting glucose in studies lasting 8 weeks and using quercetin in doses equal to or > 500 mg/day. Better effects were found in individuals <45 years of age. Regarding lipid levels, a meta-analysis of 9 clinical studies [163] found a significant reduction in LDL in overweight and obese human subjects who took doses ≥250 mg/day of quercetin for rather extended periods, reaching a total dose of ≥14,000 mg; however, HDL cholesterol, triglyceride and total cholesterol levels remained unchanged (p > 0.05).

The supplementation of nutrition with quercetin on blood pressure and endothelial function among patients with MetS was investigated with a meta-analysis [164]. The authors found a significant reduction in systolic blood pressure but not diastolic pressure.

Finally, the health of the intestine cannot be neglected, which is an organ where viral infections tend to be found, and it is also fundamental because the release of endotoxins (LPS) due to an increased mucosa permeability or intestinal dysmicrobism could enhance systemic inflammatory reactions. It has been argued that the interaction between the lung and gut could lead to a vicious cycle of lung and intestinal inflammation which may be a potential factor leading to the death of patients with COVID-19 [165]. Citrus flavanones may have an impact on the intestinal microbiome, exerting beneficial effects on the intestinal barrier function and gastrointestinal inflammation [166]. In intervention studies on volunteers, orange juice positively modulated the composition and metabolic activity of the microbiota, increasing the population of Bifidobacterium spp. and Lactobacillus spp. [167] or of Lactobacillus spp., Akkermansia spp. and Ruminococcus spp. according to other authors [168], suggesting that orange juice showed a prebiotic effect, modulating the intestinal microbiota by improving blood sugar and the lipid profile. In a recent review [169], it was highlighted how the beneficial effects of hesperidin on cardiovascular risk factors can be partly attributed to the modulation of the intestinal microbiota. Based on the current evidence, some of the contradictory effects of hesperidin in human studies are in part due to the interindividual variability of hesperidin in its bioavailability. Quercetin also has a profound influence on the intestinal microbiome, which in turn modulates its bioavailability [170].

In conclusion, the results indicate that supplementation with hesperidin or quercetin may have mild antihypertensive effects, improve metabolic lipid abnormalities and inflammatory status in patients with MetS. All these beneficial effects can only be reflected in a more favourable clinical course when viral infectious diseases cause systemic disorders involving oxidative stress and inflammation.

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4. Conclusions

The scientific literature is filled with works that support the beneficial effects of citrus flavonoids and quercetin on viral respiratory diseases, including COVID-19, and there are several possible mechanisms by which this effect is carried out (Figure 7).

Figure 7.

Summary of the possible actions of flavonoids hesperidin and quercetin to prevent the progression of SARS-CoV-2 virus infection and its major clinical consequences.

Inhibition of cellular infection can occur through the intercalation of these molecules between viruses and receptors and by inhibition of intracellular replication. This phenomenon could have a protective role especially in the oral cavity and in the gastrointestinal system, where the concentrations of the active ingredients are undoubtedly higher than in the blood after intestinal absorption and diffusion in the body. Furthermore, the two flavonoids are able to prevent cell damage due to the virus by enhancing the antioxidant defences through the Nrf2 system and by the direct scavenger action.

The close relationship between cell damage/death and inflammation means that a positive effect can be expected in mitigating the systemic consequences of an inflammation that has eluded controls. Finally, hesperidin and quercetin can exert an indirect beneficial effect, favouring carbohydrate and lipid metabolism, improving general health conditions and thus preventing comorbidities that are contributory causes of the most serious complications. All the experimental models cited here would make it plausible for an increase in the consumption of flavonoid-rich foods, or flavonoid supplementation during periods of increased commitment of the body defences, to help the immune system in the fight against virus infections. It is therefore desirable that further suitable clinical studies are conducted to investigate the potential of these natural substances and to define effective dosages.

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Acknowledgments

The article processing charges were borne by Vanda Omeopatici s.r.l. (Frascati, Roma). The sponsor had no role in the conception, writing or revision of the manuscript.

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Conflict of interest

The author is scientific consultant from Vanda Omeopatici s.r.l. (Frascati, Roma), a company that produces food supplements.

