key: cord-0005288-7udwhbrx authors: Rani, Nidhi; Velan, Lakshmi Palanisamy Thanga; Vijaykumar, Saravanan; Arunachalam, Annamalai title: An insight into the potentially old-wonder molecule—quercetin: the perspectives in foresee date: 2015-09-09 journal: Chin J Integr Med DOI: 10.1007/s11655-015-2073-x sha: 778e07b469795ce077d20a389241f26813c9844b doc_id: 5288 cord_uid: 7udwhbrx Use of phyto-medicine and digitalization of phyto-compounds has been fallen enthralling field of science in recent years. Quercetin, a flavonoid with brilliant citron yellow pigment, is typically found in fruits and leafy vegetables in reasonable amount. Quercetin’s potentials as an antioxidant, immune-modulator, antiinflammatory, anti-cancer, and others have been the subject of interest in this review. Although, profiling the insights in to the molecular characterization of quercetin with various targets provided the loop-holes in understanding the knowledge for the aforementioned mechanisms, still necessitates research globally to unearth it completely. Thus, the available science on the synthesis and significant role played by the old molecule - quercetin which does wonders even now have been vividly explained in the present review to benefit the scientific community. In recent years, the values of synthetic drugs have almost lost due to its significant side effects and most of them have been withdrawn from the market because of their high toxicity. In fact, researchers have realized the potentials of herbs, which have been very well documented even before thousands of years. Generally, synthetic drugs are synthesized by pure ingredients, while herbal medicines are made up of complex ingredients. Those different ingredients in one or many herbs may balance each other, or in other words buffer each other, and act synergistically to make the systemic effect more potent. Moreover, some synthetic drugs may target only one molecule and therefore, its effect on other molecules in the pathways or systems are unknown and this often could lead to severe side effects. However, in contrast to this, herbs act on multiple targets, for example, one formulation may have effects on major diseases such as anti-inflammatory, antiallergic, (1) anti-oxidant, anti-toxic, including improvement of cardiovascular functions, anti-cancererous, (2) anti-diabetic, (3) and anti-osteoporotic. (4) Generally, bioflavonoids are a large group of non-nitrogenous class of plant secondary metabolites that provide pigmentation to flower and protect from ultraviolet light, microbes, and insects, apart from imparting flavors to the fruits and vegetables of the plants. (5) They are identifi ed as a good alternative to the synthetic drugs. One of the most valuable biofl avonoid is quercetin, which needs to be explored to a larger extent as it is reported to be the highly competitive and potential component in drug formulations. (6) Therefore, the present review was written to emphasize the information on quercetin's structure, synthesis, metabolism, medicinal value, proteomic, and genomic information, which in turn may provide evidence about its role as a therapeutic and outlines gap in the available data that need to be fi lled in order to determine the quercetin's appreciable role in future disease therapy. plants and are reported to exhibit the difference by the position of their functional group (Table 1) . sugars (glycosyl groups)] or as aglycones (without attached sugars). The hydroxyl group at the C-3 carbon is easily glycosylated to form quercetin glycosides. The monosaccharides such as glucose, galactose, rhamnose, or xylose are attached with quercetin at C-3 carbon and form quercetin 3-O-glycosides, (8) as found in sage (Salvia officinalis) and mango fruit (Mangifera indica), (9, 10) while quercetin 3-O-rhamnoside is found in olive (Olea europaea) oil, (11) peppers (Piper nigrum), (12) and spinach (Spinacia oleracea). (13) During glycosylation of the hydroxyl group (commonly at position 3), quercetin derivatives undergo a change from lipophilic to hydrophilic to form glycosylated quercetin, which is cytosol-soluble and could be easily transported to various parts of the plant. (14, 7) In general the physical and chemical properties (such as absorption, solubility, and in-vivo effects) of the glycosylated quercetin differ from aglycosylated quercetin. (15, 16) Disaccharides are also found to be attached with quercetin molecule such as rutin3-Orhamnosylglucoside as in tea (Camellia sinensis), (17) spinach, (13) chokeberries (Aronia arbutifolia), (18) and buckwheat (Fagopyrum esculentum ). (19) Another glycosylation site (hydroxyl group) is observed at C-7 as 3-O-rhamnoside-7-O-glucoside as seen in peppers (12) and quercetin 7-O-glucoside in beans (20) respectively. Perhaps, C-glycosides and sulphate derivatives of quercetin such as 3, 4, 7, 3', 4'-pentahydroxy-6-glucose flavon and quercetin 3-O-glucoside-3'sulfate were also found in Ageratina calophylla (21) and cornflower (Centaurea cyanus) (22) respectively, but these compounds occur relatively rare in nature. Q u e r c e t i n ( m o l e c u l a r f o r m u l a C 15 H 10 O 7 ; molecular weight of 302.236 g/mol) is a heterocyclic pyrone ring (aromatic trimeric heterocyclic) with two benzene rings. According to IUPAC, quercetin is a 3,3',4',5,7-pentahydroxyflavanone (synonym 3,3',4',5,7-pentahydroxy-2-phenylchromen-4-one), a compound with five hydroxyl groups attached in the ring structure at the position 3, 5, 7, 3', and 4' (Figure 2 ), giving it a status of amphipathic, i.e., both lipophilic and hydrophilic in nature. Those quercetin derivatives which have O-methyl, C-methyl, and prenyl derivatives are lipophilic and are reported in glands located on the surface of the leaves, fl owers, or fruits in members of Labiatae or Compositae families. (7) Basically, it is a brilliant citron yellow color compound which is often found in plant as either glycosides [with attached Quercetin is consumed daily by millions of people as a dietary source due to its presence in vegetables and fruits such as beans, onions, grapes, apple, green tea, berries, vegetables, nuts either in the fruits, fl owers, barks, and leaves ( Figure 3 ). Digestion of quercetin begins from oral cavity by cleavage of glycosides molecule by β-glycosidases, while aglycosylated molecule become more lipophilic and could be absorbed into the epithelial cell of the colon. (23) Generally, absorbed quercetins are metabolized in liver and unabsorbed in intestine involving four processes namely, glucuronidation, methylation, hydroxylation, and sulfonylation. galactonojirimycin (as an inhibitor of the lactase domain of LPH) in a rat everted-jejunal sac model. (30) Quercetin-3-glucuronides and quercetin-7-glucuronides, the major product of quercetin metabolism in the intestine are further absorbed or excreted by two pathways: (i) methylation of both quercetin-3-glucuronides and quercetin-7-glucuronides by methyltransferases, and (ii) hydroxylation of endogenous β-glucuronidase followed by sulfonylation to quercetin-3'-sulfate. (31, 32) Quercetin agylocones were found in human plasma as main circulating metabolite in an un-conjugated form, which resulted in deconjugation of quercetin glucuronides by the enzyme β-glucuronidase. (33) Nevertheless, an alternate mechanism for quercetin absorption was also revealed in small intestinal tract of human, where the flavonoid degrading strict anaerobic microorganism Eubacterium ramulus resides and cleaves quercetin ring structure into 3, 4-dihydroxy phenyl acetic acid. (34) Mainly, by the fact that the quercetin has all the right structural features for free radical scavenging activity, they exert beneficial health effects such as anti-inflammatory, anti-allergic, anti-oxidant, anti-toxic, and anti-viral against reverse transcriptase of human immuno deficiency virus (HIV) and other retroviruses including Herpes simplex virus type 1, polio-virus type 1, parainfluenza virus type 3, respiratory syncytial virus (RSV), and HIV-1 integrase. (35) Additionally, it is also reported to interact with cyclin-dependent kinases such as CDK6, CDK5, and CDK1, (36) fatty acid synthesizing enzyme (enoyl-acyl carrier protein reductase), (37) and G protein-coupled receptor (38) to label a few. Moreover, it has remarkably proven to improve the cardiovascular functions, reducing the risk for cancer. Although potential benefits are extraneous, it is not possible to highlight all of them individually and therefore, with much care, effort has been undertaken to cover at most under the four major headings. An immune response produces effector molecules that act to remove antigen by various mechanisms. Generally these effector molecules induce a subclinical and localized inflammatory response that eliminates antigen without extensively damaging the host tissue. An allergy is a hypersensitivity disorder of the immune system. An excessive activation of white blood cells, mast cells and basophils, through the immunoglobulin Glucuronidation is one of the detoxifying mechanisms in liver which play a major role in metabolism of xenobiotic compound with the help of uridine 5'-diphospho (UDP)-glucuronosyltransferase enzyme. (24) Quercetin is reported to be glucoronidized during passage across the epithelium in the liver by UDP-glucuronosyl transferase (25, 26) and further conjugates with glucose transporter receptor in small intestine. (27) For instance, a study on a rat's small intestine revealed the uptake of quercetin conjugate that interacted with intestinal hexose transport pathway through glucose transporter receptor and competitively inhibited the uptake of galactose, due to the presence of quercetin-3-glucoside in the mucosal medium, indicating its interaction with the sodium-dependent glucose transporter pathway (SGLT1). (28) However, several observations suggested that quercetin could be absorbed by two ways; as stated above, one in the