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Quercetin: A flavonol with multifaceted therapeutic applications?
Quercetin: A flavonol with multifaceted therapeutic applications? Gabriele D’Andrea PII: DOI: Reference:
S0367-326X(15)30092-7 doi: 10.1016/j.fitote.2015.09.018 FITOTE 3271
To appear in:
Fitoterapia
Received date: Revised date: Accepted date:
22 July 2015 16 September 2015 18 September 2015
Please cite this article as: Gabriele D’Andrea, Quercetin: A flavonol with multifaceted therapeutic applications?, Fitoterapia (2015), doi: 10.1016/j.fitote.2015.09.018
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ACCEPTED MANUSCRIPT Quercetin: A flavonol with multifaceted therapeutic applications? Gabriele D’Andrea*
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University of L’Aquila, Dept. of Biotechnological and Applied Clinical Sciences, Via Vetoio,
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Coppito 2, 67100 L’Aquila, Italy
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*: Corresponding author
Fax:
+39-862-433433
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email: [email protected]
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Phone: +39-862-433464
Keywords: quercetin; dietary sources; metabolism; therapeutic applications; toxicity; drug
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interactions.
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ACCEPTED MANUSCRIPT ABSTRACT Great interest is currently centered on the biologic activities of quercetin a polyphenol belonging to the class of flavonoids, natural products well known for their beneficial effects on health, long before their biochemical characterization. In particular, quercetin is categorized as a flavonol, one of the five subclasses of flavonoid compounds.
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Although flavonoids occur as either glycosides (with attached glycosyl groups) or as aglycones, most altogether of the dietary intake concerning quercetin is in the glycoside form. Following chewing, digestion, and absorption sugar
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moieties can be released from quercetin glycosides. Several organs contribute to quercetin metabolism, including the small intestine, the kidneys, the large intestine, and the liver, giving rise to glucuronidated, methylated, and sulfated forms of quercetin; moreover, free quercetin (such as aglycone) is also found in plasma. Quercetin is now largely
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utilized as a nutritional supplement and as a phytochemical remedy for a variety of diseases like diabetes/obesity, circulatory dysfunction, including inflammation as well as mood disorders. Owing to its basic chemical structure the
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most obvious feature of quercetin is its strong antioxidant activity which potentially enables it to quench free radicals from forming resonance-stabilized phenoxyl radicals.
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In this review the molecular, cellular, and functional bases of therapy will be emphasized taking strictly into
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account data appearing in the peer-reviewed literature and summarizing the main therapeutic applications of quercetin;
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furthermore, the drug metabolism and the main drug interaction as well as the potential toxicity will be also spotlighted.
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ACCEPTED MANUSCRIPT 1. INTRODUCTION Most of the successful medical treatments in ancient times seem due to the employment of flavonoids, which use has persevered until now. Consequently, new interest by the scientific community towards flavonoids and their derivatives centers on numerous flavonoid compounds and their diverse biological properties (e.g. antioxidative,
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antimicrobial, anticarcinogenic, cardioprotective). Certainly, in this context quercetin is one of the most often studied dietary flavonoid ubiquitously present in various vegetables as well as in tea and red wine [1-3]. In a typical Western
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diet the daily intake of quercetin is estimated to be in the range of 0 and 30 mg (median of 10 mg). Tea, red wine, fruits, and vegetables are the chief dietary sources of quercetin in Western populations [4, 5]. In some countries quercetin is available as a dietary supplement with daily doses between 200 and 1200 mg. In addition, as a nutraceutical for
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functional foods, quercetin may be used within 0.008-0.5% or 10-125 mg/serving [6]. Yet, like other similar antioxidant flavonoids quercetin is an exceptional free radical scavenger [7] and from
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that feature arises the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical; for this reason quercetin is suggested to be involved in imaginable beneficial health effects. On the contrary,
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only few, and mostly in vitro, studies report some damaging effects of quercetin; in particular, its oxidation product
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such as quercetin-quinone seems to be very reactive towards thiols and can instantaneously form an adduct with glutathione, the most abundant endogenous thiol [8, 9]. Furthermore, amongst other damaging effects quercetin has
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also been reported to display genotoxic effects in vitro, but these mutagenic effects of quercetin have been found only in bacteria and are suggested to require the quinone formation as mediators as well [10-13]. In any case, it is assumed that the bioactivity of quercetin is mainly due to its metabolization in the intestines
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and/or liver starting from various naturally occurring conjugated isoforms that are absorbed and extensively distributed in animal tissues [14-16]. In particular, quercetin-3-O-β-D-glucuronide (Q3GA), a major metabolite of quercetin and found as such in many foods (Table 1), seems to exert the foremost beneficial functions in target tissues [17].
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ACCEPTED MANUSCRIPT Table 1. Quercetin-3-O-β-D-glucuronide content in selected food1
Grape, black
2.15 mg/100 g
Strawberry, raw
1.74 mg/100 g
Grape, green
1.50 mg/100 g
Cloudberry
0.79 mg/100 g
Red raspberry, raw
0.63 mg/100 g
Red raspberry, pure juice
6.18 mg/100 mL
Fennel, tea
3.26 mg/100 mL
Grape, green, pure juice
0.05 mg/100 mL
Lettuce, red, raw
2.65 mg/100 g
Lettuce, green, raw
1.34 mg/100 g
Green bean, raw
0.80 mg/100 g
Fruit juices - Berry juices
Herb infusion
Pod vegetables 1
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Leafy vegetables
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Vegetables
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Non-alcoholic beverages
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Fruits - Berries
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Fruits and fruit products
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: Adapted from Phenol-Explorer, Database on polyphenol content in foods [205].
Thus, since numerous studies have been performed to gather scientific evidence for these beneficial health
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claims the principal aim of this review is to evaluate these studies in order to elucidate the possible health-beneficial
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effects of quercetin. In particular, among the beneficial effects, the antihypertensive effects of quercetin in humans and the improvement of endothelial function seem to be the most relevant. Nevertheless, besides its anti-thrombotic and anti-inflammatory effects, quercetin could be used for preventing obesity related diseases, but also to treat some kinds
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of cancer. Most exciting are the recent findings that quercetin enhances physical power by yet unclear mechanisms. Even though quercetin bioavailability is generally poor it is a critical mediator of its bioactivities, in this review besides the molecular, cellular, and functional bases of therapy that will be emphasized and critically evaluated, the quercetin metabolism and its main drug interaction as well as its potential toxicity will be also spotlighted.
2. CHEMICAL FEATURES OF QUERCETIN 2.1. Structural features of quercetin The name quercetin derives from quercetum (oak forest), after Quercus and has been used since 1857. Naturally, quercetin is a polar auxin transport inhibitor [18] whose structure is shown in Fig. 1 whereas its main identifiers and properties are reported in Table 2.
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Figure 1. The chemical structure of quercetin.
IUPAC Name PubChem CID
Solubility
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Density Color Boiling Point Melting Point
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Trivial Chemical Names Molecular Weight Molecular Formula
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MeSH Synonyms
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InChl Key Canonical SMILE CAS EC Number UN Number UNII
Physical Description
IDENTIFIERS 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one 5280343 1S/C15H10O7/c16-7-4-10(19)12-11(5-7)22-15(14(21)13(12)20)6-1-28(17)9(18)3-6/h1-5,16-19,21H REFJWTPEDVJJIY-UHFFFAOYSA-N C1=CC(=C(C=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O)O)O 117-39-5 204-187-1 2811 9IKM0I5T1E 1. 3,3',4',5,7-pentahydroxyflavone 2. dikvertin 3. quercetin Sophoretin; Xanthaurine; Meletin 302.2357 g/mol C15H10O7 PROPERTIES Yellow needles or yellow powder. Converts to anhydrous form at 203-207 °F. Alcoholic solutions taste very bitter. 1.799 g/cm3 Yellow needles (dilute alcohol, + 2 water) Sublimes 316.5 °C In water: 60 mg/mL at 16 °C; < 1mg/mL at 70 °F Very soluble in ether, methanol; soluble in ethanol, acetone, pyridine, acetic acid. 2.81x10-14 mm Hg at 25 °C When heated to decomposition it emits acrid smoke and irritating fumes.
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InChl
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Table 2. Quercetin identifiers and properties1
Vapor Pressure Decomposition Dissociation Constants (in phenol) Spectral Properties
pKa1 = 7.17; pKa2 = 8.26; pKa3 = 10.13; pKa4 = 12.30; pKa5 = 13.11 Max Absorption: 256 nm (log E= 4.32); 301 nm (log E= 3.89); 373 nm (log E= 4.32); Sadler Ref. Number: 594 (IR, PRISM)
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: Adapted from U.S. National Library of Medicine [206].
Chemically speaking quercetin belongs to the class of flavonoids (from flavus which means yellow, their common color), natural products derived from 2-phenylchromen-4-one (flavone) (Fig. 2).
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Figure 2. The chemical structure of 2-phenylchromen-4-one.
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However, further derivations encompass the reduction of the 2(3) carbon-carbon double bond (flavanones)
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(Fig. 3), the reduction of the keto group (flavanols), and the hydroxylation at diversified positions. (Fig. 4).
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Figure 3. The chemical structure of major flavanones.
Figure 4. The chemical structure of major flavanols.
Anyway, and more precisely, quercetin is a representative of the flavonols family (Fig. 5) that is compounds that have the 3-hydroxyflavone backbone. Flavonols (with an "o") (Fig. 5) are not to be misled with flavanols (with an "a"), another subclass of flavonoids containing the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton (Fig. 4).
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Figure 5. Molecules belonging to the flavonols’ family and their chemical structures.
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Interestingly, flavonoids were formerly referred to as Vitamin P, presumably due to the effect they had on the
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permeability of vascular capillaries, but this term is rarely used now [19].
2.2. Antioxidative properties of quercetin
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Quercetin is considered to be a strong antioxidant due to its ability to scavenge free radicals and bind transition
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metal ions [20]. Its antioxidative capacities are primarily ascribed to the presence of two antioxidant pharmacophores within the molecule that have the optimal configuration for free radical scavenging, i.e. the catechol group in the B ring
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and the OH group at position 3 of the A ring [21] (Fig. 1). As accounted by some research teams, within the flavonoid family, quercetin is the most potent scavenger of ROS, including O2 (- [22-25] and ONOO− [26, 27]. These properties make quercetin a good lipid peroxidation inhibitor [28, 29]; this type of peroxidation can create deleterious effects
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throughout the body, such as cardiovascular and neurodegenerative diseases; however, lipid peroxidation can be terminated by antioxidants, like quercetin, which interfere by reacting with the radicals formed [28, 30, 31]. In addition, quercetin does not only stop the propagation of lipid peroxidation, but also increases glutathione levels [32] contributing in preventing free radicals formation [31]. In this context, the oxidation of lipid biomolecules such as lowdensity lipoproteins (LDL) can give rise to the formation of atherosclerotic plaques responsible of cardiovascular diseases [28]; moreover, brain lipid membranes damages due to lipid peroxidation are thought to lead to neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease [31]. By scavenging free radicals quercetin can also reduce inflammation [33]. Interestingly, by preventing Ca2+dependent cell death quercetin can protect cells suffering oxidative stress [28]. Furthermore, quercetin can also protect against smoking that is the more obvious environmental cause of free radicals. In fact, Begum and Terao [34] found that the quercetin aglycone and its conjugate metabolites (i.e. quercetin-3-O-β-glucuronide and quercetin-3-O- β -glucoside) could protect erythrocytes from the damage caused by smoking. Moreover, as reported in a study of 40 athletes [35], quercetin could prevent the increased oxidative stress induced by exercise.
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ACCEPTED MANUSCRIPT Additionally, whereas the contribution of both vitamin C and uric acid virtually equals that of trolox (6hydroxy-2, 5,7,8-tetramethylchroman-2-carboxylic acid) quercetin is suggested to substantially empower the endogenous antioxidant shield due to its contribution to the total plasma antioxidant capacity (6.24 times higher than the reference antioxidant trolox) [36]. The antioxidative properties of quercetin were also investigated against sodium
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fluoride induced oxidative stress in rats. In particular, pretreatment with quercetin (as well as with vitamin C) before NaF administration prevented either liver and renal injury and led to a significant revival of the oxidative status, thus
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the antioxidant activity of quercetin played an important protective role in the liver and kidneys of rats, respectively [37, 38]. In a similar study, investigating upon the cardioprotective properties of quercetin, authors found that although NaF intoxication significantly altered all the indices related to the pro-oxidant-antioxidant status of the heart, quercetin
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treatment prior to NaF administration prevented these alterations, probably via antioxidant quercetin’s properties [39]. Anyway, like many antioxidant compounds, quercetin might show pro-oxidant activity, at least under some
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circumstances. This happens because quercetin-quinone (QQ), the main oxidation product of quercetin, strongly react with thiols causing the loss of the protein function. Such QQ-induced toxicity has been demonstrated in various in
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vitro studies and has recently been defined as the quercetin paradox, i.e. while offering protection by scavenging ROS
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quercetin is converted into a potential toxic product [40]. Moreover, QQ is so very reactive that it instantaneously forms an adduct with glutathione, the most abundant endogenous thiol [8, 9]. However, although based on the Ames
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test [41] quercetin has to be considered a mutagenic compound, in 1999 the International Agency for Research on Cancer (IARC) concluded that quercetin should not be classified as carcinogenic to humans [42, 43]. Among other interesting features, quercetin is an excellent free radical scavenging antioxidant [8] and as such
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could form products that usually have got over some of the responsiveness of the radical that has been scavenged [44]. This antioxidant activity recognized for flavonoids such as quercetin has often been associated with the reduced risk of oxidative-stress related chronic diseases such as diabetes, coronary heart disease and stroke [45, 46]. In this regard, catechol products containing antioxidants such as quercetin react with thiols impairing - in isolated membranes and blood plasma - several enzymes [47, 48]. In any event, in relation to the protective power of the flavonoid itself, the potential toxicity of quercetin metabolites formed during the shelter offered by quercetin has not been measured in intact cells before. However, Mendoza and Burd [49] explored the fine structure and mechanical properties of quercetin as they pertain to its ability to work as a chemopreventative compound.
3. DIETARY SOURCES The edible portions of many food plants, leafy vegetables, tubers and bulbs, various fruits, herbs and spices, as well as tea and wine contain flavonols mainly in the form of glycosides [50]. Amongst flavonols molecules quercetin is the most abundant (see Table 3 for selected foods containing quercetin), anyway the majority of the dietary intake of
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ACCEPTED MANUSCRIPT quercetin-type flavonols consists of quercetin glycosides a kind of conjugates in which quercetin is linked either with one or two glucose residues (quercetin glucosides) or with rutinose (quercetin rutinoside) (Fig. 6); thus fewer amounts of (aglycones) quercetin are found in the common diet. Fascinatingly, the amount of quercetin in food might significantly be influenced by growing conditions, e.g., organically grown tomatoes show a higher quercetin aglycone
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content than conventionally cultivated tomatoes [51]. In any case, vegetables and fruits, particularly onions, peppers cranberries, blueberries, apples, cherries and grapes which contain the flavonol at levels as high as about 350 ppm
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(expressed as the aglycones) are the primary sources of naturally-occurring dietary quercetin of the typical Western diet [52, 53]. Brewed black tea, as well as red table wine and various fruit juices, also were identified as dietary sources abundant of quercetin [54, 55].
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In addition, although occurring relatively rarely in nature, first identified in Ageratina calophylla [56], Cglycosides are another type of quercetin derivatives where the most frequent site of the C-glycosylation is the C-6
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carbon. One more very rare quercetin derivative, such as quercetin 3-O-α-L-fucopyranoside, was found both in the red alga Acanthophora spicifera [57] and in the Vitis vinifera [58]; in this case quercetin is attached to a α-L-fucopyranosyl
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moiety at position C-3 via a glycosidic linkage. Anyway, for these very rare quercetin derivatives, no clinical studies are
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Table 3. Quercetin content of selected foods1
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Capers, raw Peppers, hot, yellow, raw Onions, red, raw Asparagus, cooked Cranberries, raw Peppers, hot, green, raw Lingonberries, raw Blueberries, raw Lettuce, red leaf, raw Onions, white, raw Tomato, canned Apples, Red delicious, with skin Apples, Gala, with skin Apples, Golden delicious, with skin Broccoli, raw Tea, green, brewed Cherries, sweet, raw Tea, black, brewed Grapes, black Grapes, white Wine, red, table Wine, white, table
Quercetin amount (mg/100 g) edible portion 233.84 50.73 39.21 15.16 14.84 14.70 13.30 7.67 7.61 6.17 4.12 3.86 3.80 3.69 3.26 2.49 2.29 2.19 2.08 1.12 1.04 0.04
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: Adapted from USDA Database for the Flavonoid Content of Selected Foods [207].
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Figure 6. a): quercetin-3-glucoside (isoquercetin); b): quercetin-3,4’-diglucoside; c): quercetin-3-rutinoside (rutin; sophorin).