References

  1. 1. Aune D, Keum N, Giovannucci E, Fadnes LT, Boffetta P, Greenwood DC, et al. Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies. Am J Clin Nutr. 2018;108(5):1069-1091.
  2. 2. Wallace TC, Bailey RL, Blumberg JB, Burton-Freeman B, Chen CO, Crowe-White KM, et al. Fruits, vegetables, and health: A comprehensive narrative, umbrella review of the science and recommendations for enhanced public policy to improve intake. Crit Rev Food Sci Nutr. 2019;1-38.
  3. 3. Zhang Q , Yang W, Liu J, Liu H, Lv Z, Zhang C, et al. Identification of Six Flavonoids as Novel Cellular Antioxidants and Their Structure-Activity Relationship. Oxid Med Cell Longev. 2020;2020:4150897.
  4. 4. Spiegel M, Andruniów T, Sroka Z. Flavones' and Flavonols' Antiradical Structure-Activity Relationship-A Quantum Chemical Study. Antioxidants (Basel). 2020;9(6).
  5. 5. Zhao J, Huang L, Sun C, Zhao D, Tang H. Studies on the structure-activity relationship and interaction mechanism of flavonoids and xanthine oxidase through enzyme kinetics, spectroscopy methods and molecular simulations. Food Chem. 2020;323:126807.
  6. 6. Magar RT, Sohng JK. A Review on Structure, Modifications and Structure-Activity Relation of Quercetin and Its Derivatives. J Microbiol Biotechnol. 2020;30(1):11-20.
  7. 7. Gattuso G, Barreca D, Gargiulli C, Leuzzi U, Caristi C. Flavonoid composition of Citrus juices. Molecules. 2007;12(8):1641-1673.
  8. 8. Meneguzzo F, Ciriminna R, Zabini F, Pagliaro M. Review of Evidence Available on Hesperidin-Rich Products as Potential Tools against COVID-19 and Hydrodynamic Cavitation-Based Extraction as a Method of Increasing Their Production. Processes. 2020; 8: 549.
  9. 9. Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, Kuwahara Y, et al. Flavonoids and related compounds as anti-allergic substances. Allergol Int. 2007;56(2):113-123.
  10. 10. Boots AW, Wilms LC, Swennen EL, Kleinjans JC, Bast A, Haenen GR. In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers. Nutrition. 2008;24(7-8):703-710.
  11. 11. Formica JV, Regelson W. Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol. 1995;33(12):1061-1080.
  12. 12. Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schäfer B, Hirsch-Ernst KI, et al. Safety Aspects of the Use of Quercetin as a Dietary Supplement. Mol Nutr Food Res. 2018;62(1).
  13. 13. Checconi P, De AM, Marcocci ME, Fraternale A, Magnani M, Palamara AT, et al. Redox-Modulating Agents in the Treatment of Viral Infections. Int J Mol Sci. 2020;21(11).
  14. 14. Bellavite P, Donzelli A. Hesperidin and SARS-CoV-2: New Light on the Healthy Function of Citrus Fruits. Antioxidants (Basel). 2020;9(8): 9080742
  15. 15. Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, et al. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020;12(6).
  16. 16. Filardo S, Di PM, Mastromarino P, Sessa R. Therapeutic potential of resveratrol against emerging respiratory viral infections. Pharmacol Ther. 2020;107613.
  17. 17. Marinella MA. Indomethacin and resveratrol as potential treatment adjuncts for SARS-CoV-2/COVID-19. Int J Clin Pract. 2020;e13535.
  18. 18. Mrityunjaya M, Pavithra V, Neelam R, Janhavi P, Halami PM, Ravindra PV. Immune-Boosting, Antioxidant and Anti-inflammatory Food Supplements Targeting Pathogenesis of COVID-19. Front Immunol. 2020;11:570122.
  19. 19. Vijayakumar BG, Ramesh D, Joji A, Jayachandra PJ, Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur J Pharmacol. 2020;886:173448.
  20. 20. Russo M, Moccia S, Spagnuolo C, Tedesco I, Russo GL. Roles of flavonoids against coronavirus infection. Chem Biol Interact. 2020;328:109211.
  21. 21. Mani JS, Johnson JB, Steel JC, Broszczak DA, Neilsen PM, Walsh KB, et al. Natural product-derived phytochemicals as potential agents against coronaviruses: A review. Virus Res. 2020;284:197989.
  22. 22. Arslan B, Ergun NU, Topuz S, Semerci SY, Suner N, Kocatas A, et al. Synergistic effect of quercetin and vitamin C against COVID-19: Is a possible guard for front liners. Lancet (Preprints). 2020. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3682517.
  23. 23. Kaul TN, Middleton E Jr, Ogra PL. Antiviral effect of flavonoids on human viruses. J Med Virol. 1985;15(1):71-79.
  24. 24. Piva HMR, Sa JM, Miranda AS, Tasic L, Fossey MA, Souza FP, et al. Insights into Interactions of Flavanones with Target Human Respiratory Syncytial Virus M2-1 Protein from STD-NMR, Fluorescence Spectroscopy, and Computational Simulations. Int J Mol Sci. 2020;21(6).