small intestine by SGLT1 with subsequent deglycosylation within the enterocyte by cytosolic β-glucosidase, or luminal hydrolysis of the glucoside by lactase phlorizin hydrolase (LPH); and the other is absorption by passive diffusion of the released aglycone. (29) However, the first hypothesis was evaluated with the use of phlorizin (the inhibitor of SGLT1) and N-(n-butyl)-deoxy E antibody (IgE) is a symptom of allergic reaction. Quercetin exerts many effects on anti-allergic response; to inhibit histamine release in rat connective tissue mast cells, mucosal mast cells, (39) human lung, and intestinal mast cells. (40) In fact, quercetin isolated from Gingko biloba is reported to inhibit the lipopolysaccharide (LPS)induced tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β transcription by inhibiting the activation of ERK1/2 and p38 MAPK in macrophages. (41) The pathologic role of TNF-α and IL-4, which are involved in the onset of various allergic diseases including atopic dermatitis, atopic rhinitis, and asthma, were arrested even at the lower (100 μmol/L) concentration of quercetin, when applied on human umbilical cord blood-derived cultured mast cells (hCBMCs). (42) In another study, IgE or phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-mediated histamine release were blocked by quercetin in RBL-2H3 cells and also it inhibited the elevation of intracellular calcium as well as gene expression and production of all the pro-inflammatory cytokines. (43) In an experiment, quercetin also inhibited the expression of CD63 and CD203c and the histamine release by the basophils that were activated with anti-IgE. (44) Yet another investigation reported that quercetin inhibited the process of degranulation and suppressed the CD23 mRNA expression in RBL-2H3 cells at 10 μmol/L concentration. (45) Likewise, when FcεRI-anti-IgE activated model was treated with 1.8-20 μmol/L quercetin, it interacted with catalytic pocket of the enzyme and inhibited P13K, consequently leading to the loss of phosphorylation of kinases (such as Bruton's tyrosine kinase) (46) which otherwise would phosphorylate phosphoinositide phospholipase C-γ (PLCγ) and lead to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG) that may be responsible for the activation of membrane markers up-regulation and histamine production. (47) Moreover, quercetin is also reported to be effective on N-formyl-methionine-leucinephenylalanine (fMLP) triggered basophil function, which activate the P13Kγ and G-coupled receptor kinase (GRK) that are basically responsible for degranulation event by IP3-calcium signaling or by the activation of diacylglycerol-protein kinase C-PKC pathway. The calcium ionophore A23187 induced the expression of CD63 and CD203c and these markers promote the activation of Ca 2+ /calmodulin pathway, which is inhibited by quercetin. (48) Thus collectively, quercetin acts as a strong inhibitor of components those involved in allergic reaction and found to be functional even at the micromolar concentrations and thereby arising as a novel alternative for allergic treatments. Infl ammation is a mechanism of innate immunity which act as a first response from immune system against harmful stimuli, such as injury caused by pathogens, damaged cells, and irritation. (49) It is characterized by increased blood flow to the tissue, raise in temperature, redness, swelling, and pain. It may involve in developing various diseases such as allergy, asthma, arthritis, atherosclerosis, cancer, aging, etc. (50) Inflammation is a complex response which is caused by numerous biological factors such as LPS (major component of the Gram-negative bacteria cell wall), (51) enzymes [cyclooxygenase (COX) and lipoxygenase (LOX)], (52) nitric oxide production, and nitric oxide synthase (NOS) expression. (53) LPS is one of the major factor for infl ammation which is recognized by Toll-like receptor (TLR4) receptors that is found on the immune cells, including macrophages. (54) When LPS bind with specific TLR4 receptor, it can trigger signaling pathways and activate nuclear factor (NF)-κB. (55) Under normal conditions, NF-κB occurs in cytoplasm in an inactive state, bound to the inhibitory κB (IκB) proteins. The NF-κB is activated by IκB kinase (IKK) complex, that are composed of Ser/Thr kinases IKKα and IKKβ associated with other signal transducers IKKγ and IKAP. Signal components activate Ser/Thr kinases in IKK complex and activated IKK complex phosphorylates IκB and then followed by proteasomemediated degradation of IκB. (56, 57) After IκB degradation NF-κB enters into the nucleus and bind to the promoter regions of immune genes including IL-6 for transcriptional activation. (58) IL-6 is a pleiotropic interleukin that acts as both pro-inflammatory and anti-inflammatory cytokine. It is produced by T cells and macrophages as well as varieties of other cell types including adipocytes and microglial cell. (59) However, the effect of quercetin 