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In the United States, from a normal mixed diet the average daily intake of all flavonoids (i.e. flavanones, flavones, flavonols, anthocyanins, catechins, and biflavans) is calculated to be about 1 g/day [expressed as quercitrin equivalents, considering that one biflavan molecule equals to 2 molecules of quercitrin], of which, depending on
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seasonal changes, 160-175 mg/day is accounted only for flavanones, flavones, and flavonols [50, 59]. However,
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expressed as quercetin equivalents, it is estimated that flavonol glycosides are consumed at levels of up to about 100 mg/day [50, 55, 60, 61]. On the other hand, the national dietary record-based cohort assessments (i.e. from Australia,
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Croatia, Finland, Italy, Japan, the Netherlands, and the United States) of the intake of quercetin from the customary diet indicated mean consumption levels in the range < 5 mg to about 40 mg quercetin/day [61-66]; however, daily amounts
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of quercetin as high as 200-500 mg may be reached by high-end consumers of fruits and vegetables, notably in cases where the individuals ingest the peel portion of quercetin-rich fruits and vegetables, such as tomatoes, apples, and onions [60].
4. QUERCETIN BIOAVAIABILITY Bioavailability is defined as a ratio between the amount of an orally administered substance and the amount which is absorbed and then available for physiologic activity or storage [67]. Founded on its pharmacokinetics assessment bioavailability could be sorted out as absolute or relative [68]. Absolute bioavailability is more accurate, whereas relative bioavailability is simpler, but less accurate [53]. As already reported [69] the factors that most influence quercetin absorption are the “nature of the attached sugar, and secondly, the solubility as modified by ethanol, fat, and emulsifiers”. The earliest human quercetin research suggested very poor oral bioavailability after a single oral dose (~2%) [70]; subsequently, the absolute bioavailability of quercetin in humans was estimated at 44.8% when radiolabeled quercetin aglycone solubilized in ethanol was administered prior to measuring the total radioactivity of
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ACCEPTED MANUSCRIPT plasma [71]. Moreover, to produce an adequate plasma response, > 50 mg quercetin aglycone or quercetin aglycone equivalents are usually provided, which is higher than typical dietary intakes (i.e., 6-18 mg/day) [1, 55, 72]. However, in view of the potential clinical use of the molecule, quercetin half-life and tissue distribution provide useful information. Being the half-life of the atom and its metabolites in the range of 11-28 h, this indicates a likely significant
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increased plasma concentration consequent to continuous supplementation [73, 74]. Nonetheless, until nowadays researches conducted upon animal and human beings have enlightened an extensive understanding about quercetin
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bioavailability.
5. QUERCETIN METABOLISM
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5.1. Quercetin metabolism in vivo overview
As stated above quercetin as such is usually found linked to a sugar moiety giving rise β-glycosides derivatives
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which, once ingested, undergo hydrolysis by the glycosidase activity of intestinal bacteria releasing quercetin (the aglycone form) and the sugar moiety [75]. However, it was recently demonstrated that the predominant quercetin
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conjugates in human plasma, in which the quercetin as such could not be detected, are quercetin 3-O-β-D-glucuronide
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(Q3GA) and quercetin-3′-sulfate [76-78]. Upon ingestion, quercetin glycosides are rapidly hydrolyzed during the transit through the small intestine or by bacterial activity in the colon to generate quercetin aglycone, which is further
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metabolized in the so-called phase II reactions into the glucuronidated and/or sulfated derivatives (Fig. 7).
Figure 7. a): quercetin 3-O-β-D-glucuronide (Q3GA); b): quercetin-3′-sulfate.
Studies using rodents have also demonstrated that orally administered quercetin is converted to its conjugates before accumulation in plasma [79, 80]. In addition, it was reported and clarified that conjugated metabolites of quercetin accumulate in human plasma in the concentration range of 10–7-10–6 M after the periodic ingestion of onions with meals for 1 week [77]. Thus, the pharmacological role of dietary quercetin, including its antioxidant action, should be reached solely by its conjugated metabolites. In any case, most of the in vitro pharmacological studies have been done by utilizing only the quercetin aglycone form.
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ACCEPTED MANUSCRIPT 5.2. Quercetin metabolism Quercetin metabolism is complex and involves intestinal uptake and/or deglycosylation, glucuronidation, sulfation, methylation, possible deglucuronidation and ring fission [81]. Various quercetin metabolites are generated
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following its biotransformation; in particular, as above described, it has been recently demonstrated that quercetin 3-O-
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β-D-glucuronide (Q3GA) and quercetin-3′-sulfate are the predominant quercetin conjugates in human plasma [76-78].
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In any case, factors regulating absorption, metabolism and elimination are important mediators of its bioavailability. Typically, the human quercetin plasma concentration is in the order of nanomolar, but upon quercetin supplementation it may increase in between the high nanomolar and the low micromolar range [82, 83]. Generally,
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depending on eating habits, average daily intake of quercetin could vary between 10 and 100 mg although high concentrations (>170 mg per 100 g) of quercetin are particularly found in capers and lovage leaves (Table 3; [207]).
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Nevertheless, an ingested amount of 500-1000 mg per day can be easily achieved using selected nutraceuticals with
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highly purified quercetin extracts [84].
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5.3. Quercetin absorption
The site and the manner in which quercetin is absorbed depends upon its chemical structure. Studies using rat
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models indicate that quercetin aglycone absorption occurs either in the stomach and at the small intestine level [85, 86]. Although the mechanisms explaining gastric absorption of quercetin aglycone remain unclear, in vitro studies support that human intestinal absorption of quercetin aglycone occurs primarily by passive diffusion and secondarily by organic
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anion transporting polypeptide (OATP) [87]. By contrast, quercetin aglycone and glycosylated forms of quercetin (quercetin glucoside, quercetin rutinoside) are not absorbed in the stomach [85]. However, prior to absorption at the small intestine, specifically quercetin glycosides (i.e. quercetin glucosides, quercetin galactoside, quercetin arabinoside) are deglycosylated to quercetin aglycone [88] by the lactase phlorizin hydrolase (LPH), a β-glucosidase residing in the brush border [89]. Thus, only the quercetin aglycone is subsequently passively absorbed [90]. Fascinatingly, quercetin rutinoside is absorbed in the colon following deglycosylation [91] which seems to be mediated by gut microbiota-derived β-glucosidase [92] that generates quercetin aglycone facilitating its colonic absorption [60]. In this regard, a study in an in vitro model showed that 60% of quercetin rutinoside were degraded to 3,4dihydroxyphenylacetic acid within 2 h by the colonic microbiota [93], suggesting that most quercetin rutinoside is initially deglycosylated to quercetin aglycone prior to degradation to 3,4-dihydroxyphenylacetic acid. Anyway, further studies are required to better determine the possible health benefits of quercetin metabolites [74] and than the influence of gut microbiota composition on their formation.
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ACCEPTED MANUSCRIPT 5.4. Quercetin biotransformation Being a xenobiotic quercetin biotransformation occurs through the classical xenobiotic metabolism pathway [94]. In general, xenobiotic metabolism consists of three phases: phase I modification, phase II conjugation and phase
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III elimination [95]. Phase I metabolism of quercetin has not been described, but it is said to be structurally similar to the flavone apigenin [96]. Phase II conjugation of quercetin at the small intestine involves glucuronidation, sulfation
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and methylation, as evidenced by the appearance of glucuronidated, sulfated and methylated metabolites of quercetin following incubation of quercetin aglycone with human small intestinal microsomes [97]. Therefore, numerous phase II metabolites arise from quercetin including quercetin monoglucuronide, quercetin diglucuronide, quercetin sulfate,
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quercetin monoglucuronide sulfate and methylated quercetin monoglucuronide sulphate [14, 98]. Other metabolites include isorhamnetin and tamarixetin which are methylated forms of quercetin. Phase II metabolites of quercetin are
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secreted into the portal and lymph circulation, with evidence that most quercetin in the portal vein plasma or lymph appears as conjugated quercetin being quercetin aglycone below the detection limit [88, 99]. Phase III efflux of phase
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II metabolites of quercetin also occurs in the small intestine. Studies in a rat model showed that glucuronides and
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sulfates of quercetin, isorhamnetin and tamarixetin appear in the effluent collected from the intestinal lumen [86]. Intestinal efflux of quercetin metabolites is likely mediated through breast cancer resistance protein 1 (BCRP1) and
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multidrug resistance associated-protein 2 (MRP2), the phase III transporters occur on the apical side of enterocytes [100, 101]. On the other hand, phase II metabolites of quercetin secreted from the small intestine reach the liver via the portal vein [88]. Hepatocyte uptake of quercetin metabolites involves passive diffusion as well as organic anion
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transporters (OAT) and/or anion transporting polypeptide (OATP)-mediated transport [102]. Following hepatic uptake, quercetin metabolites are further metabolized by phase II conjugating enzymes. However, quercetin metabolites formed in the liver either enter the circulation or are directed to biliary excretion [88], with the latter likely occurring in a MRP2-dependent manner [103]. Additionally, renal phase II metabolism of quercetin may also take place, but no reports currently exist to directly support renal phase II metabolism of quercetin.
5.5. Degradation and disposition of quercetin Ingested quercetin is rapidly eliminated via feces and urine [104]. The profile of metabolites excreted via feces and urine, while also comprised of glucuronide and sulfate conjugates, appears to differ significantly from those found in the plasma. However, many of the major urinary components, including quercetin-3’-glucuronide, two quercetin glucoside sulphates, and a methylquercetin diglucuronide, are either absent or present only in trace amounts in the bloodstream, for that after they arrive in the blood quercetin metabolites probably undergo a further phase II metabolism [105, 106]. The fecal recovery appears to be in the range of 1.6-4.6 percent of an oral dose. In one study,
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ACCEPTED MANUSCRIPT the majority of the quercetin that was unaccounted for in urinary and fecal excretion was recovered as exhaled carbon dioxide (CO2), suggesting that a high amount of absorbed quercetin is extensively metabolized and eventually eliminated by the lungs [71]. However, and in particular, most quercetin-derived metabolites are identified as 3hydroxyphenylacetic acid, benzoic acid and hippuric acid [104], suggesting that phase II metabolites of quercetin are
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deconjugated to quercetin aglycone prior to ring fission to yield phenolic acids. The mechanism by which conjugated metabolites of quercetin are degraded in vivo is not well defined, but it should be considered that both the colonic
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microflora and kidneys express β-glucuronidase activity [93, 107], supporting deglucuronidation of quercetin glucuronides prior to degradation of quercetin aglycone to phenolic acids, and their subsequent elimination.
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6. THERAPEUTIC APPLICATIONS OF QUERCETIN 6.1. Clinical trials
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Since the first Phase I clinical trial in which, following a tyrosine kinase inhibition, an evidence of antitumor activity was seen [108], several very recent randomized, double-blind, placebo-controlled, crossover trials have been
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performed with quercetin demonstrating that: a) quercetin supplementation reduced systolic blood pressure
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significantly but had no effect on other cardiovascular risk factors and inflammatory biomarker [109]; b) quercetin (3glucoside) supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors [110];
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c) quercetin may contribute to the cardioprotective effects of tea possibly by improving endothelial function and reducing inflammation [111]; d) no significant therapeutic effect can be considered for quercetin in treatment of oral Lichen planus [112].
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Nevertheless, in addition to the above mentioned clinical trials, quercetin as such or as a derivative has been tried and applied for many different specific multifaceted therapeutic applications of which the most prominent will now be reported.
6.2. Aging The biological processes responsible of ageing can be positively counteracted by few environmental factors, such as natural antioxidants. In this context vitamin E [113], kinetin [114], carnosine [115] and garlic [116] are only few examples of natural sources that have been shown to exert a noticeable pro-longevity effect on human primary cultures. Passed on the antioxidant properties of quercetin and the association between ageing and oxidative stress [117], Chondrogianni et al. [118] investigating the role of quercetin established a positive influence on survival, viability, and lifespan of primary human fibroblasts (HFL-1); moreover, when senescent fibroblasts were grown in the presence of quercetin, a rejuvenating effect was observed.
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ACCEPTED MANUSCRIPT Attractively, other authors [119] report that quercetin, considered a senolytic agent, is positively effective also against senescent human endothelial cells likely showing a special promise in eliminating senescent cells as already reported [120, 121].
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6.3. Allergy
Like histamine and most cyclin-dependent kinases quercetin inhibits the in vitro growth of certain malignant
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cells and also displays unique anti-cancer properties, moreover quercetin is a natural compound that blocks substances involved in allergies and is able to act as an inhibitor of mast cell secretion, causing a decrease in the release of tryptase, MCP-1 and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from few mast cell lines [122].
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As other flavonoids polyphenolic compounds that exert many anti-inflammatory and anti-microbial effects, and exhibit an anti-allergic action, quercetin has been recently shown as a potential drug against allergy; thus, quercetin
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appears to possess the same potential of Food Allergy Herbal Formula (FAHF) as a safe anti-allergic substance but it opens only a wide perspective, at the moment, due to several complex issues that hamper the possibility to use natural
6.4. Angioprotective Properties
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medicine and phytochemicals as a true drug [123].
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Considerable attention has been directed to quercetin also as a promising compound to be dispensed for heart disease, prevention, and therapy; in fact, it has been linked to decreased mortality from heart disease and decreased incidence of stroke. In this regard, Pashevin et al. [124] report new data from which the angioprotective properties of
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quercetin seem to be mediated by its effects on proteasomal proteolysis. In particular, by using rabbits with cholesterolinduced atherosclerosis the study investigated the ability of quercetin to modulate proteasomal activity. First, following an 8 week cholesterol-rich diet, results indicated that the proteasomal trypsin-like (TL) activity increased up to 2.4-fold, whereas chymotrypsin-like (CTL) activity and peptidyl-glutamyl peptide-hydrolyzing (PGPH) activity increased by 43% and up to 10%, respectively. A remarkable decrease of proteasomal TL activity (1.85-fold in monocytes), and a decrease of both the CTL and PGPH activities (more than 2-fold in polymorphonuclear leukocytes) were observed after 2 h following a single intravenous injection of the water-soluble form of quercetin (Corvitin). Furthermore, after a cholesterol-rich diet the prolonged administration (1 month) of Corvitin significantly decreased all types of proteolytic proteasome activities both in tissues and in circulating leukocytes, additionally a reduction of atherosclerotic lesions in the aorta was detected. Unfortunately, besides their antioxidant effect, flavonols like quercetin interfere with a great bit of biochemical signaling pathways and therefore with many physio- pathological processes. However, there are strong evidences that quercetin as well as related flavonols exert in vitro protective effects on nitric oxide and endothelial function under
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ACCEPTED MANUSCRIPT oxidative stress, endothelium-independent vasodilator and platelet anti-aggregant effects, inhibition of LDL oxidation, reduction of adhesion molecules and other inflammatory markers, prevention of neuronal oxidative and inflammatory damage [125]. Nevertheless, all these effects could be primarily due to quercetin metabolites which in general protect the endothelium from LDL oxidation.
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Furthermore, as meta-analysis studies of epidemiological studies report, quercetin produces undisputed antihypertensive and anti-atherogenic effects, preventing endothelial dysfunction and protecting the myocardium from
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ischemic damage [125]. Quercetin had no clear effects on serum lipid profile and on insulin resistance, but although there is no solid proof yet a substantial body of evidence suggests that quercetin may prevent the most common forms of cardiovascular disease contributing to the protective effects afforded by fruits and vegetables. Worthwhile, recent
in blood pressure after quercetin supplementation [126].
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work using hypertensive animals and humans (> 140 mm Hg systolic and > 90 mm Hg diastolic) indicates a reduction
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Noteworthy, two very recent studies demonstrate further evidence backing up the point of view that quercetin should be regarded a possible healing agent against cardiovascular diseases [127, 128]. In particular, Hung et al. [128]
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findings provide new insight regarding the possible molecular mechanisms of quercetin; in fact quercetin seems to
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suppress oxLDL-induced endothelial oxidative injuries by activating SIRT1 and by modulating the AMPK/NADPH
6.5. Anti-Cancer
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oxidase/AKT/eNOS signaling pathway.
As found for many other flavonoids, a number of reports have assessed the pro-apoptotic activity of quercetin
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in cancer cells; in fact, quercetin is a forthright inhibitor of PI3K, NF-B, and other kinases involved in intracellular signaling [129]. Nevertheless, although mitochondria seem to be targeted by quercetin inducing apoptosis and the cancer cell death in vitro [130] until nowadays a reliable quercetin intracellular target has not yet been found; of course, the challenge is to identify an eligible target in order to better define possible natural compounds to be added in food extracts or pharmaceuticals. Certainly, the antioxidative effects as well as the kinase and cell cycle inhibition, and the induced apoptosis are all essential for the anti-cancer properties shown by quercetin. In particular, the different interactions and activities of quercetin that fine tunes the phosphorylation state of molecules as well as the gene expression would act upon the intracellular signaling equilibrium, either inhibiting or reinforcing survival signals. Anyhow, these mechanisms, which have been mainly observed in in vitro studies, cannot easily explain the anti-cancer effects observed in vivo because of the relatively low quercetin bioavailability in plasma and also because the nature of the actual active molecules is not clearly known [131]. Thus, to partly explain the molecular effect of quercetin on cancer cells, among the different
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ACCEPTED MANUSCRIPT substrates suspected to be triggered by quercetin a study reports the capability of quercetin to inhibit some protein kinases involved in deregulating the cell growth in cancer cells [132]. Furthermore, quercetin can exert its anti-cancer effect also inhibiting the mTOR activity by multiple pathways [133]. On the other hand, in ascite cells of lymphoma-bearing mice, it is suggested that the cancer preventive activity of
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quercetin is accomplished via the induction of apoptosis and modulation of the PKC signaling which brings to the reduction of oxidative stress [134].