  25. 25. Neznanov N, Kondratova A, Chumakov KM, Neznanova L, Kondratov R, Banerjee AK, et al. Quercetinase pirin makes poliovirus replication resistant to flavonoid quercetin. DNA Cell Biol. 2008;27(4):191-198.
  26. 26. Ganesan S, Faris AN, Comstock AT, Wang Q , Nanua S, Hershenson MB, et al. Quercetin inhibits rhinovirus replication in vitro and in vivo. Antiviral Res. 2012;94(3):258-271.
  27. 27. Farazuddin M, Mishra R, Jing Y, Srivastava V, Comstock AT, Sajjan US. Quercetin prevents rhinovirus-induced progression of lung disease in mice with COPD phenotype. PLoS ONE. 2018;13(7):e0199612.
  28. 28. Gonzalez O, Fontanes V, Raychaudhuri S, Loo R, Loo J, Arumugaswami V, et al. The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production. Hepatology. 2009;50(6):1756-1764.
  29. 29. Lipson SM, Ozen FS, Louis S, Karthikeyan L. Comparison of α-glucosyl hesperidin of citrus fruits and epigallocatechin gallate of green tea on the Loss of Rotavirus Infectivity in Cell Culture. Front Microbiol. 2015;6:359.
  30. 30. Davis JM, Murphy EA, McClellan JL, Carmichael MD, Gangemi JD. Quercetin reduces susceptibility to influenza infection following stressful exercise. Am J Physiol Regul Integr Comp Physiol. 2008;295(2):R505-R509.
  31. 31. Saha RK, Takahashi T, Suzuki T. Glucosyl hesperidin prevents influenza a virus replication in vitro by inhibition of viral sialidase. Biol Pharm Bull. 2009;32(7):1188-1192.
  32. 32. Choi HJ, Song JH, Park KS, Kwon DH. Inhibitory effects of quercetin 3-rhamnoside on influenza A virus replication. Eur J Pharm Sci. 2009;37(3-4):329-333.
  33. 33. Kim Y, Narayanan S, Chang KO. Inhibition of influenza virus replication by plant-derived isoquercetin. Antiviral Res. 2010;88(2):227-235.
  34. 34. Dong W, Wei X, Zhang F, Hao J, Huang F, Zhang C, et al. A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways. Sci Rep. 2014;4.
  35. 35. Wu W, Li R, Li X, He J, Jiang S, Liu S, et al. Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry. Viruses. 2015;8(1).
  36. 36. Ding Z, Sun G, Zhu Z. Hesperidin attenuates influenza A virus (H1N1) induced lung injury in rats through its anti-inflammatory effect. Antivir Ther. 2018;23(7):611-615.
  37. 37. Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, et al. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res. 2005;68(1):36-42.
  38. 38. Wang Q , Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 2020;181(4):894-904.
  39. 39. Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581(7807):215-220.
  40. 40. Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care. 2020;24(1):422.
  41. 41. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-1032.
  42. 42. Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8.
  43. 43. Nuzzo D, Picone P. Potential neurological effects of severe COVID-19 infection. Neurosci Res. 2020;158:1-5.
  44. 44. Watzky M, de DM, Letessier A, Saint-Ruf C, Miotto B. Assessing the consequences of environmental exposures on the expression of the human receptor and proteases involved in SARS-CoV-2 cell-entry. Environ Res. 2020;110317.
  45. 45. Lamers MM, Beumer J, van d, V, Knoops K, Puschhof J, Breugem TI, et al. SARS-CoV-2 productively infects human gut enterocytes. Science. 2020;369(6499):50-54.
  46. 46. Wu C, Liu Y, Yang Y, Zhang P, Zhong W, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B. 2020; 5:766-788.
  47. 47. Chen YW, Yiu CB, Wong KY. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL (pro)) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000Res. 2020;9:129.
  48. 48. Adem S, Eyupoglu V, Sarfraz I, Rasul A, Ali M. Identification of Potent COVID-19 Main Protease (Mpro) Inhibitors from Natural Polyphenols: An in Silico Strategy Unveils a Hope against CORONA. Preprints. 2020; 2020030333.
  49. 49. Utomo RY, Ikawati M, Meyianto E. Revealing the potency of citrus and galangal constituents to halt SARS-CoV-2 infection. Preprints. 2020. doi:10.20944/preprints202003.0214.v1
  50. 50. Das S, Sarmah S, Lyndem S, Singha RA. An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study. J Biomol Struct Dyn. 2020;1-11.
  51. 51. Joshi RS, Jagdale SS, Bansode SB, Shankar SS, Tellis MB, Pandya VK, et al. Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease. J Biomol Struct Dyn. 2020;1-16.
  52. 52. Basu A, Sarkar A, Maulik U. Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2. Sci Rep. 2020;10(1):17699.
  53. 53. Behloul N, Baha S, Guo Y, Yang Z, Shi R, Meng J. In silico identification of strong binders of the SARS-CoV-2 receptor-binding domain. Eur J Pharmacol. 2020;173701.