3-O-β-(2"galloyl)-glucopyranoside (QG-32) from Persicaria lapathifolia (polygonacease) was realized when it inhibited reactive superoxide (ROS) production in human monocytes. (60) Perhaps, studies showed that ROS could increases the LPS-induced IL-6 expression at the transcription level. In spite of ROS's independent production, it could still amplify TLR4-mediated inflammatory responsiveness. (61) When endotoxin LPS-activated macrophages RAW 264.7 were treated with various concentrations (10-100 μmol/L) of QG-32 or pyrrolidine dithiocarbamate (PDTC) within 24 h, it inhibited the production of IL-6 as well as downregulated the LPS-induced IL-6 expression at the transcription level. (62) Similarly, NF-κB, a transcription factor that is involved in proteolytic degradation of IκB was also inhibited by the administration of quercetin. (62) In fact, quercetin inhibits cyclooxygenase and lipoxygenase at concentration of 10-20 μmol/L, which is an important mediator in inflammation and tumor promotion. (52) The NOS expression is also found to suppressed by administration of 100 μmol/L quercetin, resulting in inhibition of nitric oxide (a pro-inflammatory mediator) production. (53) Hence these factors may attribute a major role in numerous chronic diseases such as allergy, (50) diabetes, (63) atherosclerosis, (64) depression, (65) Alzheimer's disease, (66) systemic lupus erythematosus, (67) prostate cancer, (68) and rheumatoid arthritis. (69) Since these studies have given lots of pharmacological potential of quercetin in the inflammatory disorders, the action of quercetin against numerous inflammatory factors may provide a better option to cure above mentioned diseases in the future. The antioxidant activity of a compound is determined by the presence of free hydroxyl groups as well as position of double bond (14) that can donate electron through resonance to stabilize the free radicals. (70) The radical scavenging property defends the body against oxidative stress, reduces heart disease, prevents cancer, and slows the aging process in cells. (71) Lipid peroxidation is an oxidative degradation of lipid in which unsaturated fatty acids are converted to free radicals via the abstraction of hydrogen and further these free radicals are oxidized by molecular oxygen to create lipid peroxy radicals. Quercetin shows inhibitory effect against human lipoxygenase (hLO) isozymes (71) that catalyzes the dioxygenation of polyunsaturated fatty acids to their hydroperoxy acids that have been implicated in several diseases including inflammation, immune disorders, and various types of cancers. (72) The low-density lipoprotein (LDL) is another reason for cardiovascular disease. While, studies have shown the ability of quercetin to inhibit LDL oxidation, (73) it not only stops the lipid peroxidation but also increases the glutathione (GSH) level, (74) which is a tripeptide that acts as an antioxidant in our body and neutralizes the free radicals by regulating the nitric oxide cycle (75) and other biochemical reactions involved in DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Administration of quercetin-3'-glucuronidequercetin is also reported to inhibit xanthine oxidase, (76) which catalyzes the oxidation of hypoxanthine and xanthine to uric acid and superoxide radicals. The former plays a crucial role in gout, while the latter is involved in oxidative stress including infl ammation, atherosclerosis, cancer, and aging. So, an increase in xanthine oxidase infl uences the rate of hepatitis and the degree of brain edema and its control by derivative of quercetin could accomplish a good measure for treating hepatitis, brain edema and also reduce the oxidative stress. (77, 78) In view of the number of studies, it is clear that quercetin possesses the structure that act as an effective and powerful antioxidants and since it is playing a major role in preventing the above mentioned diseases, and hence quercetin could be a subject of interest to control them naturally. Oxidative DNA damage by oxygen species superoxide, hydroxyl, peroxyl, and alkoxyl, and reactive nitrogen species play a key role in human cancer development. The hydroxyl groups of quercetin have electron accepting capacity, while the catechol group chelate with metal ions. (23) In-vitro studies indicate that quercetin plays an important role in cancer treatment with the ability to act as potential antioxidants and there by inducing numerous molecular pathways such as apoptotic pathway, down-regulation of mutant P53 protein, G 1 -phase arrest, inhibition of tyrosine kinase, inhibition of heat shock proteins, inhibition of ras protein expression, and estrogen receptor binding capacity. Quercetin is reported to induce cell death by apoptosis in leukemia, lung, hepatoma, oral, and colon cancer cell lines. (79) For instance, administration o f 4 0 -5 0 μ m o l / L o f q u e r c e t i n i n d u c e d t h e mitochondrial apoptotic pathway through initiating Bcl-2-associated X protein (Bax) and/or Bcl-2 homologous antagonist/killer (Bak) proteins. These proteins are involved in increasing the size of outer mitochondrial membrane pore and cytochrome C leakage into the cytoplasm which further activates the apoptotic protease activating-factor 1 (APAF-1) and produces apoptosome. (80) The P53 is another important tumor suppression protein which activates the Bax and initiate cell death. When human hepatocellular carcinoma cell was treated with 40-120 μmol/L of quercetin, p53 expression was increased, while down-regulating the anti-apoptotic protein survivin that regulates the caspase activation and Bcl-2 that prevents mitochondrial mediated apoptosis. (81) TNF-α-related apoptosis-inducing ligand (TRAIL or Apo2L) that belongs to the TNF cytokine family is produced by the activated macrophages and it is responsible for inducing inflammation, apoptotic cell death, and inhibiting tumorogenesis through enhancing the transcription of Bcl-2. (82) TRAIL, however, binds with the death receptors DR4/DR5, which further interact with the adaptor protein Fas-associated death domain (FADD) and procaspase-8 and form the death-inducing signaling complex (DISC). Procaspase-8 activation and DISC lead to cleavage of procaspase-3 and engagement of the cellular machinery associated with the type Ⅰ extrinsic apoptotic pathway. However, evidence claim that these attributes by the TRAIL proves futile under glioma cells and many cancer cell lines became more or less resistant to the apoptotic effect. (83) Thus the administration of quercetin especially 250 μmol/L was revealed to reducing the viability of U251, LN229, U87-MG, MDA-MD-231 and A172 glioma cells and also affecting the estrogen receptor α (ER-α) by inducing cytotoxicity in some cancer cell lines. (84) Moreover, quercetin is also reported to prevent the ROS production in the human cervix epithelial carcinoma cell line (HeLa) and stimulate the activation of p38/MAPK, (85) which are responsible for proapoptotic caspase-3 activation and mediate poly (adenosine diphosphate-ribose) polymerase (PARP) cleavage. In another study quercetin (50 μmol/L) in combination with ascorbate bound to the estrogen receptor (ER-β) and induced apoptosis of breast cancer (T47D-ER-α) and osteosarcoma (U2OS-ER-α and -ER-β) by increasing the intracellular pH through the modulation of the cells Na + /H + exchanger. (86) Quercetin reportedly evidenced the inhibition of malfunction of protein chaperons that are basically responsible for protein folding and maintenance of protein structure in our body. The disturbed chaperons are unable to perform their function and eventually result is death. Moreover, the heat shock proteins (HSP) such as HSP90, HER2, and IGFBP-2 allowed tumor cells to bypass normal mechanisms of cell cycle and allowed survival of cancer cell in unfavorable condition viz., hypoxic condition, low circulation, high temperature etc. However, these conditions were reported to be suppressed by quercetin (1-100 μmol/L) in several malignant cell lines namely colon cancer, (87, 88) breast cancer, and prostate cancer. (89) Thus, the ability of quercetin to interact with electrons even at lesser concentrations plays a central role in its mechanism of action, mainly by the activation of proteins and DNA damage, leading to the induction of many downstream pathways of the cancer. Thus quercetin is the subject of intense research on the basis of its anti-inflammatory, anti-allergic, antioxidant, and anti-cancer activities, as well as many therapeutic targets to cure different kinds of diseases such as Alzheimer's disease, diabetes, malaria, Chagas' disease, Schizophrenia etc. Apart from this, studies also suggested that quercetin is effective against antibiotic resistance bacteria. For instance, the antibacterial activities of quercetin has been tested on anti-methicillin resistant Staphylococcus aureus (MRSA), which uncovered the unique antibacterial properties of quercetin against Staphylococcus aureus (S. aureus). (90) The study was further substantiated by in-silico approach, which showed a strong interaction of quercetin and kaempferol with multidrug resistant β lactamase of S. aureus. (91) Thus, collectively, one could say that the quercetin has risen as a novel alternate to the synthetic molecules as evidenced by the enlisted literature presented in Table 2 . Realizing the potentials, it has become essential to know about the synthesis of quercetin, which involves in multiple enzymatic processes in the cytoplasm and associated with endoplasmic reticulum (137) via phenyl propanoid pathway (Figure 4 ). The first step of this pathway is deamination of phenylalanine by the enzyme L-phenylalanine ammonia-lyase (PAL), (138) which acts as a precursor molecule to synthesize 4-coumarate that further acts as a substrate for formation of 4-coumaroyl coenzyme (CoA) with the help of 4-coumarate-CoA ligase using 1 ATP molecule. The 4-coumaroyl CoA also participates in 6'-deoxychalcone