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It has been proven that the most effective quercetin action is on blood, brain, lung, uterine, and salivary gland cancer as good as upon melanoma with a cytotoxic activity much higher in the more aggressive cells than in the slow
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growing cells suggesting that the most harmful cells are the ones mainly targeted [135].
6.6. Anti-Inflammatory
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What is nowadays known is that quercetin inhibits the in vitro production of enzymes usually induced by inflammation (i.e. cyclooxygenase [COX] and lipoxygenase [LOX]) [136, 137]; however, also in vivo experiments
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substantiate the anti-inflammatory effect. In particular, as already reported [138] quercetin significantly inhibits pro-
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inflammatory cytokines in cultured fibroblasts from Graves' orbitopathy (GO). This study investigated the inhibitory effect of quercetin on inflammation in cultured whole orbital tissue. Therefore, inhibition of pro-inflammatory
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cytokines by the natural product quercetin in both primary orbital fibroblasts and tissue culture could provide the foundation for its potential use as an anti-inflammatory agent in the treatment of GO. However, the mechanisms behind the anti-inflammatory properties of quercetin are poorly understood.
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Certainly, in inflammation, nitric oxide (NO) acts as a pro-inflammatory mediator and is synthesized by the inducible nitric oxide synthase (iNOS) in response to pro-inflammatory compounds such as lipopolysaccharide (LPS). As described elsewhere [139] pretreatment of H9c2 cardiomyoblasts with quercetin inhibited LPS-induced iNOS expression and NO production and counteracted oxidative stress induced by the unregulated NO production that normally contributes to the generation of peroxynitrite and other reactive nitrogen species. In addition, quercetin pretreatment remarkably counteracted apoptosis cell death as measured by immunoblotting of the cleaved caspase 3 and caspase 3 activity. Besides the induction of apoptosis, quercetin inhibited the phosphorylation (LPS-induced) of two kinases such as the stress-activated protein kinases (JNK/SAPK) and the p38 MAP kinase, enzymes that are involved in the inhibition of cell growth. In closing, these outcomes indicate that quercetin might serve as a valuable protective agent at least in cardiovascular inflammatory diseases. Interestingly, since at nanomolar doses quercetin has shown a biphasic behavior in basophils a beneficial action on cells involved in allergic inflammation could be hypothesized [140].
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ACCEPTED MANUSCRIPT 6.7. Anti-Obesity As aforementioned quercetin is the most abundant flavonoid and it is thought to have protective functions against the pathogenesis of multiple diseases associated with oxidative stress. In this setting, a peculiar study upon 3T3L1 cells investigated the molecular mechanisms through which quercetin could influence adipogenesis and apoptosis
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[141]. The exposure of 3T3-L1 preadipocytes to quercetin resulted in decreased expression of adipogenesis-related factors and enzymes and then attenuated adipogenesis. Moreover, the levels of phosphorylated adenosine
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monophosphate-activated protein kinase (AMPK) and one of its substrates, namely acetyl-CoA carboxylase (ACC), were up-regulated in the presence of quercetin; in the same time apoptosis was induced and a concomitant decrease in ERK and JNK phosphorylation was observed. Put together, these data indicate that quercetin could exert its anti-
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adipogenesis activity by activating the AMPK signal pathway, whereas the quercetin-induced apoptosis of mature adipocytes seems to be mediated by the fine tuning of the ERK and JNK pathways which play crucial roles during
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apoptosis.
On the other hand, to ascertain the molecular mechanisms influenced by quercetin on the physiological effects
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of hyperlipidemia, some authors found that quercetin regulates the hepatic gene expression related to lipid metabolism
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[142]. In particular, quercetin supplementation in mice significantly diminished the high-fat diet (HFD) -induced obesity, reducing the weight of the body, liver, and white adipose tissue compared with the mice fed only with HFD. It
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also deeply reduced the HFD-induced increments in serum lipids, including cholesterol, triglyceride, and thiobarbituric acid-reactive substance (TBARS). Consistent with the reduced liver weight and white adipose tissue weight, hepatic lipid accumulation and the size of lipid droplets, pads in the epididymal fat were also reduced by quercetin
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supplementation. To further investigate how quercetin might reduce obesity, lipid metabolism-related genes in the liver were also examined. In this case, relative to those in HFD control mice, the quercetin supplementation modified the expression profiles of several lipid metabolism-related genes, including Fnta, Pon1, Pparg, Aldh1b1, Apoa4, Abcg5, Gpam, Acaca, Cd36, Fdft1, and Fasn, The expression patterns of these genes observed by quantitative reverse transcriptase-polymerase chain reaction were confirmed by immunoblot assays. Jointly, these results indicated that quercetin prevents HFD-induced obesity in C57B1/6 mice, and its anti-obesity effects may be linked to the regulation of lipogenesis at the level of transcription. More lately, several valuable reviews have been published on the role of dietary phytochemicals in obesity, quercetin included [143, 144]. Nevertheless, it is necessary to establish a clean differentiation between the anti-obesity effects of quercetin when it is meted out as pure aglycone, from its putative functions, and when it is present in polyphenolic extracts, as described in many works cited in the above mentioned last two reviews [143, 144].
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ACCEPTED MANUSCRIPT 6.8. Arthritis In combination with other nutrients, quercetin might reduce symptoms of osteoarthritis (OA), but at the same time it does not appear to be beneficial in rheumatoid arthritis (RA). In fact, as a study report [145], twenty patients with rheumatoid arthritis daily received three capsules of quercetin (166 mg/capsule) plus vitamin C (133 mg/capsule),
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-lipoic acid (300 mg/capsule), or placebo for four weeks allowing a two-week washout period before the next supplementation. After this period the serum concentrations of pro-inflammatory cytokines or C-reactive protein (CRP)
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did not show considerable differences and disease scores severity did not differ among treatment periods. When glucosamine, chondroitin, and quercetin glucoside were given for three months to 46 persons with OA and 22 persons with RA, appreciable ameliorations in daily activities (walking and climbing up and down stairs), pain symptoms,
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visual analogue scale, and synovial fluid properties were observed in OA subjects; conversely, no beneficial effects
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were noticed in RA subjects [146].
6.9. Asthma
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Point of interest, human epidemiological researches indicate an inverse association between intakes of
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quercetin and asthma incidence [147]. Nevertheless, although human intervention studies investigating the effect of quercetin upon asthma and other atopic disease are currently missing, two written reports have looked into the effects
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of an enzymatically-modified isoquercitrin (a quercetin glycoside) on allergic symptoms [148, 149]. In this case, starting four weeks prior to the onset of pollen release, subjects took 100-200 mg/day of isoquercitrin or a placebo for eight weeks. Results proved that this specific quercetin glycoside enzymatically-modified provided a statistically
6.10. Diabetes
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relevant relief of ocular symptoms, but no statistically significant relief of nasal symptoms caused by pollen.
Quite recently, in an animal model with type 2 diabetes mellitus the hypoglycemic, hypolipidemic, and antioxidant effects of dietary quercetin have been investigated. In this study [150] to C57BL/KsJ-db/db mice (n = 18) were offered an AIN-93G diet or a diet containing quercetin at 0.04% (low quercetin, LQE) or 0.08% of the diet (high quercetin, HQE) for 6 weeks after 1 week of adaptation. Plasma glucose, insulin, adiponectin, lipid profiles, and lipid peroxidation of the liver were determined. At the end of the experiment, glucose plasma levels were markedly lower in the LQE group than in the control group, and those in the HQE group were even further reduced than the LQE group. Lower values were found for both LQE and HQE groups than in the control group with no changes in insulin levels by considering the homeostasis model assessment of insulin resistance (HOMA-IR). Furthermore, compared with the control group, 0.08% of dispensed quercetin increased plasma adiponectin, decreased plasma total cholesterol and increased HDL-cholesterol. Nevertheless, plasma triacylglycerols in both the LQE and HQE groups were lower than
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ACCEPTED MANUSCRIPT those in the control group. Moreover, either low and high quercetin reduced thiobarbituric acid reactive substances (TBARS) levels incremented the activity of specific liver enzymes deeply involved in detoxification processes from ROS (reactive oxygen species) i.e. superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Thus, quercetin could be efficient in improving hyperglycemia, dyslipidemia, and the antioxidant status in type 2
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diabetes.
On the other hand, one of the primary causes of end-stage renal disease is diabetic nephropathy (DN). Many
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studies have pointed out that the transforming growth factor-β1 (TGF-β1) and the connective tissue growth factor (CTGF) are both involved in the DN pathophysiological mechanisms. Since quercetin has been proposed to alleviate DN, researchers have investigated whether quercetin ameliorates the renal function likely affecting the expressions of
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TGF-β1 and CTGF in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats [151]. Rats were then subdivided in control group, diabetic group and quercetin therapy group. At the end of the 12th week, body weight, kidney
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weight/body weight ratio, blood glucose, urine albumin excretion (UAE), serum creatinine (sCr), blood urea nitrogen (BUN), and creatinine clearance (Ccr) were measured. The expressions of TGF-β1 and CTGF in the kidneys were
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determined by using real-time PCR and Western blot method. The study reports that diabetic rats showed conspicuous
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increases in kidney weight/body weight ratio, blood glucose, UAE, sCr, BUN, and Ccr; whereas quercetin treatment improved these parameters except for blood glucose. The expressions of TGF-β1 and CTGF were higher in the diabetic
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group than in the control group. However, the overexpression of both TGF-β1 and CTGF in the renal tissues of diabetic rats were reduced following quercetin administration. These results clearly suggest that quercetin improved renal function in DN rats by inhibiting the overexpressions of TGF-β1 and CTGF in the kidney.
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Moreover, aldose reductase, the enzyme that catalyzes the conversion of glucose to sorbitol, is particularly important in the eye and plays an essential role in the formation of diabetic cataracts. Thus, it has been demonstrated that quercetin is an in vitro inhibitor of lens aldose reductase [152, 153] and effectively blocks polyol accumulation in intact rat lenses immersed in a medium with a high sugar concentration [154]. In humans with diabetes type 1 or 2 and diabetic neuropathy, a decrease in the severity of numbness, jolting pain, and irritation was reported, as well as an improvement in quality-of-life measures with active treatment [155]. However, from the molecular basis point of view, it is reported that the antidiabetic action of quercetin is fulfilled by stimulating glucose uptake through an insulin-independent mechanism involving adenosine monophosphate-activated protein kinase (AMPK) whose activation in skeletal muscle leads to the glucose transporter GLUT4 translocation to the plasma membrane; whereas, in liver, AMPK decreases glucose production mainly through the downregulation of the key gluconeogenesis enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose -6-phosphatase (G6Pase) [156].
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ACCEPTED MANUSCRIPT 6.11. Exercise Performance Besides studies that have investigated whether quercetin supplementation can prevent post-exercise immune system changes and sensitivity to infections (discussed in the subsection below on “Immunity and Infections”), other studies have sought to determine whether quercetin shows some ergogenic potential. Existing evidence seems to
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support some ergogenic effect of quercetin in untrained people, but not in trained athletes.
In this contest, eleven studies were identified and a total of 254 human subjects were engaged [157]. Across
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all studies, before supplementation VO2max ranged from 41 to 64 mL·kg-1·min-1 (median = 46), whereas median treatment duration was 11 d with a median dosage of 1000 mg·d-1. Effect sizes (ES) were computed as the standardized mean difference, and meta-analyses were done by using a random-effects model.
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On average, quercetin provided a statistically noticeable benefit in human endurance exercise capacity (VO2max) and performance, but the effect was irrelevant or of a small magnitude, with ES = 0.15 equating roughly to a
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3% improvement with quercetin over the placebo group. Unluckily, these studies designed to examine human performance following quercetin administration did not show the same level of efficacy as formerly observed in mice.
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Experimental factors that explain the between-study variation have to be still elucidated.
6.12. Gastroprotection
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Some in vivo studies report a protective effect of quercetin against ethanol-induced gastric ulceration [158, 159] as well as against the oesophagitis reflux [160, 161]. In any case, it has been demonstrated that quercetin weakly inhibits the growth of Helicobacter pylori in vitro [162]. However, Helicobacter pylori-infected guinea pigs treated for
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15 days with 200 mg/kg of quercetin exhibited a decreased bacterial infection in the gastric mucosa and also a reduced inflammatory response [163]. Worthy of interest, topical quercetin directly spread on minor mouth aphthous ulcers three times daily relieved pain and produced a complete healing in 35% of subjects within 2-4 days, 90% of subjects within 4-7 days, and 100% of subjects within 7-10 days 193 [164]. Nevertheless, although quercetin has been found to possess gastroprotective activity, whether it has a protective activity against less related injury to gastric epithelial cells remains unknown. Anyhow, at least in human gastric epithelial GES-1cells pretreated with quercetin and then challenged with H2O2 it has been observed: a) a decrease of H2O2-induced cell viability loss; b) a reduction of intracellular reactive oxygen species and Ca 2+ influx; c) upregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) expression under the state of oxidative stress; d) a significant decline of the downstream cell apoptosis, then there is a strong evidence that quercetin can protect gastric epithelial GES-1 cells from oxidative damage and ameliorate reactive oxygen species production during acute gastric mucosal injury [165].
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ACCEPTED MANUSCRIPT 6.13. Human Prostate Adenocarcinoma Prostate cancer is a common male malignant disease and its incidence is increasing worldwide with an incidence rate of new cases around 27% occupying the first place and the mortality rate of about 10% occupying the second place only inferior to lung cancer among body sites where tumorigenesis may occur [156]. Concerning human
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prostate adenocarcinoma, some authors evaluated the effects of quercetin on PC-3 cells [157]. Lactate dehydrogenase (LDH) release, microculture tetrazolium test (MTT assay) and real-time PCR array were employed to evaluate the
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effects of quercetin on cell cytotoxicity, cell proliferation and expression of various genes. Results showed that quercetin inhibited cell proliferation and modulated the expression of factors involved in DNA repair, matrix degradation and tumor spreading, cell cycle, programmed cell death, angiogenesis, and metabolism (i.e. glycolysis). No
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cytotoxicity of quercetin on PC-3 cells was observed. These findings indicate that quercetin could be recommended as an effective anti-cancer agent to be used in the future nutritional transcriptomic studies and in multi-target therapy thus
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to overcome the current therapeutic approaches against prostate cancer.
Anyhow, previous findings demonstrated that quercetin treatment of prostate cancer cells caused a decreased
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cell proliferation and viability [168]. In particular, it was shown that quercetin induced cancer cell apoptosis by down-
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regulating the levels of heat shock protein (Hsp) 90 and this Hsp90 decrease was conceivable bound to the decreased cell viability, the apoptosis induction and the caspases activation in cancer cells but not in normal prostate epithelial
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cells. Noteworthy, as indicated by annexin V staining knockdown of Hsp90 by short interfering RNA (siRNA) originated the induction of apoptosis in a similar way like that of cancer cells quercetin-treated [168]. Another interesting study suggests that in the presence of quercetin the c-Jun protein might play an important role in the
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androgen receptor (AR) suppression; in fact, the ternary protein complex (i.e. c-Jun/Sp1/AR) induced by quercetin represents a peculiar mechanism that in prostate cancer cells could be involved in down-regulation of the AR function [169].
Remarkably, it has been lately established that the combination of quercetin and 2-methoxyestradiol can serve as a novel clinical treatment regiment owning the potential of enhancing antitumor effect on prostate cancer in vivo and lessening the dose and side effects of either quercetin or 2-methoxyestradiol [170]; these in vivo results will lay a further solid basis for subsequent researches on this novel therapeutic regimen in human prostate cancer. However, a complete list of mechanisms of the in vitro and in vivo effects of quercetin on prostate cancer is elsewhere summarized [171].
6.14. Immunity and Infections As elsewhere reported quercetin exhibits an in vitro antiviral activity against HIV as well as against other retroviruses [172, 173]; moreover, as above mentioned it also shows in vitro and in vivo antibacterial activity against
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ACCEPTED MANUSCRIPT Helicobacter pylori [162, 163]. Despite positive results obtained both in vitro and in vivo from animal studies, evidence in human beings is mixed as to whether chronic quercetin supplementation has plausible positive effects on the immune system. Usually, quercetin (100 mg/day) does not alter exercise-induced changes in several components belonging to the immune system [174] and no differences are found in the post-race illness rates between quercetin-
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treated and placebo groups [175].
In addition, the natural compounds epigallocatechin gallate (1) and quercetin (2) alone and in combination
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have been recently tested as potential antimicrobial clinical therapies [176]. In this latter study authors report a strong antimicrobial activity produced by 1 alone against methicillin-resistant Staphylococcus aureus, whereas the activity was significantly increased in the presence of 2. Furthermore, a synergistic interaction was observed between the two
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compounds with a bactericidal effect over 24 h when the two compounds were administered in combination.