  54. 54. Mahdian S, Ebrahim-Habibi A, Zarrabi M. Drug repurposing using computational methods to identify therapeutic options for COVID-19. J Diabetes Metab Disord. 2020;1-9.
  55. 55. Balmeh N, Mahmoudi S, Mohammadi N, Karabedianhajiabadi A. Predicted therapeutic targets for COVID-19 disease by inhibiting SARS-CoV-2 and its related receptors. Inform Med Unlocked. 2020;20:100407.
  56. 56. Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, 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. 2020;1-11.
  57. 57. Glinsky GV. 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. 2020;8(5).
  58. 58. Jiang Y, Liu L, Manning M, Bonahoom M, Lotvola A, Yang Z, et al. Structural analysis, virtual screening and molecular simulation to identify potential inhibitors targeting 2'-O-ribose methyltransferase of SARS-CoV-2 coronavirus. J Biomol Struct Dyn. 2020;1-16.
  59. 59. Nguyen TT, Woo HJ, Kang HK, Nguyen VD, Kim YM, Kim DW, et al. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris. Biotechnol Lett. 2012;34(5):831-838.
  60. 60. Park JY, Yuk HJ, Ryu HW, Lim SH, Kim KS, Park KH, et al. Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors. J Enzyme Inhib Med Chem. 2017;32(1):504-515.
  61. 61. Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S, Soetjipto S. Potential Inhibitor of COVID-19 Main Protease (Mpro) From Several Medicinal Plant Compounds by Molecular Docking Study. Preprints. 2020;202003.0226.v1.
  62. 62. Abian O, Ortega-Alarcon D, Jimenez-Alesanco A, Ceballos-Laita L, Vega S, Reyburn HT, 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.
  63. 63. da Silva FMA, da Silva KPA, de Oliveira LPM, Costa EV, Koolen HH, Pinheiro MLB, et al. Flavonoid glycosides and their putative human metabolites as potential inhibitors of the SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). Mem Inst Oswaldo Cruz. 2020;115:e200207.
  64. 64. Erlund I, Kosonen T, Alfthan G, Mäenpää J, Perttunen K, Kenraali J, et al. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol. 2000;56(8):545-553.
  65. 65. Manach C, Donovan JL. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic Res. 2004;38(8):771-785.
  66. 66. Manach C, Williamson G, Morand C, Scalbert A, Rémésy C C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81(1 Suppl):230S–242S.
  67. 67. Khomich OA, Kochetkov SN, Bartosch B, Ivanov AV. Redox Biology of Respiratory Viral Infections. Viruses. 2018;10(8).
  68. 68. Zhang X, Wu X, Hu Q , Wu J, Wang G, Hong Z, et al. Mitochondrial DNA in liver inflammation and oxidative stress. Life Sci. 2019;236:116464.
  69. 69. Bhargava A, Raghuram GV, Pathak N, Varshney S, Jatawa SK, Jain D, et al. Occult hepatitis C virus elicits mitochondrial oxidative stress in lymphocytes and triggers PI3-kinase-mediated DNA damage response. Free Radic Biol Med. 2011;51(9):1806-1814.
  70. 70. Kido H, Indalao IL, Kim H, Kimoto T, Sakai S, Takahashi E. Energy metabolic disorder is a major risk factor in severe influenza virus infection: Proposals for new therapeutic options based on animal model experiments. Respir Investig. 2016;54(5):312-319.
  71. 71. Saleh J, Peyssonnaux C, Singh KK, Edeas M. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion. 2020;54:1-7.
  72. 72. Keles ES. Mild SARS-CoV-2 infections in children might be based on evolutionary biology and linked with host reactive oxidative stress and antioxidant capabilities. New Microbes New Infect. 2020;36:100723.
  73. 73. Delgado-Roche L, Mesta F. Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection. Arch Med Res. 2020;51(5):384-387.
  74. 74. Trujillo JA, Croft NP, Dudek NL, Channappanavar R, Theodossis A, Webb AI, et al. The cellular redox environment alters antigen presentation. J Biol Chem. 2014;289(40):27979-27991.
  75. 75. Hati S, Bhattacharyya S. Impact of Thiol-Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin-Converting Enzyme 2 Receptor. ACS Omega. 2020;5(26):16292-16298.
  76. 76. Dalan R, Bornstein SR, El-Armouche A, Rodionov RN, Markov A, Wielockx B, et al. The ACE-2 in COVID-19: Foe or Friend? Horm Metab Res. 2020;52(5):257-263.
  77. 77. Lavillette D, Barbouche R, Yao Y, Boson B, Cosset FL, Jones IM, et al. Significant redox insensitivity of the functions of the SARS-CoV spike glycoprotein: comparison with HIV envelope. J Biol Chem. 2006;281(14):9200-9204.
  78. 78. Sestili P, Fimognari C. Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Front Pharmacol. 2020;11:579944.
  79. 79. Silvagno F, Vernone A, Pescarmona GP. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants (Basel). 2020;9(7).