metabolism and in isoflavonoid biosynthesis Ⅰ, in addition to the synthesis of naringenin chalcone, which involves in the precipitation of bioflavonoid or may form many (112, 113, 71) Cyclooxygenase-1/Cyclooxygenase-2 -50000.0 Rattus norvegicus Formation of prostaglandins, prostacyclin and thromboxane (112, 114, 113) Tyrosine-protein kinase LCK, Tyrosine-protein kinase SRC, EGF-R Tyrosine Kinase where the former is important for synthesizing derivatives of auronem that imparts yellow color to flowers, (139) while the later is involved in synthesizing chalcone 2'-O-glucoside. The most stereochemically important reaction of flavonoid biosynthesis is conversion of naringenin chalcone to naringenin (2S-flavanones) using chalcone isomerase (CHI, 4th step) or chalcone-flavanone isomerase. (140) Precisely, the synthesized naringenin acts as an intermediate for formation of flavones, flavonols, flavan-4-ols, anthocyanins, and isoflavonoids. Thus, naringenin is involved in five different pathways that include ponciretin biosynthesis, sakuranetin biosynthesis, naringenin glycoside biosynthesis, luteolin biosynthesis, and isoflavonoid biosynthesis Ⅱ, which synthesizes ponciretin, 2S-sakuranetin, naringenin, luteolin, and pratensein respectively. In the meanwhile as a 5th step dihydrokaempferol is synthesized using naringenin 3-dioxygenase, which leads to the leucopelargonidin, leucocyanidin and kaempferolglucoside biosynthesis apart from quercetin/flavonol biosynthesis. Further, dihydrokaempferol in the presence of flavonoid 3'-monoxygenase is converted to dihydroquercetin. Thus it is evident from the step 7 that the synthesis of quercetin is dependent on 2-oxoglutarate-dependent dioxygenases flavonol synthase (FLS), which is an enzyme that belongs to oxidoreductases family and shows a broad substrate and product selectivity. (141, 142) Since FLS is an enzyme that catalyzes the formation of quercetin, it is considered to be vital in the quercetin biosynthetic pathway. Eventually the synthesis of glycosylated quercetin from aglycosylated quercetin is catalyzed by the quercetin 3-O-glucosyltransferase and quercetin 3-O-rhamnosyltransferase enzyme (8th and 9th step) (143) by the transfer of a glucosyl group from UDP-glucose to the 3'-hydroxy group (of a quercetin molecule). Thus, the glycosylation of aglycosylated quercetin is responsible for the modifi cation of stability, solubility, or localization, and the biological properties of the quercetin glycosides. (143) Taking into account the importance of each enzyme or the intermediary products formed during the process of secondary metabolite (quercetin) synthesis, it has become necessary to know about the genes involved in the system. With this perception, the literary surfi ng earmarked the remarkable quantity of work done on this segment. In fact, the genes responsible for almost all the enzymes involved in the pathway has been studied and very well documented (Table 3) . However, when observed keenly, one could realize that the plant systems, that has been explored is very limited (http://medicinalplantgenomics.msu. edu/; http://www.plantcyc.org/). When the medicinal plants find application in pharmaceutical, cosmetic, agricultural, and food industry right from the prehistoric era and that when the plant diversity is rich in the world, (144) why there is scarce research on the molecular investigation of this vital compound in the herbal systems? Digital inventory has a significant role in the pharmaceutical market as many drug interaction studies use these databases for either virtual screening of ligand based on plant origin or proteins, which are of clinical importance (Table 4 ). (91) Although many plant databases are available (many are licensed/commercialized), most of them reveals less information on the important secondary metabolites, which once again give us a scope in the future for extending research in this frontier area. Quercetin derivatives are available not only in dietary vegetables; also it is present in plants that are non-dietary such as Ginkgo biloba and Hypericum perforatum. Quercetin derivatives are generally nontoxic and manifest a diverse range of beneficial biological activities which are abundantly present in the human diet, as evidenced through the ongoing epidemiological studies, promotion as an effective anti-oxidative agent with scavenging (chelating) capacities and interaction with diverse range of therapeutic target. Therefore, this compound is being intensively investigated, which indicated its role as anti-inflammatory, anti-allergic, antioxidant, anti-cancerous, etc. This has proportionally increased the demand for quercetin from the pharmaindustry as an alternate for the synthetic molecules and has given scope for two important concepts to be concentrated in the future. One, in spite of the diverse medicinal properties upholded by quercetin, the lack of experiments in testing quercetin's effi ciency on various diseases