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6.14. Mood Disorders
Quercetin has shown anxiolytic- and antidepressant-like effects in animal experiments; anyway, no studies
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have investigated whether quercetin has similar effects in humans. However, quercetin dose dependently increases
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social interaction time decreasing immobility time; it also minimizes changes in the animal behavior, such as the swim test or forced immobilization, tests which are planned to cause anxiety and behavioral despair [177-179]. In diabetic rats
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this effect was comparable to that of the antidepressants fluoxetine and imipramine [180]. Nonetheless, it is suggested that the antidepressant effect of quercetin is dependent on the inhibition of the NMDA receptors and/or synthesis of nitric oxide, findings that contribute to the understanding of the mechanisms involved in the antidepressant effect of
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quercetin and reinforce the involvement of the NMDA receptors and the nitric oxide on the pathophysiology of depression [181].
Quercetin also helps protect against changes in behavior caused by alcohol withdrawal [182]. Several possible mechanisms might explain the ability of quercetin to improve mood. Thus, in vitro and in vivo evidences indicate that quercetin can inhibit monoamine oxidase A [183], whereas in vivo experiments indicate that quercetin can decrease the levels of the stress-induced brain corticotrophin releasing factor (CRF) which is associate to anxiety and depression [178]. In addition, quercetin-treatment also reduces the stress-induced increases of both the plasma corticosterone and the adrenocorticotropic hormone [184]. However, some latest studies report more information about the protection of quercetin against behavioral deficiencies and memory impairment. Specifically, lead treated rats showing a marked behavioral impairment, when treated with quercetin maintain their normal behavioral functions despite the increased oxidative stress; from a molecular point of view this happens because quercetin seems to restore the normal morphology of the brain and the expressions of Bak, Bcl-2 and Hsp-70 [185]. On the other hand cadmium (Cd) exposure is recognized to cause
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ACCEPTED MANUSCRIPT impairment of memory and anxiogenic-like behavior. Thus, rats exposed to Cd (2.5mg/kg) and quercetin (5, 25 or 50mg/kg) by gavage for 45days, compared to rats exposed only to Cd (2.5mg/kg), did not show neither the reduction of total thiols, reduced glutathione , and reductase glutathione activities nor the rise of glutathione S-transferase activity, furthermore, the administration of quercetin prevented alterations in acetylcholinesterase and Na+,K+-ATPase activities,
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consequently preventing anxiogenic-like behavior and memory impairment displayed by Cd exposure [186].
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7. DRUG INTERACTION
Quercetin exhibits an in vivo inhibitory effect both on CYP3A4 [187, 188] and CYP1A2 whereas it increases CYP2A6, xanthine oxidase, and N-acetyltransferase activity [189]. Quercetin in vivo inhibits also the P-glycoprotein
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(Pgp), a drug efflux transporter that can play a pivotal role in the intestinal and biliary transport and elimination of many drugs and their metabolites [187, 188, 190, 191]. Due to these interactions, quercetin might alter the serum levels
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of all drugs metabolized by these enzymes. However, although the daily administration of rutin (quercetin rutinoside) reduces the anticoagulant effect of racemic warfarin [192], reliable interactions between quercetin as such and
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anticoagulants have not yet been investigated. Interactions between quercetin and different drugs have been however
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studied especially because of its interaction with the CYP3A4 and the P-glycoprotein. In this regard, Fig. 8 shows the severity grade of known interactions between quercetin and different drugs. In most of the interactions reported in Fig.
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8 quercetin decreases the level or the effect of the drug by P-glycoprotein (MDR1) efflux transporter; on the other hand, particularly in the case of “Minor severity”, quercetin decreases the effect(s) of the drug by pharmacodynamic antagonism. As expected, drug-nutrient interaction might also be influenced by the quercetin dose. Thus, a study carried
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out on pigs reported a lethal interaction between digoxin – a substrate of P-glycoprotein with very narrow therapeutic range – and quercetin; in fact, the co-administration of quercetin (50 mg/kg) and digoxin (0.02 mg/kg) resulted in the sudden death of two out of the three pigs within 30 minutes of administration. Surprisingly, although the co-administration with a lower dose of quercetin (40 mg/kg) powerfully elevated the Cmax (maximum concentration) of digoxin by 413% it did not have lethal effects [191]. As can be imagined quercetin might also alter the bioavailability of some dietary supplements; for example, it appears to improve the bioavailability of epigallocatechin gallate [193] and possibly other flavonoids [194]. Finally, preliminary evidence indicates that quercetin might have synergistic effects with some drugs [195] and might play a character in multi-drug resistance [196].
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Figure 8. Quercetin drug interaction severity. Adapted from [208].
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8. TOXICITY
Most in vivo animal studies certify that quercetin is not carcinogenic; anyway, based on the Ames test
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quercetin is regarded as mutagenic. Interestingly, in 1999 the International Agency for Research on Cancer (IARC)
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ascertained that quercetin should not be classified as carcinogenic to humans [42, 43, 197]. Although in vitro studies suggest that quercetin might have mild negative effects on embryo development [198], until nowadays there is no
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definitive evidence regarding some teratogenic effects of quercetin on embryonic development. Intriguingly, prenatal exposure to quercetin yielded a slight increase in the incidence of malignancies in mice offspring [199]. However, in human studies, quercetin has been mostly well tolerated. Doses up to 1,000 mg/day for several months did not produce
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adverse effects on blood parameters, liver and kidney function, hematology, or serum electrolytes. On the other hand, the results of numerous genotoxicity and mutagenicity on short- and long-term animal as well as on human subjects consistently demonstrated that the quercetin-related mutagenicity did not develop carcinogenicity in vivo; thus, in general, the plentiful available evidences support the safety of quercetin for addition to food [6]. In fact, in the U.S. and Europe supplements of quercetin are commercially purchasable subsequently the quercetin supplements beneficial effects described in clinical trials [42]. Unfortunately, depending on the dose, quercetin as such or as its analogue. quercetin-3-O-glucoside has been shown to inhibit topoisomerase II catalytic activity bringing to an extraordinarily high yields of metaphases showing diplochromosomes [200-202], for that given the established relationship of polyploidy with tumor development via aneuploidy and genetic instability, these results partly question the usefulness of quercetin. Conversely, synthetic quercetin acylglycoside analogues (i.e. 3,7-diacylquercetin, quercetin 6-acylgalactoside, and quercetin 2',6'-diacylgalactoside) have been shown to inhibit either DNA gyrase and topoisomerase IV [203].
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ACCEPTED MANUSCRIPT Anyway, from a molecular point of view toxic effects of quercetin are most likely connected with the formation of possible toxic products upon oxidation of quercetin during its ROS scavenging activities. As stated above, the most important oxidation product of quercetin that is quercetin-quinone is highly thiol reactive and reacts almost immediately with glutathione or in its absence with protein sulfhydryl groups, thereby damaging the function of several
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crucial enzymes [8, 9, 40]. Consequently, during in vivo quercetin supplementation care should be needed of the possible toxicity of its metabolites; especially in a chronic disorder, when supplementation has to extend over a much
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longer time period, the safety, tolerability and efficacy of (long term) quercetin supplementation remain to be established [73].
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CONCLUSIONS
The bioflavonoid quercetin has an extended spectrum of well characterized biological effects that include the
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promotion of health, the enhancement of physical and mental activity, and several distinct pharmacological effects. Of course, bioavailability of quercetin is an important mediator of its health benefits and, for that, a better understanding of
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the factors regulating quercetin metabolism and bioavailability is expected to confirm its potential role in managing
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different diseases.
Despite the plethora of studies on quercetin and its derivatives, it is not yet possible to establish dietary
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recommendations with regard to the types and amounts to be consumed. The inherent diversity of its derivatives analogous structure, chemistry, and natural distribution in foods lends itself to errors in reporting the types and/or amounts consumed, as well as incomplete recognition of requirements for intervention studies that aim to assess their
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benefits in a clinical setting. Thus, in the face of the scientific progress made over the past decades, several critical issues in the design and reporting of studies continue to limit progress in leveraging quercetin research findings into meaningful recommendations for consumers. These issues mainly include: 1) incomplete/inappropriate application of analytic methods, making determination of food content and dietary intake levels challenging; 2) limited data and/or description of test materials used in dietary intervention trials; 3) challenges with the application of appropriate methods for assessment of relevant bioavailability and metabolite formation in biological tissues that can provide key insights into food and clinical markers/outcomes. In particular, as elsewhere already reported [204] high-priority areas suggested for research of quercetin should include: a) Large clinical trials to compare the efficacy of different doses of quercetin versus standard-of-care angiotensin converting enzyme inhibitors for control of hypertension; b) Investigation of the biologic activity of quercetin aglycone versus quercetin glycosides, versus quercetin metabolites;
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ACCEPTED MANUSCRIPT c) Quercetin has multiple modes of action, but it is not known whether all of these actions are required for specific biologic effects. For instance, does quercetin’s ability to inhibit cell proliferation work through multiple mechanisms, similar to its effect on the cardiovascular system? d) Large multi-institutional trial with a stringent protocol to resolve the disparate results of quercetin treatment on
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exercise tolerance;
e) The ability of quercetin to either sensitize cells to cancer chemotherapeutic agents or to counteract the resistance to
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these drugs needs to be translated into animal studies using a variety of models. If results verify the findings observed with tissue culture cells, then phase I/II clinical trials need to be carried on.
However, in this review after reporting the main chemical features of quercetin and its metabolism, - when and
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where possible – pointing out the molecular, cellular, and functional bases of therapy, data appearing in the peerreviewed literature and focusing on the main therapeutic applications of quercetin are summarized. In particular, since
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the quercetin therapeutic applications are very spread out (Fig. 9), in the present review only the ones established by
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scientific researchers have been taken into account.
Figure 9. Quercetin prominent therapeutic applications. Thick arrows: most suggested uses in humans; thin arrows: uses mainly derived from animal studies. Partly adapted from [209].
Nonetheless, it is worth mentioning that many of these therapeutic applications require safety and quite often for most of them effectiveness has not been rigorously proven. Furthermore, some of these ill conditions are potentially grave and should be treated by a qualified healthcare staff. Due to all these features, the question mark which ends the title of the present review is justified because it underlines a key issue; in fact, although for several of the above mentioned therapeutic treatments there is some a strong evidence in humans and as a consequence a suggested use of quercetin, in most cases results derive from in vitro studies and/or from other animal species. On the other hand, scientific evidences for these specific treatments are sometimes good and well supported, but in other cases they are quite unclear, whereas for all other uses there are only unclear results. For that, since numerous studies herein described and regarding the therapeutic applications of quercetin have
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ACCEPTED MANUSCRIPT been performed either in vitro, by using cell cultures, and in vivo utilizing animal models, additional data are warranted to better assess the quercetin antioxidant activity and biological properties in human beings. Thus, it is hoped that in the near future well designed clinical studies in healthy individuals as well as in patients will be carried out to confirm the aforementioned beneficial quercetin effects, setting the optimal doses and forms of delivery, comparing quercetin with
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established procedures and assessing the possible side effects most of which are probably due to quercetin drug
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interaction.
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The author declares that there are no conflicts of interest.
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CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
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Financial support from MIUR (Ministero dell’Istruzione, Università e Ricerca), Rome, Italy, is gratefully
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acknowledged. Susan Edwards deserves sincere thanks for her considerable skill in helping to edit the manuscript.
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and rutin in golden hamsters by oral administration. Carcinogenesis, 1982, 3, 93-97. [198] Pérez-Pastén, R.; Martínez-Galero, E.; Chamorro-Cevallos, G. Quercetin and naringenin reduce abnormal development of mouse embryos produced by hydroxyurea. J. Pharm., Pharmacol., 2010, 62, 1003-1009. [199] Vanhees, K.; de Bock, L.; Godschalk, R.W.; van Schooten, F.J.; van Waalwijk van Doorn-Khosrovani, S.B. Prenatal exposure to flavonoids: implication for cancer risk. Toxicol. Sci., 2011, 120, 59-67. [200] Cantero, G.; Campanella, C.; Mateos, S.;.Corte´s, F. Topoisomerase II inhibition and high yield of endoreduplication induced by the flavonoids luteolin and quercetin. Mutagenesis, 2006, 21, 321-325. [201] Sudan, S.; Rupasinghe, H.P. Quercetin-3-O-glucoside induces human DNA topoisomerase II inhibition, cell cycle arrest and apoptosis in hepatocellular carcinoma cells. Anticancer Res., 2014, 34, 1691-1699. [202] Sudan, S.; Rupasinghe, H.V. Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in hepatocellular carcinoma HepG2 cells. Exp. Biol. Med. (Maywood), 2015, Feb 13 [Epub ahead of print].
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ACCEPTED MANUSCRIPT [203] Hossion, A.M.; Zamami, Y.; Kandahary, R.K.; Tsuchiya, T.; Ogawa, W.; Iwado, A.; Sasaki, K. Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents. J. Med. Chem., 2011, 54, 3686-3703. [204] Miles, S.L.; McFarland, M., Niles, R.M. Molecular and physiological actions of quercetin: need for clinical trials
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to assess its benefits in human disease. Nutr. Rev., 2014, 72, 720-734.
[205] Phenol-Explorer, Database on polyphenol content in food, Food composition; http://phenol-
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explorer.eu/contents/polyphenol/330 (Accessed September 16, 2015). [206] U.S. National Library of Medicine, Open Chemistry Database,
http://pubchem.ncbi.nlm.nih.gov/compound/5280343#section=Top (Accessed September 16, 2015).
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[207] USDA Database for the Flavonoid Content of Selected Foods, Release 3.1, December 2013, Slightly revised, May 2014, prepared by Bhagwat, S.; Haytowitz, D.B.; Holden, J.M. (ret.),
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http://www.ars.usda.gov/News/docs.htm?docid=6231 (Accessed September 16, 2015). [208] Medscape, Drug & Disease, Quercetin (Herbs/Suppl.), http://reference.medscape.com/drug/quercetin-344495#3
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(Accessed September 16, 2015).
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[209] Medscape, Drug & Disease, Quercetin (Herbs/Suppl.), http://reference.medscape.com/drug/quercetin-344495#2
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(Accessed September 16, 2015).
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ACCEPTED MANUSCRIPT Tables (1-3) to: Quercetin: A flavonol with multifaceted therapeutic applications? Gabriele D’Andrea University of L’Aquila, Dept. of BACS, Coppito 2, 67100 L’Aquila, Italy
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email: [email protected]
: Adapted from Phenol-Explorer, Database on polyphenol content in foods [205].
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Table 1. Quercetin-3-O-β-D-glucuronide content in selected food1 Fruits and fruit products Fruits - Berries Grape, black 2.15 mg/100 g Strawberry, raw 1.74 mg/100 g Grape, green 1.50 mg/100 g Cloudberry 0.79 mg/100 g Red raspberry, raw 0.63 mg/100 g Non-alcoholic beverages Fruit juices - Berry juices Red raspberry, pure juice 6.18 mg/100 mL Fennel, tea 3.26 mg/100 mL Herb infusion Grape, green, pure juice 0.05 mg/100 mL Vegetables Leaf vegetables Lettuce, red, raw 2.65 mg/100 g Lettuce, green, raw 1.34 mg/100 g Pod vegetables Green bean, raw 0.80 mg/100 g
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Table 2. Quercetin identifiers and properties1 IDENTIFIERS 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one IUPAC Name 5280343 PubChem CID 1S/C15H10O7/c16-7-4-10(19)12-11(5-7)22InChl 15(14(21)13(12)20)6-1-2-8(17)9(18)3-6/h1-5,16-19,21H REFJWTPEDVJJIY-UHFFFAOYSA-N InChl Key C1=CC(=C(C=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O)O)O Canonical SMILE 117-39-5 CAS 204-187-1 EC Number 2811 UN Number 9IKM0I5T1E UNII 1. 3,3',4',5,7-pentahydroxyflavone 2. dikvertin MeSH Synonyms 3. quercetin Trivial Chemical Names Sophoretin; Xanthaurine; Meletin 302.2357 g/mol Molecular Weight C15H10O7 Molecular Formula PROPERTIES Yellow needles or yellow powder. Converts to anhydrous form at Physical Description 203-207 °F. Alcoholic solutions taste very bitter. 1.799 g/cm3 Density Yellow needles (dilute alcohol, + 2 water) Color Sublimes Boiling Point 316.5 °C Melting Point In water: 60 mg/mL at 16 °C; < 1mg/mL at 70 °F Very soluble in ether, methanol; soluble in ethanol, acetone, Solubility pyridine, acetic acid. 2.81x10-14 mm Hg at 25 °C Vapor Pressure When heated to decomposition it emits acrid smoke and irritating Decomposition fumes. pKa1 = 7.17; pKa2 = 8.26; pKa3 = 10.13; pKa4 = 12.30; pKa5 = Dissociation Constants (in phenol) 13.11 Max Absorption: 256 nm (log E= 4.32); 301 nm (log E= 3.89); Spectral Properties 373 nm (log E= 4.32); Sadler Ref. Number: 594 (IR, PRISM) 1
: Adapted from U.S. National Library of Medicine [206].
