Biological Properties of Flavonoid Quercetin: Comparison
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Quercetin is a dietary flavonoid present in vegetables, fruits, and beverages, such as onions, apples, broccoli, berries, citrus fruits, tea, and red wine. Flavonoids have antioxidant and anti-inflammatory effects, acting in the prevention of several diseases. 

  • quercetin
  • metabolism
  • inflammatory

1. Introduction

 Flavonoids are dietary phytochemicals, from the polyphenol class, found in a variety of fruits, vegetables, and beverages, including citrus fruits, strawberries, raspberries, apples, grapes, cocoa, legumes, grains, coffee, green tea, and red wine [1]. According to their chemical characteristics, flavonoids are classified into subgroups, such as flavonols, flavones, isoflavones, flavanones, flavanols, and anthocyanidins [2]. In general, flavonoid subgroups have nutritional properties and therapeutic potential on different pathologies, such as cancer, cardiovascular, neurological, inflammatory, and metabolic diseases [2][3][4]. Due to their antioxidant, anti-inflammatory, antiallergic, antimicrobial, antitumor, and antiviral properties, flavonoids can exert significant beneficial effect, modulating various biological processes [5]. Flavonoids exhibit the ability to scavenge ROS, activate antioxidant enzymes and inhibit enzymes related to the production of free radicals, as well as downregulate the expression and synthesis of factors related to oxidative stress, such as iNOS and nitric oxide (NO) [6][7]. Thus, the main mechanisms of action by which flavonoids exert their effect are related to their ability to inhibit ROS production and reduce the synthesis of inflammatory mediators, such as TNF-α, IL-6, interleukin-1 beta (IL-1β), COX-2, and prostaglandin E2 (PGE2) [4][8].