clinically has necessitated the need to clarify the nature of the impact and interactions between quercetin on different types of targets; and the other concept probably would be a mechanism to determine how effi cient and practical it would be to increase the production of quercetin using the available proteomic and genomic details, as the role of quercetin is limitless. Nidhi Characteristics of lymphocyte nuclear factor-kappaB signal transduction kinase expression in aging process and regulatory effect of epimedium flavonoids Anticancer activity of total fl avonoids isolated from Xianhe Yanling Recipe Mechanism of action of natural products used in the treatment of diabetes mellitus Interventional value of total fl avonoids from Rhizoma Drynariae on Cathepsin K, a potential target of osteoporosis Advances in fl avonoid research since 1992 The fl avonoid quercetin in disease prevention and therapy: facts and fancies Anthocyanins and other fl avonoids Food fl avonoids Polyphenolics of Salvia -a review Screening of mango (Mangifera indica L.) cultivars for their contents of flavonol O-and xanthone Determination of phenolic compounds in olives by reversed-phase chromatography and mass spectrometry Isolation and structure elucidation of flavonoid and phenolic acid glycosides from pericarp of hot pepper fruit Capsicum annuum L Antioxidant capacity and phenolic content in leaf extracts of tree spinach (Cnidoscolus spp Flavonoids in health and disease The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man Dietary flavonoids: bioavailability, metabolic effects, and safety Consumption of black currants, lingonberries and bilberries increases serum quercetin concentrations Flavonoids from black chokeberries, Aronia melano-carpa Distribution of vitamin E, squalene, epicatechin, and rutin in common buckwheat plants (Fagopyrum esculentum Moench) Identification of flavonoids in Hakmeitau beans (Vigna sinensis) by high-performance liquid chromatography-electrospray mass spectrometry (LC-ESI/MS) The fl avonoids: advances in research since 1986 Two fl avonoids and other compounds from the aerial parts of Centaurea bracteata from Italy Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin Regioselectivity of phase Ⅱ metabolism of luteolin and quercetin by UDP-glucuronosyl transferases Metabolism of quercetin and kaempferol by rat hepatocytes and the identification of flavonoid glycosides in human plasma Quercetin glucosides interact with the intestinal glucose transport pathway Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway Absorption of quercetin-3-glucoside and quercetin-4'-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter Inhibition of the intestinal glucose transporter GLUT2 by fl avonoids Metabolism of quercetin-7-and quercetin-3-glucuronides by an in vitro hepatic model: the role of human beta-glucuronidase, sulfotransferase, catechol-Omethyltransferase and multi-resistant protein 2 (MRP2) in fl avonoid metabolism Breast cancer resistance protein (Bcrp1/ Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of glucuronides Inhibition of phenol sulfotransferase (SULT1A1) by quercetin in human adult and foetal livers Transformation of flavonoids by intestinal microorganisms Three-dimensional quantitative structure-activity relationship (QSAR) of HIV integrase inhibitors: a comparative molecular fi eld analysis (CoMFA) study Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR). J • 13 • Chin Lessons learned from herbal medicinal products: the example of St. John's Wort (perpendicular) Role of mast cells in gastrointestinal mucosal defense Comparison of human lung and intestinal mast cells Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages Flavonols inhibit proinfl ammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells Flavonoids inhibit histamine release and expression of proinfl ammatory cytokines in mast cells Bimodal action of the flavonoid quercetin on basophil function: an investigation of the putative biochemical targets Quercetin and kaempferol suppress immunoglobulin E-mediated allergic infl ammation in RBL-2H3 and Caco-2 cells PI3K delta and PI3K gamma: partners in crime in infl ammation in rheumatoid arthritis and beyond? Expression of protein kinase C isozymes in human basophils: regulation by physiological and nonphysiological stimuli Roles of G beta gamma in membrane recruitment and activation of p110 gamma phosphoinositide 3-kinase gamma Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells Quercetin tetraacetyl derivative inhibits LPS-induced nitric oxide synthase (iNOS) expression in J774A.1 cells Innate recognition of lipopolysaccharide by Tolllike receptor 4-MD-2 Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4 s ubiquitination: the control of NF-[kappa]B activity The ubiquitindependent proteolytic system and other potential targets for the modulation of nuclear factor-κB (NF-κB) Identifi cation of a nuclear factor kappa B-dependent gene network