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ACCEPTED MANUSCRIPT Table 3. Quercetin content of selected foods1
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Quercetin amount (mg/100 g) edible portion 233.84 50.73 39.21 15.16 14.84 14.70 13.30 7.67 7.61 6.17 4.12 3.86 3.80 3.69 3.26 2.49 2.29 2.19 2.08 1.12 1.04 0.04
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Food source Capers, raw Peppers, hot, yellow, raw Onions, red, raw Asparagus, cooked Cranberries, raw Peppers, hot, green, raw Lingonberries, raw Blueberries, raw Lettuce, red leaf, raw Onions, white, raw Tomato, canned Apples, Red delicious, with skin Apples, Gala, with skin Apples, Golden delicious, with skin Broccoli, raw Tea, green, brewed Cherries, sweet, raw Tea, black, brewed Grapes, black Grapes, white Wine, red, table Wine, white, table
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: Adapted from USDA Database for the Flavonoid Content of Selected Foods [207].
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Graphical abstract
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S0367-326X(15)30092-7 doi: 10.1016/j.fitote.2015.09.018 FITOTE 3271
To appear in:
Fitoterapia
Received date: Revised date: Accepted date:
22 July 2015 16 September 2015 18 September 2015
Please cite this article as: Gabriele D’Andrea, Quercetin: A flavonol with multifaceted therapeutic applications?, Fitoterapia (2015), doi: 10.1016/j.fitote.2015.09.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Quercetin: A flavonol with multifaceted therapeutic applications? Gabriele D’Andrea*
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University of L’Aquila, Dept. of Biotechnological and Applied Clinical Sciences, Via Vetoio,
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Coppito 2, 67100 L’Aquila, Italy
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*: Corresponding author
Fax:
+39-862-433433
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email: [email protected]
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Phone: +39-862-433464
Keywords: quercetin; dietary sources; metabolism; therapeutic applications; toxicity; drug
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interactions.
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ACCEPTED MANUSCRIPT ABSTRACT Great interest is currently centered on the biologic activities of quercetin a polyphenol belonging to the class of flavonoids, natural products well known for their beneficial effects on health, long before their biochemical characterization. In particular, quercetin is categorized as a flavonol, one of the five subclasses of flavonoid compounds.
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Although flavonoids occur as either glycosides (with attached glycosyl groups) or as aglycones, most altogether of the dietary intake concerning quercetin is in the glycoside form. Following chewing, digestion, and absorption sugar
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moieties can be released from quercetin glycosides. Several organs contribute to quercetin metabolism, including the small intestine, the kidneys, the large intestine, and the liver, giving rise to glucuronidated, methylated, and sulfated forms of quercetin; moreover, free quercetin (such as aglycone) is also found in plasma. Quercetin is now largely
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utilized as a nutritional supplement and as a phytochemical remedy for a variety of diseases like diabetes/obesity, circulatory dysfunction, including inflammation as well as mood disorders. Owing to its basic chemical structure the
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most obvious feature of quercetin is its strong antioxidant activity which potentially enables it to quench free radicals from forming resonance-stabilized phenoxyl radicals.
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In this review the molecular, cellular, and functional bases of therapy will be emphasized taking strictly into
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account data appearing in the peer-reviewed literature and summarizing the main therapeutic applications of quercetin;
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furthermore, the drug metabolism and the main drug interaction as well as the potential toxicity will be also spotlighted.
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ACCEPTED MANUSCRIPT 1. INTRODUCTION Most of the successful medical treatments in ancient times seem due to the employment of flavonoids, which use has persevered until now. Consequently, new interest by the scientific community towards flavonoids and their derivatives centers on numerous flavonoid compounds and their diverse biological properties (e.g. antioxidative,
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antimicrobial, anticarcinogenic, cardioprotective). Certainly, in this context quercetin is one of the most often studied dietary flavonoid ubiquitously present in various vegetables as well as in tea and red wine [1-3]. In a typical Western
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diet the daily intake of quercetin is estimated to be in the range of 0 and 30 mg (median of 10 mg). Tea, red wine, fruits, and vegetables are the chief dietary sources of quercetin in Western populations [4, 5]. In some countries quercetin is available as a dietary supplement with daily doses between 200 and 1200 mg. In addition, as a nutraceutical for
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functional foods, quercetin may be used within 0.008-0.5% or 10-125 mg/serving [6]. Yet, like other similar antioxidant flavonoids quercetin is an exceptional free radical scavenger [7] and from
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that feature arises the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical; for this reason quercetin is suggested to be involved in imaginable beneficial health effects. On the contrary,
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only few, and mostly in vitro, studies report some damaging effects of quercetin; in particular, its oxidation product
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such as quercetin-quinone seems to be very reactive towards thiols and can instantaneously form an adduct with glutathione, the most abundant endogenous thiol [8, 9]. Furthermore, amongst other damaging effects quercetin has
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also been reported to display genotoxic effects in vitro, but these mutagenic effects of quercetin have been found only in bacteria and are suggested to require the quinone formation as mediators as well [10-13]. In any case, it is assumed that the bioactivity of quercetin is mainly due to its metabolization in the intestines
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and/or liver starting from various naturally occurring conjugated isoforms that are absorbed and extensively distributed in animal tissues [14-16]. In particular, quercetin-3-O-β-D-glucuronide (Q3GA), a major metabolite of quercetin and found as such in many foods (Table 1), seems to exert the foremost beneficial functions in target tissues [17].
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ACCEPTED MANUSCRIPT Table 1. Quercetin-3-O-β-D-glucuronide content in selected food1
Grape, black
2.15 mg/100 g
Strawberry, raw
1.74 mg/100 g
Grape, green
1.50 mg/100 g
Cloudberry
0.79 mg/100 g
Red raspberry, raw
0.63 mg/100 g
Red raspberry, pure juice
6.18 mg/100 mL
Fennel, tea
3.26 mg/100 mL
Grape, green, pure juice
0.05 mg/100 mL
Lettuce, red, raw
2.65 mg/100 g
Lettuce, green, raw
1.34 mg/100 g
Green bean, raw
0.80 mg/100 g
Fruit juices - Berry juices
Herb infusion
Pod vegetables 1
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Leafy vegetables
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Vegetables
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Non-alcoholic beverages
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Fruits - Berries
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Fruits and fruit products
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: Adapted from Phenol-Explorer, Database on polyphenol content in foods [205].
Thus, since numerous studies have been performed to gather scientific evidence for these beneficial health
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claims the principal aim of this review is to evaluate these studies in order to elucidate the possible health-beneficial
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effects of quercetin. In particular, among the beneficial effects, the antihypertensive effects of quercetin in humans and the improvement of endothelial function seem to be the most relevant. Nevertheless, besides its anti-thrombotic and anti-inflammatory effects, quercetin could be used for preventing obesity related diseases, but also to treat some kinds
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of cancer. Most exciting are the recent findings that quercetin enhances physical power by yet unclear mechanisms. Even though quercetin bioavailability is generally poor it is a critical mediator of its bioactivities, in this review besides the molecular, cellular, and functional bases of therapy that will be emphasized and critically evaluated, the quercetin metabolism and its main drug interaction as well as its potential toxicity will be also spotlighted.
2. CHEMICAL FEATURES OF QUERCETIN 2.1. Structural features of quercetin The name quercetin derives from quercetum (oak forest), after Quercus and has been used since 1857. Naturally, quercetin is a polar auxin transport inhibitor [18] whose structure is shown in Fig. 1 whereas its main identifiers and properties are reported in Table 2.
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Figure 1. The chemical structure of quercetin.
IUPAC Name PubChem CID
Solubility
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Density Color Boiling Point Melting Point
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Trivial Chemical Names Molecular Weight Molecular Formula
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MeSH Synonyms
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InChl Key Canonical SMILE CAS EC Number UN Number UNII
Physical Description
IDENTIFIERS 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one 5280343 1S/C15H10O7/c16-7-4-10(19)12-11(5-7)22-15(14(21)13(12)20)6-1-28(17)9(18)3-6/h1-5,16-19,21H REFJWTPEDVJJIY-UHFFFAOYSA-N C1=CC(=C(C=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O)O)O 117-39-5 204-187-1 2811 9IKM0I5T1E 1. 3,3',4',5,7-pentahydroxyflavone 2. dikvertin 3. quercetin Sophoretin; Xanthaurine; Meletin 302.2357 g/mol C15H10O7 PROPERTIES Yellow needles or yellow powder. Converts to anhydrous form at 203-207 °F. Alcoholic solutions taste very bitter. 1.799 g/cm3 Yellow needles (dilute alcohol, + 2 water) Sublimes 316.5 °C In water: 60 mg/mL at 16 °C; < 1mg/mL at 70 °F Very soluble in ether, methanol; soluble in ethanol, acetone, pyridine, acetic acid. 2.81x10-14 mm Hg at 25 °C When heated to decomposition it emits acrid smoke and irritating fumes.
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Table 2. Quercetin identifiers and properties1
Vapor Pressure Decomposition Dissociation Constants (in phenol) Spectral Properties
pKa1 = 7.17; pKa2 = 8.26; pKa3 = 10.13; pKa4 = 12.30; pKa5 = 13.11 Max Absorption: 256 nm (log E= 4.32); 301 nm (log E= 3.89); 373 nm (log E= 4.32); Sadler Ref. Number: 594 (IR, PRISM)
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: Adapted from U.S. National Library of Medicine [206].
Chemically speaking quercetin belongs to the class of flavonoids (from flavus which means yellow, their common color), natural products derived from 2-phenylchromen-4-one (flavone) (Fig. 2).
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Figure 2. The chemical structure of 2-phenylchromen-4-one.
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However, further derivations encompass the reduction of the 2(3) carbon-carbon double bond (flavanones)
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(Fig. 3), the reduction of the keto group (flavanols), and the hydroxylation at diversified positions. (Fig. 4).
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Figure 3. The chemical structure of major flavanones.
Figure 4. The chemical structure of major flavanols.
Anyway, and more precisely, quercetin is a representative of the flavonols family (Fig. 5) that is compounds that have the 3-hydroxyflavone backbone. Flavonols (with an "o") (Fig. 5) are not to be misled with flavanols (with an "a"), another subclass of flavonoids containing the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton (Fig. 4).
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Figure 5. Molecules belonging to the flavonols’ family and their chemical structures.
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Interestingly, flavonoids were formerly referred to as Vitamin P, presumably due to the effect they had on the
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permeability of vascular capillaries, but this term is rarely used now [19].
2.2. Antioxidative properties of quercetin
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Quercetin is considered to be a strong antioxidant due to its ability to scavenge free radicals and bind transition
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metal ions [20]. Its antioxidative capacities are primarily ascribed to the presence of two antioxidant pharmacophores within the molecule that have the optimal configuration for free radical scavenging, i.e. the catechol group in the B ring
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and the OH group at position 3 of the A ring [21] (Fig. 1). As accounted by some research teams, within the flavonoid family, quercetin is the most potent scavenger of ROS, including O2 (- [22-25] and ONOO− [26, 27]. These properties make quercetin a good lipid peroxidation inhibitor [28, 29]; this type of peroxidation can create deleterious effects
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throughout the body, such as cardiovascular and neurodegenerative diseases; however, lipid peroxidation can be terminated by antioxidants, like quercetin, which interfere by reacting with the radicals formed [28, 30, 31]. In addition, quercetin does not only stop the propagation of lipid peroxidation, but also increases glutathione levels [32] contributing in preventing free radicals formation [31]. In this context, the oxidation of lipid biomolecules such as lowdensity lipoproteins (LDL) can give rise to the formation of atherosclerotic plaques responsible of cardiovascular diseases [28]; moreover, brain lipid membranes damages due to lipid peroxidation are thought to lead to neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease [31]. By scavenging free radicals quercetin can also reduce inflammation [33]. Interestingly, by preventing Ca2+dependent cell death quercetin can protect cells suffering oxidative stress [28]. Furthermore, quercetin can also protect against smoking that is the more obvious environmental cause of free radicals. In fact, Begum and Terao [34] found that the quercetin aglycone and its conjugate metabolites (i.e. quercetin-3-O-β-glucuronide and quercetin-3-O- β -glucoside) could protect erythrocytes from the damage caused by smoking. Moreover, as reported in a study of 40 athletes [35], quercetin could prevent the increased oxidative stress induced by exercise.
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ACCEPTED MANUSCRIPT Additionally, whereas the contribution of both vitamin C and uric acid virtually equals that of trolox (6hydroxy-2, 5,7,8-tetramethylchroman-2-carboxylic acid) quercetin is suggested to substantially empower the endogenous antioxidant shield due to its contribution to the total plasma antioxidant capacity (6.24 times higher than the reference antioxidant trolox) [36]. The antioxidative properties of quercetin were also investigated against sodium
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fluoride induced oxidative stress in rats. In particular, pretreatment with quercetin (as well as with vitamin C) before NaF administration prevented either liver and renal injury and led to a significant revival of the oxidative status, thus
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the antioxidant activity of quercetin played an important protective role in the liver and kidneys of rats, respectively [37, 38]. In a similar study, investigating upon the cardioprotective properties of quercetin, authors found that although NaF intoxication significantly altered all the indices related to the pro-oxidant-antioxidant status of the heart, quercetin
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treatment prior to NaF administration prevented these alterations, probably via antioxidant quercetin’s properties [39]. Anyway, like many antioxidant compounds, quercetin might show pro-oxidant activity, at least under some
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circumstances. This happens because quercetin-quinone (QQ), the main oxidation product of quercetin, strongly react with thiols causing the loss of the protein function. Such QQ-induced toxicity has been demonstrated in various in
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vitro studies and has recently been defined as the quercetin paradox, i.e. while offering protection by scavenging ROS
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quercetin is converted into a potential toxic product [40]. Moreover, QQ is so very reactive that it instantaneously forms an adduct with glutathione, the most abundant endogenous thiol [8, 9]. However, although based on the Ames
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test [41] quercetin has to be considered a mutagenic compound, in 1999 the International Agency for Research on Cancer (IARC) concluded that quercetin should not be classified as carcinogenic to humans [42, 43]. Among other interesting features, quercetin is an excellent free radical scavenging antioxidant [8] and as such
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could form products that usually have got over some of the responsiveness of the radical that has been scavenged [44]. This antioxidant activity recognized for flavonoids such as quercetin has often been associated with the reduced risk of oxidative-stress related chronic diseases such as diabetes, coronary heart disease and stroke [45, 46]. In this regard, catechol products containing antioxidants such as quercetin react with thiols impairing - in isolated membranes and blood plasma - several enzymes [47, 48]. In any event, in relation to the protective power of the flavonoid itself, the potential toxicity of quercetin metabolites formed during the shelter offered by quercetin has not been measured in intact cells before. However, Mendoza and Burd [49] explored the fine structure and mechanical properties of quercetin as they pertain to its ability to work as a chemopreventative compound.
3. DIETARY SOURCES The edible portions of many food plants, leafy vegetables, tubers and bulbs, various fruits, herbs and spices, as well as tea and wine contain flavonols mainly in the form of glycosides [50]. Amongst flavonols molecules quercetin is the most abundant (see Table 3 for selected foods containing quercetin), anyway the majority of the dietary intake of
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ACCEPTED MANUSCRIPT quercetin-type flavonols consists of quercetin glycosides a kind of conjugates in which quercetin is linked either with one or two glucose residues (quercetin glucosides) or with rutinose (quercetin rutinoside) (Fig. 6); thus fewer amounts of (aglycones) quercetin are found in the common diet. Fascinatingly, the amount of quercetin in food might significantly be influenced by growing conditions, e.g., organically grown tomatoes show a higher quercetin aglycone
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content than conventionally cultivated tomatoes [51]. In any case, vegetables and fruits, particularly onions, peppers cranberries, blueberries, apples, cherries and grapes which contain the flavonol at levels as high as about 350 ppm
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(expressed as the aglycones) are the primary sources of naturally-occurring dietary quercetin of the typical Western diet [52, 53]. Brewed black tea, as well as red table wine and various fruit juices, also were identified as dietary sources abundant of quercetin [54, 55].
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In addition, although occurring relatively rarely in nature, first identified in Ageratina calophylla [56], Cglycosides are another type of quercetin derivatives where the most frequent site of the C-glycosylation is the C-6
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carbon. One more very rare quercetin derivative, such as quercetin 3-O-α-L-fucopyranoside, was found both in the red alga Acanthophora spicifera [57] and in the Vitis vinifera [58]; in this case quercetin is attached to a α-L-fucopyranosyl
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Table 3. Quercetin content of selected foods1
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Capers, raw Peppers, hot, yellow, raw Onions, red, raw Asparagus, cooked Cranberries, raw Peppers, hot, green, raw Lingonberries, raw Blueberries, raw Lettuce, red leaf, raw Onions, white, raw Tomato, canned Apples, Red delicious, with skin Apples, Gala, with skin Apples, Golden delicious, with skin Broccoli, raw Tea, green, brewed Cherries, sweet, raw Tea, black, brewed Grapes, black Grapes, white Wine, red, table Wine, white, table
Quercetin amount (mg/100 g) edible portion 233.84 50.73 39.21 15.16 14.84 14.70 13.30 7.67 7.61 6.17 4.12 3.86 3.80 3.69 3.26 2.49 2.29 2.19 2.08 1.12 1.04 0.04
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: Adapted from USDA Database for the Flavonoid Content of Selected Foods [207].