  80. 80. Dattilo M. The role of host defences in Covid 19 and treatments thereof. Mol Med. 2020;26(1):90.
  81. 81. Bertolini A, van de Peppel IP, Bodewes FAJA, Moshage H, Fantin A, Farinati F, et al. Abnormal Liver Function Tests in Patients With COVID-19: Relevance and Potential Pathogenesis. Hepatology. 2020 ;72(5):1864-1872.
  82. 82. Piano S, Dalbeni A, Vettore E, Benfaremo D, Mattioli M, Gambino CG, et al. Abnormal liver function tests predict transfer to intensive care unit and death in COVID-19. Liver Int. 2020;40(10):2394-2406.
  83. 83. Park HK, Kang SW, Park MS. Hesperidin Ameliorates Hepatic Ischemia-Reperfusion Injury in Sprague-Dawley Rats. Transplant Proc. 2019;51(8):2828-2832.
  84. 84. Jo SH, Kim ME, Cho JH, Lee Y, Lee J, Park YD, et al. Hesperetin inhibits neuroinflammation on microglia by suppressing inflammatory cytokines and MAPK pathways. Arch Pharm Res. 2019;42(8):695-703.
  85. 85. 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.
  86. 86. Boots AW, Kubben N, Haenen GR, Bast A. Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation. Biochem Biophys Res Commun. 2003;308(3):560-565.
  87. 87. Kerimi A, Williamson G. Differential Impact of Flavonoids on Redox Modulation, Bioenergetics, and Cell Signaling in Normal and Tumor Cells: A Comprehensive Review. Antioxid Redox Signal. 2018;29(16):1633-1659.
  88. 88. Chen M, Gu H, Ye Y, Lin B, Sun L, Deng W, et al. Protective effects of hesperidin against oxidative stress of tert-butyl hydroperoxide in human hepatocytes. Food Chem Toxicol. 2010;48(10):2980-2987.
  89. 89. Roohbakhsh A, Parhiz H, Soltani F, Rezaee R, Iranshahi M. Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases. Life Sci. 2015;124:64-74.
  90. 90. Oh YS, Jun HS. Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling. Int J Mol Sci. 2017;19(1).
  91. 91. Ikram M, Muhammad T, Rehman SU, Khan A, Jo MG, Ali T, et al. Hesperetin Confers Neuroprotection by Regulating Nrf2/TLR4/NF-ΰB Signaling in an AÎ2 Mouse Model. Mol Neurobiol. 2019;56(9):6293-6309.
  92. 92. Wu J, Huang G, Li Y, Li X. Flavonoids from Aurantii Fructus Immaturus and Aurantii Fructus: promising phytomedicines for the treatment of liver diseases. Chin Med. 2020;15:89.
  93. 93. Kwatra M, Ahmed S, Gawali B, Panda SR, Naidu VGM. Hesperidin alleviates chronic restraint stress and lipopolysaccharide-induced Hippocampus and Frontal cortex damage in mice: Role of TLR4/NF-ΰB, p38 MAPK/JNK, Nrf2/ARE signaling. Neurochem Int. 2020;104835.
  94. 94. Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, et al. Quercetin Attenuates Inflammatory Responses in BV-2 Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1. PLoS ONE. 2015;10(10):e0141509.
  95. 95. Costa LG, Garrick JM, Roquè PJ, Pellacani C. Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More. Oxid Med Cell Longev. 2016;2016:2986796.
  96. 96. Mahmoud AM, Mohammed HM, Khadrawy SM, Galaly SR. Hesperidin protects against chemically induced hepatocarcinogenesis via modulation of Nrf2/ARE/HO-1, PPARγ and TGF-β1/Smad3 signaling, and amelioration of oxidative stress and inflammation. Chem Biol Interact. 2017;277:146-158.
  97. 97. Tabeshpour J, Hosseinzadeh H, Hashemzaei M, Karimi G. A review of the hepatoprotective effects of hesperidin, a flavanon glycoside in citrus fruits, against natural and chemical toxicities. Daru. 2020;28(1):305-317.
  98. 98. Hong Y, An Z. Hesperidin attenuates learning and memory deficits in APP/PS1 mice through activation of Akt/Nrf2 signaling and inhibition of RAGE/NF-kB signaling. Arch Pharm Res. 2018;41(6):655-663.
  99. 99. Hannan MA, Dash R, Sohag AAM, Haque MN, Moon IS. Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System. Front Mol Neurosci. 2020;13:116.
  100. 100. Elyasi L, Jahanshahi M, Jameie SB, Hamid Abadi HG, Nikmahzar E, Khalili M, et al. 6-OHDA mediated neurotoxicity in SH-SY5Y cellular model of Parkinson disease suppressed by pretreatment with hesperidin through activating L-type calcium channels. J Basic Clin Physiol Pharmacol. 2020. DOI: 10.1515/jbcpp-2019-0270
  101. 101. Kesh S, Kannan RR, Sivaji K, Balakrishnan A. Hesperidin downregulates kinases lrrk2 and Gsk3β in a 6-OHDA induced Parkinson's disease model. Neurosci Lett. 2020;740:135426.
  102. 102. Antunes MS, Cattelan SL, Ladd FVL, Ladd AABL, Moreira AL, Bortolotto VC, et al. Hesperidin Ameliorates Anxiety-Depressive-Like Behavior in 6-OHDA Model of Parkinson's Disease by Regulating Striatal Cytokine and Neurotrophic Factors Levels and Dopaminergic Innervation Loss in the Striatum of Mice. Mol Neurobiol. 2020;57(7):3027-3041.