2. Flavonoid Quercetin

The term quercetin is derived from the Latin “quercetum”, commonly referred to as “oak forest” [9][10]. Quercetin is a bioactive agent that is widely distributed among a diversity of vegetable species and medicinal plants, such as Ginkgo biloba, Hypericum perforatum, and Sambucus canadensis [10]. Structurally, quercetin (3,3′,4′,5,7-pentahydroxyflavone) has two benzene rings linked by a heterocyclic pyran or pyrone ring and five hydroxyl groups [11], with the molecular formula C15H10O7 [9][10][12]. Considering the chemical aspect, quercetin has a greenish-yellow crystalline solid appearance, being responsible for the pigmentation of various fruits, flowers, and vegetables [9][13][14]. Quercetin has an important nutritional value, constituting one of the most abundant flavonoids in the diet [10][11][13][14]. The main dietary sources of quercetin are onions and apples, in addition to other foods, such as cherries, grapes, blueberries, citrus fruits, red leaf lettuce, cabbage, broccoli, tomatoes, peppers, asparagus, wine, and tea [10][11][15][16].
In fruits and vegetables, quercetin is usually present in the form of glycosides, conjugated to carbohydrate residues, such as glucose and rutinose [9][11][15][17]. After ingestion, quercetin glycosides are hydrolyzed by β-glycosidases in the intestine. Most of the aglycone form is absorbed in the gastrointestinal tract and metabolized in the liver [9][10][11][12][15]. Thus, the microbial of the gastrointestinal tract plays an important role in the degradation and metabolism of this bioactive agent [11]. Quercetin, therefore, has a rapid and extensive metabolism, being efficiently eliminated by the intestine and kidneys [7][12]. One of the important issues in this process refers to its bioavailability. In addition to the intestinal flora, some factors, such as diet, can alter the bioavailability of quercetin and its metabolites. Certain dietary elements can interfere to increase the plasmatic concentration of these molecules. Quercetin, however, has a short half-life and relatively low bioavailability, which may influence its biological effect [9][12][13][15]. Considering these issues, some studies have investigated different delivery systems that could increase the bioavailability and facilitate the access of quercetin in the target tissues, such as the use of loaded quercetin in hydrogels, nanoparticles, nanofibers, polymeric micelles, or mucoadhesive nanoemulsions [12][18][19][20][21][22]. Thus, research has advanced in the use of these technologies since the therapeutic effect of a bioactive agent depends largely on its bioavailability.
As with the other flavonoids, quercetin has several biological properties that are responsible for its therapeutic potential. Quercetin has anti-inflammatory, antioxidant, anticancer, neuroprotective, immunoprotective, antiviral, and antibacterial properties [10][11][23][24][25][26]. Studies report that quercetin can act in the prevention of several pathologies, such as cancer, bacterial and viral infections, cardiovascular, neurodegenerative, inflammatory, immunological, and metabolic diseases, like asthma and diabetes mellitus (Figure 1) [7][9][10][11][14][26]. Therefore, regular consumption of a diet rich in quercetin may provide health benefits, contributing to the prevention of diseases related to aging and lifestyle [9][17]. Thus, considering that quercetin is already part of the diet and considering the scientific evidence from in vivo studies and clinical trials that did not indicate adverse toxicological effects, in 2010, high purity quercetin was recognized by the Food and Drug Administration (FDA) as GRAS (Generally Recognized as Safe) for use as a food ingredient [11]. In addition to its recognized nutritional properties, the effects of quercetin as a therapeutic agent have also been investigated in various pathological conditions, such as in the rehabilitation of neurological functions.
Antioxidants 12 00149 g002 550
Figure 1. Quercetin is a dietary flavonoid widely distributed among a diversity of fruits, vegetables, and medicinal plants. Quercetin has anti-inflammatory, antioxidant, antitumor, antiviral, antibacterial, and neuroprotective properties. Due to its properties, quercetin can exert beneficial biological activity, acting in the prevention of various pathologies, such as cancer, bacterial and viral infections, cardiovascular, neurodegenerative, inflammatory, immunological, and metabolic diseases. Reactive Nitrogen Species (RNS).
There is evidence in the literature that quercetin has a neuroprotective effect and the potential to favor neurogenesis and regeneration of nervous tissue [9][12]. One of the characteristics that contributes to the neuroprotective action of quercetin concerns its solubility. Despite being relatively insoluble in water, quercetin is lipophilic [9][10][12]. The lipophilic nature of quercetin facilitates its passage through the blood-brain barrier. Then, quercetin absorbed and available in the plasma can easily access the brain tissue to exert its biological activity [9][27]. In the nervous system, quercetin can act in injured areas to minimize or reverse the dysfunctions resulting from neurodegenerative disorders, as well as to delay the advance of neurological alterations [9][12]. The neuroprotective effect of quercetin is mainly related to its anti-inflammatory and antioxidant potential, since quercetin acts by protecting the tissue against oxidative stress induced or resulting from physiological metabolism [27]. In addition to physiopathological changes, physiological conditions, such as aging, can compromise the antioxidant capacity of the tissue, resulting in increased oxidative damage [12]. Overall, the antioxidant action of quercetin occurs through several mechanisms, such as free radical scavenging, chelating action on metal ions, acting on mitochondrial function, on gene expression and on the synthesis of antioxidant factors [27]. In addition to reducing ROS formation and lipid peroxidation, quercetin also acts by modulating the inflammatory response, inhibiting the synthesis of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and favoring the synthesis of anti-inflammatory cytokines, such as interleukin-10 (IL-10) [7].
The anti-inflammatory and antioxidant properties of quercetin have been reported in several studies. In vitro studies showed that quercetin reduced the production of NO and ROS, inhibited the activation of nuclear factor-kappa B (NF-kB), and downregulated the expression of inflammatory mediators, such as IL-1β, IL-6, TNF-α, and COX-2, even in lipopolysaccharide-stimulated cells (LPS) [28][29][30][31][32]. The neuroprotective properties of quercetin have also been reported in studies with animal models subjected to neuronal injury induced by trauma, hypoxia, or LPS. In animals with traumatic brain injury, quercetin administration reduced inflammatory response, oxidative stress, neuronal apoptosis, and brain edema [33][34], improving cognitive functions, biogenesis, and mitochondrial function [34][35][36][37]. Quercetin treatment also modulated the inflammatory response, minimized oxidative stress, and reduced neuronal apoptosis in animals with cerebral ischemia, suppressing the expression and synthesis of inflammatory cytokines (TNF-α, Il-1β, and Il-6), as well as inhibiting NF-kB activation [32][38]. In addition to modulating tissue responses induced by hypoxia, quercetin inhibited blood-brain barrier disruption and cerebral infarction, attenuating the neurological deficit [38].
In addition, under conditions of cerebral hypoxia, a synergistic pharmacological effect was obtained by the association of quercetin administration with the transplantation of human umbilical cord mesenchymal stromal cells (HUMSCs) [39]. In this researchtudy, treatment with quercetin and HUMSCs reduced cellular apoptosis and the synthesis of inflammatory mediators (IL-1β and IL-6), while favoring the synthesis of anti-inflammatory cytokines (IL-4, IL-10, and TGF-β1). Additionally, the combined treatment favored the survival of HUMSCs at the site of injury and promoted an improvement in the recovery of neurological functions [39]. In LPS-induced animal models, quercetin administration reduced ROS production and the synthesis of inflammatory mediators (Il-1β, TNF-α, and COX-2), minimizing neurotoxicity and neurodegeneration, in addition to improving memory function [29][40]. Similar results were obtained in studies that used quercetin to treat animals with neurodegenerative or metabolic diseases. In rotenone-induced parkinsonian rats, quercetin minimized neurological deficits and downregulated the expression of inflammatory mediators, such as Il-1β, TNF-α, and NF-kB [41]. Similarly, an inhibition of inflammatory mediator synthesis (Il-1β and TNF-α) was obtained in diabetic peripheral neuropathy animal model treated with quercetin [42]. Other in vivo studies have also reported that the administration of quercetin promoted a beneficial effect by alleviating neuropathic pain [43][44][45][46].
In general, in several studies conducted with animal models, quercetin has shown beneficial effects on the microenvironment of nervous tissue, modulating the inflammatory response, and minimizing oxidative stress, cell apoptosis and neurodegenerative disorders, in addition to alleviating neuropathic pain.

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