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Figure 6. a): quercetin-3-glucoside (isoquercetin); b): quercetin-3,4’-diglucoside; c): quercetin-3-rutinoside (rutin; sophorin).
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In the United States, from a normal mixed diet the average daily intake of all flavonoids (i.e. flavanones, flavones, flavonols, anthocyanins, catechins, and biflavans) is calculated to be about 1 g/day [expressed as quercitrin equivalents, considering that one biflavan molecule equals to 2 molecules of quercitrin], of which, depending on
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seasonal changes, 160-175 mg/day is accounted only for flavanones, flavones, and flavonols [50, 59]. However,
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expressed as quercetin equivalents, it is estimated that flavonol glycosides are consumed at levels of up to about 100 mg/day [50, 55, 60, 61]. On the other hand, the national dietary record-based cohort assessments (i.e. from Australia,
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Croatia, Finland, Italy, Japan, the Netherlands, and the United States) of the intake of quercetin from the customary diet indicated mean consumption levels in the range < 5 mg to about 40 mg quercetin/day [61-66]; however, daily amounts
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of quercetin as high as 200-500 mg may be reached by high-end consumers of fruits and vegetables, notably in cases where the individuals ingest the peel portion of quercetin-rich fruits and vegetables, such as tomatoes, apples, and onions [60].
4. QUERCETIN BIOAVAIABILITY Bioavailability is defined as a ratio between the amount of an orally administered substance and the amount which is absorbed and then available for physiologic activity or storage [67]. Founded on its pharmacokinetics assessment bioavailability could be sorted out as absolute or relative [68]. Absolute bioavailability is more accurate, whereas relative bioavailability is simpler, but less accurate [53]. As already reported [69] the factors that most influence quercetin absorption are the “nature of the attached sugar, and secondly, the solubility as modified by ethanol, fat, and emulsifiers”. The earliest human quercetin research suggested very poor oral bioavailability after a single oral dose (~2%) [70]; subsequently, the absolute bioavailability of quercetin in humans was estimated at 44.8% when radiolabeled quercetin aglycone solubilized in ethanol was administered prior to measuring the total radioactivity of
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increased plasma concentration consequent to continuous supplementation [73, 74]. Nonetheless, until nowadays researches conducted upon animal and human beings have enlightened an extensive understanding about quercetin
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bioavailability.
5. QUERCETIN METABOLISM
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5.1. Quercetin metabolism in vivo overview
As stated above quercetin as such is usually found linked to a sugar moiety giving rise β-glycosides derivatives
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which, once ingested, undergo hydrolysis by the glycosidase activity of intestinal bacteria releasing quercetin (the aglycone form) and the sugar moiety [75]. However, it was recently demonstrated that the predominant quercetin
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conjugates in human plasma, in which the quercetin as such could not be detected, are quercetin 3-O-β-D-glucuronide
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(Q3GA) and quercetin-3′-sulfate [76-78]. Upon ingestion, quercetin glycosides are rapidly hydrolyzed during the transit through the small intestine or by bacterial activity in the colon to generate quercetin aglycone, which is further
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metabolized in the so-called phase II reactions into the glucuronidated and/or sulfated derivatives (Fig. 7).
Figure 7. a): quercetin 3-O-β-D-glucuronide (Q3GA); b): quercetin-3′-sulfate.
Studies using rodents have also demonstrated that orally administered quercetin is converted to its conjugates before accumulation in plasma [79, 80]. In addition, it was reported and clarified that conjugated metabolites of quercetin accumulate in human plasma in the concentration range of 10–7-10–6 M after the periodic ingestion of onions with meals for 1 week [77]. Thus, the pharmacological role of dietary quercetin, including its antioxidant action, should be reached solely by its conjugated metabolites. In any case, most of the in vitro pharmacological studies have been done by utilizing only the quercetin aglycone form.
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ACCEPTED MANUSCRIPT 5.2. Quercetin metabolism Quercetin metabolism is complex and involves intestinal uptake and/or deglycosylation, glucuronidation, sulfation, methylation, possible deglucuronidation and ring fission [81]. Various quercetin metabolites are generated
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following its biotransformation; in particular, as above described, it has been recently demonstrated that quercetin 3-O-
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β-D-glucuronide (Q3GA) and quercetin-3′-sulfate are the predominant quercetin conjugates in human plasma [76-78].
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In any case, factors regulating absorption, metabolism and elimination are important mediators of its bioavailability. Typically, the human quercetin plasma concentration is in the order of nanomolar, but upon quercetin supplementation it may increase in between the high nanomolar and the low micromolar range [82, 83]. Generally,
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depending on eating habits, average daily intake of quercetin could vary between 10 and 100 mg although high concentrations (>170 mg per 100 g) of quercetin are particularly found in capers and lovage leaves (Table 3; [207]).
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Nevertheless, an ingested amount of 500-1000 mg per day can be easily achieved using selected nutraceuticals with
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highly purified quercetin extracts [84].
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5.3. Quercetin absorption
The site and the manner in which quercetin is absorbed depends upon its chemical structure. Studies using rat
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models indicate that quercetin aglycone absorption occurs either in the stomach and at the small intestine level [85, 86]. Although the mechanisms explaining gastric absorption of quercetin aglycone remain unclear, in vitro studies support that human intestinal absorption of quercetin aglycone occurs primarily by passive diffusion and secondarily by organic
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anion transporting polypeptide (OATP) [87]. By contrast, quercetin aglycone and glycosylated forms of quercetin (quercetin glucoside, quercetin rutinoside) are not absorbed in the stomach [85]. However, prior to absorption at the small intestine, specifically quercetin glycosides (i.e. quercetin glucosides, quercetin galactoside, quercetin arabinoside) are deglycosylated to quercetin aglycone [88] by the lactase phlorizin hydrolase (LPH), a β-glucosidase residing in the brush border [89]. Thus, only the quercetin aglycone is subsequently passively absorbed [90]. Fascinatingly, quercetin rutinoside is absorbed in the colon following deglycosylation [91] which seems to be mediated by gut microbiota-derived β-glucosidase [92] that generates quercetin aglycone facilitating its colonic absorption [60]. In this regard, a study in an in vitro model showed that 60% of quercetin rutinoside were degraded to 3,4dihydroxyphenylacetic acid within 2 h by the colonic microbiota [93], suggesting that most quercetin rutinoside is initially deglycosylated to quercetin aglycone prior to degradation to 3,4-dihydroxyphenylacetic acid. Anyway, further studies are required to better determine the possible health benefits of quercetin metabolites [74] and than the influence of gut microbiota composition on their formation.
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ACCEPTED MANUSCRIPT 5.4. Quercetin biotransformation Being a xenobiotic quercetin biotransformation occurs through the classical xenobiotic metabolism pathway [94]. In general, xenobiotic metabolism consists of three phases: phase I modification, phase II conjugation and phase
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III elimination [95]. Phase I metabolism of quercetin has not been described, but it is said to be structurally similar to the flavone apigenin [96]. Phase II conjugation of quercetin at the small intestine involves glucuronidation, sulfation
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and methylation, as evidenced by the appearance of glucuronidated, sulfated and methylated metabolites of quercetin following incubation of quercetin aglycone with human small intestinal microsomes [97]. Therefore, numerous phase II metabolites arise from quercetin including quercetin monoglucuronide, quercetin diglucuronide, quercetin sulfate,
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quercetin monoglucuronide sulfate and methylated quercetin monoglucuronide sulphate [14, 98]. Other metabolites include isorhamnetin and tamarixetin which are methylated forms of quercetin. Phase II metabolites of quercetin are
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secreted into the portal and lymph circulation, with evidence that most quercetin in the portal vein plasma or lymph appears as conjugated quercetin being quercetin aglycone below the detection limit [88, 99]. Phase III efflux of phase
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II metabolites of quercetin also occurs in the small intestine. Studies in a rat model showed that glucuronides and
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sulfates of quercetin, isorhamnetin and tamarixetin appear in the effluent collected from the intestinal lumen [86]. Intestinal efflux of quercetin metabolites is likely mediated through breast cancer resistance protein 1 (BCRP1) and
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multidrug resistance associated-protein 2 (MRP2), the phase III transporters occur on the apical side of enterocytes [100, 101]. On the other hand, phase II metabolites of quercetin secreted from the small intestine reach the liver via the portal vein [88]. Hepatocyte uptake of quercetin metabolites involves passive diffusion as well as organic anion
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transporters (OAT) and/or anion transporting polypeptide (OATP)-mediated transport [102]. Following hepatic uptake, quercetin metabolites are further metabolized by phase II conjugating enzymes. However, quercetin metabolites formed in the liver either enter the circulation or are directed to biliary excretion [88], with the latter likely occurring in a MRP2-dependent manner [103]. Additionally, renal phase II metabolism of quercetin may also take place, but no reports currently exist to directly support renal phase II metabolism of quercetin.
5.5. Degradation and disposition of quercetin Ingested quercetin is rapidly eliminated via feces and urine [104]. The profile of metabolites excreted via feces and urine, while also comprised of glucuronide and sulfate conjugates, appears to differ significantly from those found in the plasma. However, many of the major urinary components, including quercetin-3’-glucuronide, two quercetin glucoside sulphates, and a methylquercetin diglucuronide, are either absent or present only in trace amounts in the bloodstream, for that after they arrive in the blood quercetin metabolites probably undergo a further phase II metabolism [105, 106]. The fecal recovery appears to be in the range of 1.6-4.6 percent of an oral dose. In one study,
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ACCEPTED MANUSCRIPT the majority of the quercetin that was unaccounted for in urinary and fecal excretion was recovered as exhaled carbon dioxide (CO2), suggesting that a high amount of absorbed quercetin is extensively metabolized and eventually eliminated by the lungs [71]. However, and in particular, most quercetin-derived metabolites are identified as 3hydroxyphenylacetic acid, benzoic acid and hippuric acid [104], suggesting that phase II metabolites of quercetin are
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deconjugated to quercetin aglycone prior to ring fission to yield phenolic acids. The mechanism by which conjugated metabolites of quercetin are degraded in vivo is not well defined, but it should be considered that both the colonic
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microflora and kidneys express β-glucuronidase activity [93, 107], supporting deglucuronidation of quercetin glucuronides prior to degradation of quercetin aglycone to phenolic acids, and their subsequent elimination.
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6. THERAPEUTIC APPLICATIONS OF QUERCETIN 6.1. Clinical trials
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Since the first Phase I clinical trial in which, following a tyrosine kinase inhibition, an evidence of antitumor activity was seen [108], several very recent randomized, double-blind, placebo-controlled, crossover trials have been
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performed with quercetin demonstrating that: a) quercetin supplementation reduced systolic blood pressure
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significantly but had no effect on other cardiovascular risk factors and inflammatory biomarker [109]; b) quercetin (3glucoside) supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors [110];
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c) quercetin may contribute to the cardioprotective effects of tea possibly by improving endothelial function and reducing inflammation [111]; d) no significant therapeutic effect can be considered for quercetin in treatment of oral Lichen planus [112].
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Nevertheless, in addition to the above mentioned clinical trials, quercetin as such or as a derivative has been tried and applied for many different specific multifaceted therapeutic applications of which the most prominent will now be reported.
6.2. Aging The biological processes responsible of ageing can be positively counteracted by few environmental factors, such as natural antioxidants. In this context vitamin E [113], kinetin [114], carnosine [115] and garlic [116] are only few examples of natural sources that have been shown to exert a noticeable pro-longevity effect on human primary cultures. Passed on the antioxidant properties of quercetin and the association between ageing and oxidative stress [117], Chondrogianni et al. [118] investigating the role of quercetin established a positive influence on survival, viability, and lifespan of primary human fibroblasts (HFL-1); moreover, when senescent fibroblasts were grown in the presence of quercetin, a rejuvenating effect was observed.
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ACCEPTED MANUSCRIPT Attractively, other authors [119] report that quercetin, considered a senolytic agent, is positively effective also against senescent human endothelial cells likely showing a special promise in eliminating senescent cells as already reported [120, 121].
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6.3. Allergy
Like histamine and most cyclin-dependent kinases quercetin inhibits the in vitro growth of certain malignant
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cells and also displays unique anti-cancer properties, moreover quercetin is a natural compound that blocks substances involved in allergies and is able to act as an inhibitor of mast cell secretion, causing a decrease in the release of tryptase, MCP-1 and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from few mast cell lines [122].
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As other flavonoids polyphenolic compounds that exert many anti-inflammatory and anti-microbial effects, and exhibit an anti-allergic action, quercetin has been recently shown as a potential drug against allergy; thus, quercetin
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appears to possess the same potential of Food Allergy Herbal Formula (FAHF) as a safe anti-allergic substance but it opens only a wide perspective, at the moment, due to several complex issues that hamper the possibility to use natural
6.4. Angioprotective Properties
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medicine and phytochemicals as a true drug [123].
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Considerable attention has been directed to quercetin also as a promising compound to be dispensed for heart disease, prevention, and therapy; in fact, it has been linked to decreased mortality from heart disease and decreased incidence of stroke. In this regard, Pashevin et al. [124] report new data from which the angioprotective properties of
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quercetin seem to be mediated by its effects on proteasomal proteolysis. In particular, by using rabbits with cholesterolinduced atherosclerosis the study investigated the ability of quercetin to modulate proteasomal activity. First, following an 8 week cholesterol-rich diet, results indicated that the proteasomal trypsin-like (TL) activity increased up to 2.4-fold, whereas chymotrypsin-like (CTL) activity and peptidyl-glutamyl peptide-hydrolyzing (PGPH) activity increased by 43% and up to 10%, respectively. A remarkable decrease of proteasomal TL activity (1.85-fold in monocytes), and a decrease of both the CTL and PGPH activities (more than 2-fold in polymorphonuclear leukocytes) were observed after 2 h following a single intravenous injection of the water-soluble form of quercetin (Corvitin). Furthermore, after a cholesterol-rich diet the prolonged administration (1 month) of Corvitin significantly decreased all types of proteolytic proteasome activities both in tissues and in circulating leukocytes, additionally a reduction of atherosclerotic lesions in the aorta was detected. Unfortunately, besides their antioxidant effect, flavonols like quercetin interfere with a great bit of biochemical signaling pathways and therefore with many physio- pathological processes. However, there are strong evidences that quercetin as well as related flavonols exert in vitro protective effects on nitric oxide and endothelial function under
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ACCEPTED MANUSCRIPT oxidative stress, endothelium-independent vasodilator and platelet anti-aggregant effects, inhibition of LDL oxidation, reduction of adhesion molecules and other inflammatory markers, prevention of neuronal oxidative and inflammatory damage [125]. Nevertheless, all these effects could be primarily due to quercetin metabolites which in general protect the endothelium from LDL oxidation.
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Furthermore, as meta-analysis studies of epidemiological studies report, quercetin produces undisputed antihypertensive and anti-atherogenic effects, preventing endothelial dysfunction and protecting the myocardium from
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ischemic damage [125]. Quercetin had no clear effects on serum lipid profile and on insulin resistance, but although there is no solid proof yet a substantial body of evidence suggests that quercetin may prevent the most common forms of cardiovascular disease contributing to the protective effects afforded by fruits and vegetables. Worthwhile, recent
in blood pressure after quercetin supplementation [126].
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work using hypertensive animals and humans (> 140 mm Hg systolic and > 90 mm Hg diastolic) indicates a reduction
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Noteworthy, two very recent studies demonstrate further evidence backing up the point of view that quercetin should be regarded a possible healing agent against cardiovascular diseases [127, 128]. In particular, Hung et al. [128]
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findings provide new insight regarding the possible molecular mechanisms of quercetin; in fact quercetin seems to
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suppress oxLDL-induced endothelial oxidative injuries by activating SIRT1 and by modulating the AMPK/NADPH
6.5. Anti-Cancer
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oxidase/AKT/eNOS signaling pathway.
As found for many other flavonoids, a number of reports have assessed the pro-apoptotic activity of quercetin
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in cancer cells; in fact, quercetin is a forthright inhibitor of PI3K, NF-B, and other kinases involved in intracellular signaling [129]. Nevertheless, although mitochondria seem to be targeted by quercetin inducing apoptosis and the cancer cell death in vitro [130] until nowadays a reliable quercetin intracellular target has not yet been found; of course, the challenge is to identify an eligible target in order to better define possible natural compounds to be added in food extracts or pharmaceuticals. Certainly, the antioxidative effects as well as the kinase and cell cycle inhibition, and the induced apoptosis are all essential for the anti-cancer properties shown by quercetin. In particular, the different interactions and activities of quercetin that fine tunes the phosphorylation state of molecules as well as the gene expression would act upon the intracellular signaling equilibrium, either inhibiting or reinforcing survival signals. Anyhow, these mechanisms, which have been mainly observed in in vitro studies, cannot easily explain the anti-cancer effects observed in vivo because of the relatively low quercetin bioavailability in plasma and also because the nature of the actual active molecules is not clearly known [131]. Thus, to partly explain the molecular effect of quercetin on cancer cells, among the different
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ACCEPTED MANUSCRIPT substrates suspected to be triggered by quercetin a study reports the capability of quercetin to inhibit some protein kinases involved in deregulating the cell growth in cancer cells [132]. Furthermore, quercetin can exert its anti-cancer effect also inhibiting the mTOR activity by multiple pathways [133]. On the other hand, in ascite cells of lymphoma-bearing mice, it is suggested that the cancer preventive activity of
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quercetin is accomplished via the induction of apoptosis and modulation of the PKC signaling which brings to the reduction of oxidative stress [134].