  103. 103. Suganthy N, Devi KP, Nabavi SF, Braidy N, Nabavi SM. Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions. Biomed Pharmacother. 2016;84:892-908.
  104. 104. Erlich JR, To EE, Liong S, Brooks R, Vlahos R, O'Leary JJ, et al. Targeting Evolutionary Conserved Oxidative Stress and Immunometabolic Pathways for the Treatment of Respiratory Infectious Diseases. Antioxid Redox Signal. 2020;32(13):993-1013.
  105. 105. Potus F, Mai V, Lebret M, Malenfant S, Breton-Gagnon E, Lajoie AC, et al. Novel insights on the pulmonary vascular consequences of COVID-19. Am J Physiol Lung Cell Mol Physiol. 2020;319(2):L277-L288.
  106. 106. Perricone C, Bartoloni E, Bursi R, Cafaro G, Guidelli GM, Shoenfeld Y, et al. COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol Res. 2020;1-12.
  107. 107. Ruscitti P, Berardicurti O, Di BP, Cipriani P, Iagnocco A, Shoenfeld Y, et al. Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm. Front Immunol. 2020;11.
  108. 108. Uchide N, Toyoda H. Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules. 2011;16(3):2032-2052.
  109. 109. Santus P, Corsico A, Solidoro P, Braido F, Di MF, Scichilone N. Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine. COPD. 2014;11(6):705-717.
  110. 110. De FS, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997;10(7):1535-1541.
  111. 111. Soltan-Sharifi MS, Mojtahedzadeh M, Najafi A, Reza KM, Reza RM, Moradi M, et al. Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: evidence for underlying toxicological mechanisms. Hum Exp Toxicol. 2007;26(9):697-703.
  112. 112. Poe FL, Corn J. N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Med Hypotheses. 2020;143:109862.
  113. 113. Wu J. Tackle the free radicals damage in COVID-19. Nitric Oxide. 2020;102:39-41.
  114. 114. De Flora S, Balansky R, La Maestra S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J. 2020;34(10):13185-13193.
  115. 115. Elavarasan J, Velusamy P, Ganesan T, Ramakrishnan SK, Rajasekaran D, Periandavan K. Hesperidin-mediated expression of Nrf2 and upregulation of antioxidant status in senescent rat heart. J Pharm Pharmacol. 2012;64(10):1472-1482.
  116. 116. Velusamy P, Mohan T, Ravi DB, Kishore Kumar SN, Srinivasan A, Chakrapani LN, et al. Targeting the Nrf2/ARE Signalling Pathway to Mitigate Isoproterenol-Induced Cardiac Hypertrophy: Plausible Role of Hesperetin in Redox Homeostasis. Oxid Med Cell Longev. 2020;2020:9568278.
  117. 117. Miler M, Zivanovic J, Ajdzanovic V, Orescanin-Dusic Z, Milenkovic D, Konic-Ristic A, et al. Citrus flavanones naringenin and hesperetin improve antioxidant status and membrane lipid compositions in the liver of old-aged Wistar rats. Exp Gerontol. 2016;84:49-60.
  118. 118. Li S, Qin Q , Luo D, Pan W, Wei Y, Xu Y, et al. Hesperidin ameliorates liver ischemia/reperfusion injury via activation of the Akt pathway. Mol Med Rep. 2020;22(6):4519-4530.
  119. 119. Aja PM, Ekpono EU, Awoke JN, Famurewa AC, Izekwe FI, Okoro EJ, et al. Hesperidin ameliorates hepatic dysfunction and dyslipidemia in male Wistar rats exposed to cadmium chloride. Toxicol Rep. 2020;7:1331-1338.
  120. 120. Duranti G, Ceci R, Patrizio F, Sgrò P, Di LL, Sabatini S, et al. Chronic consumption of quercetin reduces erythrocytes oxidative damage: Evaluation at resting and after eccentric exercise in humans. Nutr Res. 2018;50:73-81.
  121. 121. Cavalli E, Bramanti A, Ciurleo R, Tchorbanov AI, Giordano A, Fagone P, et al. Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: Diagnostic and therapeutic perspectives (Review). Int J Mol Med. 2020;46(3):903-912.
  122. 122. Lyons-Weiler J. Pathogenic Priming Likely Contributes to Serious and Critical Illness and Mortality in COVID-19 via Autoimmunity. J Transl Autoimmun. 2020;100051.
  123. 123. Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, et al. Covid-19 and autoimmunity. Autoimmun Rev. 2020;19(8):102597.
  124. 124. Shoenfeld Y. Corona (COVID-19) time musings: Our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmun Rev. 2020;19(6):102538.
  125. 125. Ruiz-Iglesias P, Estruel-Amades S, Camps-Bossacoma M, Massot-Cladera M, Franch Ã, Pérez-Cano FJ, et al. Influence of Hesperidin on Systemic Immunity of Rats Following an Intensive Training and Exhausting Exercise. Nutrients. 2020;12(5).
  126. 126. Estruel-Amades S, Massot-Cladera M, Garcia-Cerdà P, Pérez-Cano FJ, Franch Ã, Castell M, et al. Protective Effect of Hesperidin on the Oxidative Stress Induced by an Exhausting Exercise in Intensively Trained Rats. Nutrients. 2019;11(4).