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It has been proven that the most effective quercetin action is on blood, brain, lung, uterine, and salivary gland cancer as good as upon melanoma with a cytotoxic activity much higher in the more aggressive cells than in the slow
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growing cells suggesting that the most harmful cells are the ones mainly targeted [135].
6.6. Anti-Inflammatory
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What is nowadays known is that quercetin inhibits the in vitro production of enzymes usually induced by inflammation (i.e. cyclooxygenase [COX] and lipoxygenase [LOX]) [136, 137]; however, also in vivo experiments
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substantiate the anti-inflammatory effect. In particular, as already reported [138] quercetin significantly inhibits pro-
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inflammatory cytokines in cultured fibroblasts from Graves' orbitopathy (GO). This study investigated the inhibitory effect of quercetin on inflammation in cultured whole orbital tissue. Therefore, inhibition of pro-inflammatory
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cytokines by the natural product quercetin in both primary orbital fibroblasts and tissue culture could provide the foundation for its potential use as an anti-inflammatory agent in the treatment of GO. However, the mechanisms behind the anti-inflammatory properties of quercetin are poorly understood.
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Certainly, in inflammation, nitric oxide (NO) acts as a pro-inflammatory mediator and is synthesized by the inducible nitric oxide synthase (iNOS) in response to pro-inflammatory compounds such as lipopolysaccharide (LPS). As described elsewhere [139] pretreatment of H9c2 cardiomyoblasts with quercetin inhibited LPS-induced iNOS expression and NO production and counteracted oxidative stress induced by the unregulated NO production that normally contributes to the generation of peroxynitrite and other reactive nitrogen species. In addition, quercetin pretreatment remarkably counteracted apoptosis cell death as measured by immunoblotting of the cleaved caspase 3 and caspase 3 activity. Besides the induction of apoptosis, quercetin inhibited the phosphorylation (LPS-induced) of two kinases such as the stress-activated protein kinases (JNK/SAPK) and the p38 MAP kinase, enzymes that are involved in the inhibition of cell growth. In closing, these outcomes indicate that quercetin might serve as a valuable protective agent at least in cardiovascular inflammatory diseases. Interestingly, since at nanomolar doses quercetin has shown a biphasic behavior in basophils a beneficial action on cells involved in allergic inflammation could be hypothesized [140].
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ACCEPTED MANUSCRIPT 6.7. Anti-Obesity As aforementioned quercetin is the most abundant flavonoid and it is thought to have protective functions against the pathogenesis of multiple diseases associated with oxidative stress. In this setting, a peculiar study upon 3T3L1 cells investigated the molecular mechanisms through which quercetin could influence adipogenesis and apoptosis
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[141]. The exposure of 3T3-L1 preadipocytes to quercetin resulted in decreased expression of adipogenesis-related factors and enzymes and then attenuated adipogenesis. Moreover, the levels of phosphorylated adenosine
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monophosphate-activated protein kinase (AMPK) and one of its substrates, namely acetyl-CoA carboxylase (ACC), were up-regulated in the presence of quercetin; in the same time apoptosis was induced and a concomitant decrease in ERK and JNK phosphorylation was observed. Put together, these data indicate that quercetin could exert its anti-
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adipogenesis activity by activating the AMPK signal pathway, whereas the quercetin-induced apoptosis of mature adipocytes seems to be mediated by the fine tuning of the ERK and JNK pathways which play crucial roles during
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apoptosis.
On the other hand, to ascertain the molecular mechanisms influenced by quercetin on the physiological effects
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of hyperlipidemia, some authors found that quercetin regulates the hepatic gene expression related to lipid metabolism
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[142]. In particular, quercetin supplementation in mice significantly diminished the high-fat diet (HFD) -induced obesity, reducing the weight of the body, liver, and white adipose tissue compared with the mice fed only with HFD. It
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also deeply reduced the HFD-induced increments in serum lipids, including cholesterol, triglyceride, and thiobarbituric acid-reactive substance (TBARS). Consistent with the reduced liver weight and white adipose tissue weight, hepatic lipid accumulation and the size of lipid droplets, pads in the epididymal fat were also reduced by quercetin
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supplementation. To further investigate how quercetin might reduce obesity, lipid metabolism-related genes in the liver were also examined. In this case, relative to those in HFD control mice, the quercetin supplementation modified the expression profiles of several lipid metabolism-related genes, including Fnta, Pon1, Pparg, Aldh1b1, Apoa4, Abcg5, Gpam, Acaca, Cd36, Fdft1, and Fasn, The expression patterns of these genes observed by quantitative reverse transcriptase-polymerase chain reaction were confirmed by immunoblot assays. Jointly, these results indicated that quercetin prevents HFD-induced obesity in C57B1/6 mice, and its anti-obesity effects may be linked to the regulation of lipogenesis at the level of transcription. More lately, several valuable reviews have been published on the role of dietary phytochemicals in obesity, quercetin included [143, 144]. Nevertheless, it is necessary to establish a clean differentiation between the anti-obesity effects of quercetin when it is meted out as pure aglycone, from its putative functions, and when it is present in polyphenolic extracts, as described in many works cited in the above mentioned last two reviews [143, 144].
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ACCEPTED MANUSCRIPT 6.8. Arthritis In combination with other nutrients, quercetin might reduce symptoms of osteoarthritis (OA), but at the same time it does not appear to be beneficial in rheumatoid arthritis (RA). In fact, as a study report [145], twenty patients with rheumatoid arthritis daily received three capsules of quercetin (166 mg/capsule) plus vitamin C (133 mg/capsule),
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-lipoic acid (300 mg/capsule), or placebo for four weeks allowing a two-week washout period before the next supplementation. After this period the serum concentrations of pro-inflammatory cytokines or C-reactive protein (CRP)
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did not show considerable differences and disease scores severity did not differ among treatment periods. When glucosamine, chondroitin, and quercetin glucoside were given for three months to 46 persons with OA and 22 persons with RA, appreciable ameliorations in daily activities (walking and climbing up and down stairs), pain symptoms,
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visual analogue scale, and synovial fluid properties were observed in OA subjects; conversely, no beneficial effects
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were noticed in RA subjects [146].
6.9. Asthma
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Point of interest, human epidemiological researches indicate an inverse association between intakes of
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quercetin and asthma incidence [147]. Nevertheless, although human intervention studies investigating the effect of quercetin upon asthma and other atopic disease are currently missing, two written reports have looked into the effects
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of an enzymatically-modified isoquercitrin (a quercetin glycoside) on allergic symptoms [148, 149]. In this case, starting four weeks prior to the onset of pollen release, subjects took 100-200 mg/day of isoquercitrin or a placebo for eight weeks. Results proved that this specific quercetin glycoside enzymatically-modified provided a statistically
6.10. Diabetes
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relevant relief of ocular symptoms, but no statistically significant relief of nasal symptoms caused by pollen.
Quite recently, in an animal model with type 2 diabetes mellitus the hypoglycemic, hypolipidemic, and antioxidant effects of dietary quercetin have been investigated. In this study [150] to C57BL/KsJ-db/db mice (n = 18) were offered an AIN-93G diet or a diet containing quercetin at 0.04% (low quercetin, LQE) or 0.08% of the diet (high quercetin, HQE) for 6 weeks after 1 week of adaptation. Plasma glucose, insulin, adiponectin, lipid profiles, and lipid peroxidation of the liver were determined. At the end of the experiment, glucose plasma levels were markedly lower in the LQE group than in the control group, and those in the HQE group were even further reduced than the LQE group. Lower values were found for both LQE and HQE groups than in the control group with no changes in insulin levels by considering the homeostasis model assessment of insulin resistance (HOMA-IR). Furthermore, compared with the control group, 0.08% of dispensed quercetin increased plasma adiponectin, decreased plasma total cholesterol and increased HDL-cholesterol. Nevertheless, plasma triacylglycerols in both the LQE and HQE groups were lower than
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ACCEPTED MANUSCRIPT those in the control group. Moreover, either low and high quercetin reduced thiobarbituric acid reactive substances (TBARS) levels incremented the activity of specific liver enzymes deeply involved in detoxification processes from ROS (reactive oxygen species) i.e. superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Thus, quercetin could be efficient in improving hyperglycemia, dyslipidemia, and the antioxidant status in type 2
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diabetes.
On the other hand, one of the primary causes of end-stage renal disease is diabetic nephropathy (DN). Many
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studies have pointed out that the transforming growth factor-β1 (TGF-β1) and the connective tissue growth factor (CTGF) are both involved in the DN pathophysiological mechanisms. Since quercetin has been proposed to alleviate DN, researchers have investigated whether quercetin ameliorates the renal function likely affecting the expressions of
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TGF-β1 and CTGF in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats [151]. Rats were then subdivided in control group, diabetic group and quercetin therapy group. At the end of the 12th week, body weight, kidney
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weight/body weight ratio, blood glucose, urine albumin excretion (UAE), serum creatinine (sCr), blood urea nitrogen (BUN), and creatinine clearance (Ccr) were measured. The expressions of TGF-β1 and CTGF in the kidneys were
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determined by using real-time PCR and Western blot method. The study reports that diabetic rats showed conspicuous
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increases in kidney weight/body weight ratio, blood glucose, UAE, sCr, BUN, and Ccr; whereas quercetin treatment improved these parameters except for blood glucose. The expressions of TGF-β1 and CTGF were higher in the diabetic
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group than in the control group. However, the overexpression of both TGF-β1 and CTGF in the renal tissues of diabetic rats were reduced following quercetin administration. These results clearly suggest that quercetin improved renal function in DN rats by inhibiting the overexpressions of TGF-β1 and CTGF in the kidney.
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Moreover, aldose reductase, the enzyme that catalyzes the conversion of glucose to sorbitol, is particularly important in the eye and plays an essential role in the formation of diabetic cataracts. Thus, it has been demonstrated that quercetin is an in vitro inhibitor of lens aldose reductase [152, 153] and effectively blocks polyol accumulation in intact rat lenses immersed in a medium with a high sugar concentration [154]. In humans with diabetes type 1 or 2 and diabetic neuropathy, a decrease in the severity of numbness, jolting pain, and irritation was reported, as well as an improvement in quality-of-life measures with active treatment [155]. However, from the molecular basis point of view, it is reported that the antidiabetic action of quercetin is fulfilled by stimulating glucose uptake through an insulin-independent mechanism involving adenosine monophosphate-activated protein kinase (AMPK) whose activation in skeletal muscle leads to the glucose transporter GLUT4 translocation to the plasma membrane; whereas, in liver, AMPK decreases glucose production mainly through the downregulation of the key gluconeogenesis enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose -6-phosphatase (G6Pase) [156].
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ACCEPTED MANUSCRIPT 6.11. Exercise Performance Besides studies that have investigated whether quercetin supplementation can prevent post-exercise immune system changes and sensitivity to infections (discussed in the subsection below on “Immunity and Infections”), other studies have sought to determine whether quercetin shows some ergogenic potential. Existing evidence seems to
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support some ergogenic effect of quercetin in untrained people, but not in trained athletes.
In this contest, eleven studies were identified and a total of 254 human subjects were engaged [157]. Across
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all studies, before supplementation VO2max ranged from 41 to 64 mL·kg-1·min-1 (median = 46), whereas median treatment duration was 11 d with a median dosage of 1000 mg·d-1. Effect sizes (ES) were computed as the standardized mean difference, and meta-analyses were done by using a random-effects model.
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On average, quercetin provided a statistically noticeable benefit in human endurance exercise capacity (VO2max) and performance, but the effect was irrelevant or of a small magnitude, with ES = 0.15 equating roughly to a
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3% improvement with quercetin over the placebo group. Unluckily, these studies designed to examine human performance following quercetin administration did not show the same level of efficacy as formerly observed in mice.
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Experimental factors that explain the between-study variation have to be still elucidated.
6.12. Gastroprotection
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Some in vivo studies report a protective effect of quercetin against ethanol-induced gastric ulceration [158, 159] as well as against the oesophagitis reflux [160, 161]. In any case, it has been demonstrated that quercetin weakly inhibits the growth of Helicobacter pylori in vitro [162]. However, Helicobacter pylori-infected guinea pigs treated for
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15 days with 200 mg/kg of quercetin exhibited a decreased bacterial infection in the gastric mucosa and also a reduced inflammatory response [163]. Worthy of interest, topical quercetin directly spread on minor mouth aphthous ulcers three times daily relieved pain and produced a complete healing in 35% of subjects within 2-4 days, 90% of subjects within 4-7 days, and 100% of subjects within 7-10 days 193 [164]. Nevertheless, although quercetin has been found to possess gastroprotective activity, whether it has a protective activity against less related injury to gastric epithelial cells remains unknown. Anyhow, at least in human gastric epithelial GES-1cells pretreated with quercetin and then challenged with H2O2 it has been observed: a) a decrease of H2O2-induced cell viability loss; b) a reduction of intracellular reactive oxygen species and Ca 2+ influx; c) upregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) expression under the state of oxidative stress; d) a significant decline of the downstream cell apoptosis, then there is a strong evidence that quercetin can protect gastric epithelial GES-1 cells from oxidative damage and ameliorate reactive oxygen species production during acute gastric mucosal injury [165].
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ACCEPTED MANUSCRIPT 6.13. Human Prostate Adenocarcinoma Prostate cancer is a common male malignant disease and its incidence is increasing worldwide with an incidence rate of new cases around 27% occupying the first place and the mortality rate of about 10% occupying the second place only inferior to lung cancer among body sites where tumorigenesis may occur [156]. Concerning human
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prostate adenocarcinoma, some authors evaluated the effects of quercetin on PC-3 cells [157]. Lactate dehydrogenase (LDH) release, microculture tetrazolium test (MTT assay) and real-time PCR array were employed to evaluate the
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effects of quercetin on cell cytotoxicity, cell proliferation and expression of various genes. Results showed that quercetin inhibited cell proliferation and modulated the expression of factors involved in DNA repair, matrix degradation and tumor spreading, cell cycle, programmed cell death, angiogenesis, and metabolism (i.e. glycolysis). No
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cytotoxicity of quercetin on PC-3 cells was observed. These findings indicate that quercetin could be recommended as an effective anti-cancer agent to be used in the future nutritional transcriptomic studies and in multi-target therapy thus
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to overcome the current therapeutic approaches against prostate cancer.
Anyhow, previous findings demonstrated that quercetin treatment of prostate cancer cells caused a decreased
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cell proliferation and viability [168]. In particular, it was shown that quercetin induced cancer cell apoptosis by down-
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regulating the levels of heat shock protein (Hsp) 90 and this Hsp90 decrease was conceivable bound to the decreased cell viability, the apoptosis induction and the caspases activation in cancer cells but not in normal prostate epithelial
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cells. Noteworthy, as indicated by annexin V staining knockdown of Hsp90 by short interfering RNA (siRNA) originated the induction of apoptosis in a similar way like that of cancer cells quercetin-treated [168]. Another interesting study suggests that in the presence of quercetin the c-Jun protein might play an important role in the
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androgen receptor (AR) suppression; in fact, the ternary protein complex (i.e. c-Jun/Sp1/AR) induced by quercetin represents a peculiar mechanism that in prostate cancer cells could be involved in down-regulation of the AR function [169].
Remarkably, it has been lately established that the combination of quercetin and 2-methoxyestradiol can serve as a novel clinical treatment regiment owning the potential of enhancing antitumor effect on prostate cancer in vivo and lessening the dose and side effects of either quercetin or 2-methoxyestradiol [170]; these in vivo results will lay a further solid basis for subsequent researches on this novel therapeutic regimen in human prostate cancer. However, a complete list of mechanisms of the in vitro and in vivo effects of quercetin on prostate cancer is elsewhere summarized [171].
6.14. Immunity and Infections As elsewhere reported quercetin exhibits an in vitro antiviral activity against HIV as well as against other retroviruses [172, 173]; moreover, as above mentioned it also shows in vitro and in vivo antibacterial activity against
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ACCEPTED MANUSCRIPT Helicobacter pylori [162, 163]. Despite positive results obtained both in vitro and in vivo from animal studies, evidence in human beings is mixed as to whether chronic quercetin supplementation has plausible positive effects on the immune system. Usually, quercetin (100 mg/day) does not alter exercise-induced changes in several components belonging to the immune system [174] and no differences are found in the post-race illness rates between quercetin-
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treated and placebo groups [175].
In addition, the natural compounds epigallocatechin gallate (1) and quercetin (2) alone and in combination
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have been recently tested as potential antimicrobial clinical therapies [176]. In this latter study authors report a strong antimicrobial activity produced by 1 alone against methicillin-resistant Staphylococcus aureus, whereas the activity was significantly increased in the presence of 2. Furthermore, a synergistic interaction was observed between the two
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compounds with a bactericidal effect over 24 h when the two compounds were administered in combination.
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6.14. Mood Disorders
Quercetin has shown anxiolytic- and antidepressant-like effects in animal experiments; anyway, no studies
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have investigated whether quercetin has similar effects in humans. However, quercetin dose dependently increases
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social interaction time decreasing immobility time; it also minimizes changes in the animal behavior, such as the swim test or forced immobilization, tests which are planned to cause anxiety and behavioral despair [177-179]. In diabetic rats
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this effect was comparable to that of the antidepressants fluoxetine and imipramine [180]. Nonetheless, it is suggested that the antidepressant effect of quercetin is dependent on the inhibition of the NMDA receptors and/or synthesis of nitric oxide, findings that contribute to the understanding of the mechanisms involved in the antidepressant effect of
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quercetin and reinforce the involvement of the NMDA receptors and the nitric oxide on the pathophysiology of depression [181].
Quercetin also helps protect against changes in behavior caused by alcohol withdrawal [182]. Several possible mechanisms might explain the ability of quercetin to improve mood. Thus, in vitro and in vivo evidences indicate that quercetin can inhibit monoamine oxidase A [183], whereas in vivo experiments indicate that quercetin can decrease the levels of the stress-induced brain corticotrophin releasing factor (CRF) which is associate to anxiety and depression [178]. In addition, quercetin-treatment also reduces the stress-induced increases of both the plasma corticosterone and the adrenocorticotropic hormone [184]. However, some latest studies report more information about the protection of quercetin against behavioral deficiencies and memory impairment. Specifically, lead treated rats showing a marked behavioral impairment, when treated with quercetin maintain their normal behavioral functions despite the increased oxidative stress; from a molecular point of view this happens because quercetin seems to restore the normal morphology of the brain and the expressions of Bak, Bcl-2 and Hsp-70 [185]. On the other hand cadmium (Cd) exposure is recognized to cause
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ACCEPTED MANUSCRIPT impairment of memory and anxiogenic-like behavior. Thus, rats exposed to Cd (2.5mg/kg) and quercetin (5, 25 or 50mg/kg) by gavage for 45days, compared to rats exposed only to Cd (2.5mg/kg), did not show neither the reduction of total thiols, reduced glutathione , and reductase glutathione activities nor the rise of glutathione S-transferase activity, furthermore, the administration of quercetin prevented alterations in acetylcholinesterase and Na+,K+-ATPase activities,
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consequently preventing anxiogenic-like behavior and memory impairment displayed by Cd exposure [186].
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7. DRUG INTERACTION
Quercetin exhibits an in vivo inhibitory effect both on CYP3A4 [187, 188] and CYP1A2 whereas it increases CYP2A6, xanthine oxidase, and N-acetyltransferase activity [189]. Quercetin in vivo inhibits also the P-glycoprotein
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(Pgp), a drug efflux transporter that can play a pivotal role in the intestinal and biliary transport and elimination of many drugs and their metabolites [187, 188, 190, 191]. Due to these interactions, quercetin might alter the serum levels
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of all drugs metabolized by these enzymes. However, although the daily administration of rutin (quercetin rutinoside) reduces the anticoagulant effect of racemic warfarin [192], reliable interactions between quercetin as such and
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anticoagulants have not yet been investigated. Interactions between quercetin and different drugs have been however
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studied especially because of its interaction with the CYP3A4 and the P-glycoprotein. In this regard, Fig. 8 shows the severity grade of known interactions between quercetin and different drugs. In most of the interactions reported in Fig.
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8 quercetin decreases the level or the effect of the drug by P-glycoprotein (MDR1) efflux transporter; on the other hand, particularly in the case of “Minor severity”, quercetin decreases the effect(s) of the drug by pharmacodynamic antagonism. As expected, drug-nutrient interaction might also be influenced by the quercetin dose. Thus, a study carried
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out on pigs reported a lethal interaction between digoxin – a substrate of P-glycoprotein with very narrow therapeutic range – and quercetin; in fact, the co-administration of quercetin (50 mg/kg) and digoxin (0.02 mg/kg) resulted in the sudden death of two out of the three pigs within 30 minutes of administration. Surprisingly, although the co-administration with a lower dose of quercetin (40 mg/kg) powerfully elevated the Cmax (maximum concentration) of digoxin by 413% it did not have lethal effects [191]. As can be imagined quercetin might also alter the bioavailability of some dietary supplements; for example, it appears to improve the bioavailability of epigallocatechin gallate [193] and possibly other flavonoids [194]. Finally, preliminary evidence indicates that quercetin might have synergistic effects with some drugs [195] and might play a character in multi-drug resistance [196].
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Figure 8. Quercetin drug interaction severity. Adapted from [208].
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8. TOXICITY
Most in vivo animal studies certify that quercetin is not carcinogenic; anyway, based on the Ames test
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quercetin is regarded as mutagenic. Interestingly, in 1999 the International Agency for Research on Cancer (IARC)
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ascertained that quercetin should not be classified as carcinogenic to humans [42, 43, 197]. Although in vitro studies suggest that quercetin might have mild negative effects on embryo development [198], until nowadays there is no
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definitive evidence regarding some teratogenic effects of quercetin on embryonic development. Intriguingly, prenatal exposure to quercetin yielded a slight increase in the incidence of malignancies in mice offspring [199]. However, in human studies, quercetin has been mostly well tolerated. Doses up to 1,000 mg/day for several months did not produce
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adverse effects on blood parameters, liver and kidney function, hematology, or serum electrolytes. On the other hand, the results of numerous genotoxicity and mutagenicity on short- and long-term animal as well as on human subjects consistently demonstrated that the quercetin-related mutagenicity did not develop carcinogenicity in vivo; thus, in general, the plentiful available evidences support the safety of quercetin for addition to food [6]. In fact, in the U.S. and Europe supplements of quercetin are commercially purchasable subsequently the quercetin supplements beneficial effects described in clinical trials [42]. Unfortunately, depending on the dose, quercetin as such or as its analogue. quercetin-3-O-glucoside has been shown to inhibit topoisomerase II catalytic activity bringing to an extraordinarily high yields of metaphases showing diplochromosomes [200-202], for that given the established relationship of polyploidy with tumor development via aneuploidy and genetic instability, these results partly question the usefulness of quercetin. Conversely, synthetic quercetin acylglycoside analogues (i.e. 3,7-diacylquercetin, quercetin 6-acylgalactoside, and quercetin 2',6'-diacylgalactoside) have been shown to inhibit either DNA gyrase and topoisomerase IV [203].
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ACCEPTED MANUSCRIPT Anyway, from a molecular point of view toxic effects of quercetin are most likely connected with the formation of possible toxic products upon oxidation of quercetin during its ROS scavenging activities. As stated above, the most important oxidation product of quercetin that is quercetin-quinone is highly thiol reactive and reacts almost immediately with glutathione or in its absence with protein sulfhydryl groups, thereby damaging the function of several
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crucial enzymes [8, 9, 40]. Consequently, during in vivo quercetin supplementation care should be needed of the possible toxicity of its metabolites; especially in a chronic disorder, when supplementation has to extend over a much
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longer time period, the safety, tolerability and efficacy of (long term) quercetin supplementation remain to be established [73].
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CONCLUSIONS
The bioflavonoid quercetin has an extended spectrum of well characterized biological effects that include the
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promotion of health, the enhancement of physical and mental activity, and several distinct pharmacological effects. Of course, bioavailability of quercetin is an important mediator of its health benefits and, for that, a better understanding of
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the factors regulating quercetin metabolism and bioavailability is expected to confirm its potential role in managing
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different diseases.
Despite the plethora of studies on quercetin and its derivatives, it is not yet possible to establish dietary
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recommendations with regard to the types and amounts to be consumed. The inherent diversity of its derivatives analogous structure, chemistry, and natural distribution in foods lends itself to errors in reporting the types and/or amounts consumed, as well as incomplete recognition of requirements for intervention studies that aim to assess their
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benefits in a clinical setting. Thus, in the face of the scientific progress made over the past decades, several critical issues in the design and reporting of studies continue to limit progress in leveraging quercetin research findings into meaningful recommendations for consumers. These issues mainly include: 1) incomplete/inappropriate application of analytic methods, making determination of food content and dietary intake levels challenging; 2) limited data and/or description of test materials used in dietary intervention trials; 3) challenges with the application of appropriate methods for assessment of relevant bioavailability and metabolite formation in biological tissues that can provide key insights into food and clinical markers/outcomes. In particular, as elsewhere already reported [204] high-priority areas suggested for research of quercetin should include: a) Large clinical trials to compare the efficacy of different doses of quercetin versus standard-of-care angiotensin converting enzyme inhibitors for control of hypertension; b) Investigation of the biologic activity of quercetin aglycone versus quercetin glycosides, versus quercetin metabolites;
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ACCEPTED MANUSCRIPT c) Quercetin has multiple modes of action, but it is not known whether all of these actions are required for specific biologic effects. For instance, does quercetin’s ability to inhibit cell proliferation work through multiple mechanisms, similar to its effect on the cardiovascular system? d) Large multi-institutional trial with a stringent protocol to resolve the disparate results of quercetin treatment on
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exercise tolerance;
e) The ability of quercetin to either sensitize cells to cancer chemotherapeutic agents or to counteract the resistance to
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these drugs needs to be translated into animal studies using a variety of models. If results verify the findings observed with tissue culture cells, then phase I/II clinical trials need to be carried on.
However, in this review after reporting the main chemical features of quercetin and its metabolism, - when and
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where possible – pointing out the molecular, cellular, and functional bases of therapy, data appearing in the peerreviewed literature and focusing on the main therapeutic applications of quercetin are summarized. In particular, since
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the quercetin therapeutic applications are very spread out (Fig. 9), in the present review only the ones established by
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scientific researchers have been taken into account.
Figure 9. Quercetin prominent therapeutic applications. Thick arrows: most suggested uses in humans; thin arrows: uses mainly derived from animal studies. Partly adapted from [209].
Nonetheless, it is worth mentioning that many of these therapeutic applications require safety and quite often for most of them effectiveness has not been rigorously proven. Furthermore, some of these ill conditions are potentially grave and should be treated by a qualified healthcare staff. Due to all these features, the question mark which ends the title of the present review is justified because it underlines a key issue; in fact, although for several of the above mentioned therapeutic treatments there is some a strong evidence in humans and as a consequence a suggested use of quercetin, in most cases results derive from in vitro studies and/or from other animal species. On the other hand, scientific evidences for these specific treatments are sometimes good and well supported, but in other cases they are quite unclear, whereas for all other uses there are only unclear results. For that, since numerous studies herein described and regarding the therapeutic applications of quercetin have
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ACCEPTED MANUSCRIPT been performed either in vitro, by using cell cultures, and in vivo utilizing animal models, additional data are warranted to better assess the quercetin antioxidant activity and biological properties in human beings. Thus, it is hoped that in the near future well designed clinical studies in healthy individuals as well as in patients will be carried out to confirm the aforementioned beneficial quercetin effects, setting the optimal doses and forms of delivery, comparing quercetin with
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established procedures and assessing the possible side effects most of which are probably due to quercetin drug
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interaction.
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The author declares that there are no conflicts of interest.
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CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
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Financial support from MIUR (Ministero dell’Istruzione, Università e Ricerca), Rome, Italy, is gratefully
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acknowledged. Susan Edwards deserves sincere thanks for her considerable skill in helping to edit the manuscript.
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ACCEPTED MANUSCRIPT [189] Chen, Y.; Xiao, P.; Ou-Yang, D.S.; Fan, L.; Guo, D.; Wang, Y.N.; Han, Y,; Tu, J.H.; Zhou, G.; Huang, Y.F.; Zhou, H.H. Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, Nacetyltransferase and xanthine oxidase activity in healthy volunteers. Clin. Exp. Pharmacol. Physiol., 2009, 36, 828-833.
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ACCEPTED MANUSCRIPT [203] Hossion, A.M.; Zamami, Y.; Kandahary, R.K.; Tsuchiya, T.; Ogawa, W.; Iwado, A.; Sasaki, K. Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents. J. Med. Chem., 2011, 54, 3686-3703. [204] Miles, S.L.; McFarland, M., Niles, R.M. Molecular and physiological actions of quercetin: need for clinical trials
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explorer.eu/contents/polyphenol/330 (Accessed September 16, 2015). [206] U.S. National Library of Medicine, Open Chemistry Database,
http://pubchem.ncbi.nlm.nih.gov/compound/5280343#section=Top (Accessed September 16, 2015).
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[207] USDA Database for the Flavonoid Content of Selected Foods, Release 3.1, December 2013, Slightly revised, May 2014, prepared by Bhagwat, S.; Haytowitz, D.B.; Holden, J.M. (ret.),
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http://www.ars.usda.gov/News/docs.htm?docid=6231 (Accessed September 16, 2015). [208] Medscape, Drug & Disease, Quercetin (Herbs/Suppl.), http://reference.medscape.com/drug/quercetin-344495#3
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[209] Medscape, Drug & Disease, Quercetin (Herbs/Suppl.), http://reference.medscape.com/drug/quercetin-344495#2
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ACCEPTED MANUSCRIPT Tables (1-3) to: Quercetin: A flavonol with multifaceted therapeutic applications? Gabriele D’Andrea University of L’Aquila, Dept. of BACS, Coppito 2, 67100 L’Aquila, Italy
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email: [email protected]
: Adapted from Phenol-Explorer, Database on polyphenol content in foods [205].
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Table 1. Quercetin-3-O-β-D-glucuronide content in selected food1 Fruits and fruit products Fruits - Berries Grape, black 2.15 mg/100 g Strawberry, raw 1.74 mg/100 g Grape, green 1.50 mg/100 g Cloudberry 0.79 mg/100 g Red raspberry, raw 0.63 mg/100 g Non-alcoholic beverages Fruit juices - Berry juices Red raspberry, pure juice 6.18 mg/100 mL Fennel, tea 3.26 mg/100 mL Herb infusion Grape, green, pure juice 0.05 mg/100 mL Vegetables Leaf vegetables Lettuce, red, raw 2.65 mg/100 g Lettuce, green, raw 1.34 mg/100 g Pod vegetables Green bean, raw 0.80 mg/100 g
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Table 2. Quercetin identifiers and properties1 IDENTIFIERS 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one IUPAC Name 5280343 PubChem CID 1S/C15H10O7/c16-7-4-10(19)12-11(5-7)22InChl 15(14(21)13(12)20)6-1-2-8(17)9(18)3-6/h1-5,16-19,21H REFJWTPEDVJJIY-UHFFFAOYSA-N InChl Key C1=CC(=C(C=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O)O)O Canonical SMILE 117-39-5 CAS 204-187-1 EC Number 2811 UN Number 9IKM0I5T1E UNII 1. 3,3',4',5,7-pentahydroxyflavone 2. dikvertin MeSH Synonyms 3. quercetin Trivial Chemical Names Sophoretin; Xanthaurine; Meletin 302.2357 g/mol Molecular Weight C15H10O7 Molecular Formula PROPERTIES Yellow needles or yellow powder. Converts to anhydrous form at Physical Description 203-207 °F. Alcoholic solutions taste very bitter. 1.799 g/cm3 Density Yellow needles (dilute alcohol, + 2 water) Color Sublimes Boiling Point 316.5 °C Melting Point In water: 60 mg/mL at 16 °C; < 1mg/mL at 70 °F Very soluble in ether, methanol; soluble in ethanol, acetone, Solubility pyridine, acetic acid. 2.81x10-14 mm Hg at 25 °C Vapor Pressure When heated to decomposition it emits acrid smoke and irritating Decomposition fumes. pKa1 = 7.17; pKa2 = 8.26; pKa3 = 10.13; pKa4 = 12.30; pKa5 = Dissociation Constants (in phenol) 13.11 Max Absorption: 256 nm (log E= 4.32); 301 nm (log E= 3.89); Spectral Properties 373 nm (log E= 4.32); Sadler Ref. Number: 594 (IR, PRISM) 1
: Adapted from U.S. National Library of Medicine [206].
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ACCEPTED MANUSCRIPT Table 3. Quercetin content of selected foods1
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Quercetin amount (mg/100 g) edible portion 233.84 50.73 39.21 15.16 14.84 14.70 13.30 7.67 7.61 6.17 4.12 3.86 3.80 3.69 3.26 2.49 2.29 2.19 2.08 1.12 1.04 0.04
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Food source Capers, raw Peppers, hot, yellow, raw Onions, red, raw Asparagus, cooked Cranberries, raw Peppers, hot, green, raw Lingonberries, raw Blueberries, raw Lettuce, red leaf, raw Onions, white, raw Tomato, canned Apples, Red delicious, with skin Apples, Gala, with skin Apples, Golden delicious, with skin Broccoli, raw Tea, green, brewed Cherries, sweet, raw Tea, black, brewed Grapes, black Grapes, white Wine, red, table Wine, white, table
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: Adapted from USDA Database for the Flavonoid Content of Selected Foods [207].
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Graphical abstract
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