  127. 127. Polat FR, Karaboga I, Polat MS, Erboga Z, Yilmaz A, Guzel S. Effect of hesperetin on inflammatory and oxidative status in trinitrobenzene sulfonic acid-induced experimental colitis model. Cell Mol Biol (Noisy -le-grand). 2018;64(11):58-65.
  128. 128. Duran Y, Karaboga I. Effect of hesperetin on systemic inflammation and hepatic injury after blunt chest trauma in rats. Biotech Histochem. 2020;95(4):297-304.
  129. 129. Ren H, Hao J, Liu T, Zhang D, Lv H, Song E, et al. Hesperetin Suppresses Inflammatory Responses in Lipopolysaccharide-Induced RAW 264.7 Cells via the Inhibition of NF-ΰB and Activation of Nrf2/HO-1 Pathways. Inflammation. 2016;39(3):964-973.
  130. 130. Yeh CC, Kao SJ, Lin CC, Wang SD, Liu CJ, Kao ST. The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro. Life Sci. 2007;80(20):1821-1831.
  131. 131. Wang N, Geng C, Sun H, Wang X, Li F, Liu X. Hesperetin ameliorates lipopolysaccharide-induced acute lung injury in mice through regulating the TLR4-MyD88-NF-kappaB signaling pathway. Arch Pharm Res. 2019;42(12):1063-1070.
  132. 132. Dong J, Zhou H, Zhao H, Zhao Y, Chang C. Hesperetin ameliorates lipopolysaccharide-induced acute lung injury via the miR-410/SOX18 axis. J Biochem Mol Toxicol. 2020;e22588.
  133. 133. Ma H, Feng X, Ding S. Hesperetin attenuates ventilator-induced acute lung injury through inhibition of NF-kB-mediated inflammation. Eur J Pharmacol. 2015;769:333-341.
  134. 134. Wang S, He N, Xing H, Sun Y, Ding J, Liu L. Function of hesperidin alleviating inflammation and oxidative stress responses in COPD mice might be related to SIRT1/PGC-1α/NF-kB signaling axis. J Recept Signal Transduct Res. 2020 Aug;40(4):388-394.
  135. 135. Shaik YB, Castellani ML, Perrella A, Conti F, Salini V, Tete S, et al. Role of quercetin (a natural herbal compound) in allergy and inflammation. J Biol Regul Homeost Agents. 2006;20(3-4):47-52.
  136. 136. Cho SY, Park SJ, Kwon MJ, Jeong TS, Bok SH, Choi WY, et al. Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage. Mol Cell Biochem. 2003;243(1-2):153-160.
  137. 137. Marseglia GL, Licari A, Ciprandi G. A polycentric, randomized, double blind, parallel-group, placebo-controlled study on Lertal®, a multicomponent nutraceutical, as add-on treatment in children with allergic rhinoconjunctivitis: phase I during active treatment. J Biol Regul Homeost Agents. 2019;33(2):617-622.
  138. 138. Marseglia G, Licari A, Leonardi S, Papale M, Zicari AM, Schiavi L, et al. A polycentric, randomized, parallel-group, study on Lertal®, a multicomponent nutraceutical, as preventive treatment in children with allergic rhinoconjunctivitis: phase II. Ital J Pediatr. 2019;45(1):84.
  139. 139. Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy. 2000;30(4):501-508.
  140. 140. Min YD, Choi CH, Bark H, Son HY, Park HH, Lee S, et al. Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res. 2007;56(5):210-215.
  141. 141. Kalogeromitros D, Makris M, Chliva C, Aggelides X, Kempuraj D, Theoharides TC. A quercetin containing supplement reduces niacin-induced flush in humans. Int J Immunopathol Pharmacol. 2008;21(3):509-514.
  142. 142. Park SJ, Chung HY, Lee JH. Rapid in vivo screening system for anti-oxidant activity using bacterial redox sensor strains. J Appl Microbiol. 2010;108(4):1217-1225.
  143. 143. Lee EJ, Ji GE, Sung MK. Quercetin and kaempferol suppress immunoglobulin E-mediated allergic inflammation in RBL-2H3 and Caco-2 cells. Inflamm Res. 2010; 59(10):847-854.
  144. 144. Middleton E Jr, Drzewiecki G. Flavonoid inhibition of human basophil histamine release stimulated by various agents. Biochem Pharmacol. 1984;33(21):3333-3338.
  145. 145. Chirumbolo S, Conforti A, Ortolani R, Vella A, Marzotto M, Bellavite P. Stimulus-specific regulation of CD63 and CD203c membrane expression in human basophils by the flavonoid quercetin. Int Immunopharmacol. 2010;10(2):183-192.
  146. 146. Ying B, Yang T, Song X, Hu X, Fan H, Lu X, et al. Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways. Mol Biol Rep. 2009;36(7):1825-1832.
  147. 147. Chirumbolo S, Marzotto M, Conforti A, Vella A, Ortolani R, Bellavite P. Bimodal action of the flavonoid quercetin on basophil function: an investigation of the putative biochemical targets. Clin Mol Allergy. 2010;8:13.
  148. 148. Zaplatic E, Bule M, Shah SZA, Uddin MS, Niaz K. Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer's disease. Life Sci. 2019;224:109-119.
  149. 149. Theoharides TC. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors. 2020;46(3):306-308.
  150. 150. Mohammadi-Sartang M, Mazloom Z, Sherafatmanesh S, Ghorbani M, Firoozi D. Effects of supplementation with quercetin on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2017;71(9):1033-1039.
  151. 151. Chanet A, Milenkovic D, Manach C, Mazur A, Morand C. Citrus flavanones: what is their role in cardiovascular protection? J Agric Food Chem. 2012;60(36):8809-8822.
  152. 152. Valls RM, Pedret A, Calderon-Perez L, Llaurado E, Pla-Paga L, Companys J, et al. Effects of hesperidin in orange juice on blood and pulse pressures in mildly hypertensive individuals: a randomized controlled trial (Citrus study). Eur J Nutr. 2020 Jul 13. DOI: 10.1007/s00394-020-02279-0.
  153. 153. Pittala V, Vanella L, Salerno L, Romeo G, Marrazzo A, Di GC, et al. Effects of Polyphenolic Derivatives on Heme Oxygenase-System in Metabolic Dysfunctions. Curr Med Chem. 2018;25(13):1577-1595.
  154. 154. Garcia-Garcia FJ, Monistrol-Mula A, Cardellach F, Garrabou G. Nutrition, Bioenergetics, and Metabolic Syndrome. Nutrients. 2020;12(9).
  155. 155. Yari Z, Movahedian M, Imani H, Alavian SM, Hedayati M, Hekmatdoost A. The effect of hesperidin supplementation on metabolic profiles in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial. Eur J Nutr. 2020;59(6):2569-2577.
  156. 156. Prasatthong P, Meephat S, Rattanakanokchai S, Bunbupha S, Prachaney P, Maneesai P, et al. Hesperidin ameliorates signs of the metabolic syndrome and cardiac dysfunction via IRS/Akt/GLUT4 signaling pathway in a rat model of diet-induced metabolic syndrome. Eur J Nutr. 2020 May 27. doi: 10.1007/s00394-020-02291-4.
  157. 157. Amiot MJ, Riva C, Vinet A. Effects of dietary polyphenols on metabolic syndrome features in humans: a systematic review. Obes Rev. 2016 ;17(7):573-586.
  158. 158. Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011;96(5):E782-E792.
  159. 159. Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Blood pressure lowering and anti-inflammatory effects of hesperidin in type 2 diabetes; a randomized double-blind controlled clinical trial. Phytother Res. 2018;32(6):1073-1079.
  160. 160. Cassidy A, Bertoia M, Chiuve S, Flint A, Forman J, Rimm EB. Habitual intake of anthocyanins and flavanones and risk of cardiovascular disease in men. Am J Clin Nutr. 2016;104(3):587-594.
  161. 161. Gandhi GR, Vasconcelos ABS, Wu DT, Li HB, Antony PJ, Li H, et al. Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies. Nutrients. 2020;12(10).
  162. 162. Ostadmohammadi V, Milajerdi A, Ayati E, Kolahdooz F, Asemi Z. Effects of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2019;33(5):1330-1340.
  163. 163. Guo W, Gong X, Li M. Quercetin Actions on Lipid Profiles in Overweight and Obese Individuals: A Systematic Review and Meta-Analysis. Curr Pharm Des. 2019;25(28):3087-3095.
  164. 164. Tamtaji OR, Milajerdi A, Dadgostar E, Kolahdooz F, Chamani M, Amirani E, et al. The Effects of Quercetin Supplementation on Blood Pressures and Endothelial Function Among Patients with Metabolic Syndrome and Related Disorders: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Curr Pharm Des. 2019;25(12):1372-1384.
  165. 165. Zhang M, Zhou Y, Li H, Peng Y, Qiu P, Shi X, et al. COVID-19: gastrointestinal symptoms from the view of gut-lung axis. Eur J Gastroenterol Hepatol. 2020 Oct 29. doi: 10.1097/MEG.0000000000001984
  166. 166. Stevens Y, Rymenant EV, Grootaert C, Camp JV, Possemiers S, Masclee A, et al. The Intestinal Fate of Citrus Flavanones and Their Effects on Gastrointestinal Health. Nutrients. 2019;11(7).
  167. 167. Lima ACD, Cecatti C, Fidélix MP, Adorno MAT, Sakamoto IK, Cesar TB, et al. Effect of Daily Consumption of Orange Juice on the Levels of Blood Glucose, Lipids, and Gut Microbiota Metabolites: Controlled Clinical Trials. J Med Food. 2019;22(2):202-210.
  168. 168. Fidelix M, Milenkovic D, Sivieri K, Cesar T. Microbiota modulation and effects on metabolic biomarkers by orange juice: a controlled clinical trial. Food Funct. 2020;11(2):1599-1610.
  169. 169. Mas-Capdevila A, Teichenne J, Domenech-Coca C, Caimari A, Del Bas JM, Escotà X, et al. Effect of Hesperidin on Cardiovascular Disease Risk Factors: The Role of Intestinal Microbiota on Hesperidin Bioavailability. Nutrients. 2020;12(5).
  170. 170. Murota K, Nakamura Y, Uehara M. Flavonoid metabolism: the interaction of metabolites and gut microbiota. Biosci Biotechnol Biochem. 2018;82(4):600-610.

Written By

Paolo Bellavite

Submitted: 11 December 2020 Reviewed: 17 December 2020 Published: 25 January 2021