Purification and characterization of human fi broblast derived differentiation inducing factor for human monoblastic leukemia cells identical to interleukin-6 Flavonol glycoside gallate and ferulate esters from Persicaria lapathifolia as inhibitors of superoxide production in human monocytes stimulated by unopsonized zymosan Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression Quercetin 3-O-beta-(2''-galloyl)-glucopyranoside inhibits endotoxin LPS-induced IL-6 expression and NF-kappa B activation in macrophages Interleukin-6 and diabetes: the good, the bad, or the indifferent? The role of interleukin-6 in development and progression of atherosclerosis A meta-analysis of cytokines in major depression A meta-analysis of cytokines in Alzheimer's • 14 • Chin J Integr Med disease Rationale for interleukin-6 blockade in systemic lupus erythematosus Interleukin-6 and prostate cancer progression Interleukin-6 in rheumatoid arthritis Dietary flavonoids: intake, health effects and bioavailability Structure-activity relationship studies of fl avonoids as potent inhibitors of human platelet 12-hLO, reticulocyte 15-hLO-1, and prostate epithelial Nonalcoholic red wine extract and quercetin inhibit LDL oxidation without affecting plasma antioxidant vitamin and carotenoid concentrations Protective effect of quercetin in primary neurons against -42): relevance to Alzheimer's disease Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions Free radicals, antioxidants, and human disease: where are we now? Structure-activity relationship and classifi cation of fl avonoids as inhibitors of xanthine oxidase and superoxide scavengers Characteristic of neuraminidase inhibitory xanthones from Cudrania tricuspidata Specifi c ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis Regulation of survivin and Bcl-2 in HepG2 cell apoptosis induced by quercetin The TNF and TNF receptor superfamilies: integrating mammalian biology TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specifi c apoptosis within a therapeutic window Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells Quercetin-induced apoptotic cascade in cancer cells: antioxidant versus estrogen receptor alpha-dependent mechanisms Oestrogen modulates human macrophage apoptosis via differential signalling through oestrogen receptor-alpha and beta Quercetin, an inhibitor of heat shock protein synthesis, inhibits the acquisition of thermotolerance in a human colon carcinoma cell line Modulation of prostaglandin A1-induced thermotolerance by quercetin in human leukemic cells: role of heat shock protein 70 Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells The dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the expression of heat shock protein 90 Characterisation of anti-Staphylococcus aureus activity of quercetin Molecular docking analysis of phyto-ligands with multi drug resistant β-lactamases of Staphylococcus aureus Inhibition of plasmodium falciparum fatty acid biosynthesis: evaluation of FabG, FabZ, and FabI as drug targets for fl avonoids Conformer-and alignment-independent model for predicting structurally diverse competitive CYP2C9 • 15 • Chin J Integr Med inhibitors Selective inhibition of methoxyflavonoids on human CYP1B1 activity Comparative CYP1A1 and CYP1B1 substrate and inhibitor profi le of dietary fl avonoids Casein kinase 2 is activated and essential for Wnt/beta-catenin signaling Biochemical and three-dimensionalstructural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo-(1,2-a)quinazolin-7-yl] acetic acid (IQA) Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin, and curcumin Modulation of multi drug resistance protein 1 (MRP1/ABCC1)-mediated multi drug resistance by bivalent apigenin homodimers and their derivatives Interactions of fl avonoids and other phytochemicals with adenosine receptors Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms Ⅰ-with a series of natural product polyphenols and phenolic acids Carbonic anhydrase inhibitors: Inhibition of human erythrocyte isozymes Ⅰ and Ⅱ with a series of phenolic acids Molecular docking studies of phlorotannins from Eisenia bicyclis with BACE1 inhibitory activity Structure-activity relationship studies of flavopiridol analogues CTN-986, a compound extracted from cottonseeds, increases cell proliferation in hippocampus in vivo and in cultured neural progenitor cells in vitro Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine Kinase inhibitors: not just for kinases anymore Flavonoids for controlling starch digestion: structural requirements for inhibiting human alpha-amylase Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase dioxides: new aldose reductase and L-hexonate dehydrogenase inhibitors 1-Benzopyran-4-one antioxidants as aldose reductase inhibitors Penta-and hexadienoic acid derivatives: a novel series of 5-lipoxygenase inhibitors Lipoxygenase inhibitory constituents of the fruits of noni (Morinda citrifolia) collected in Tahiti Indazolinones, a new series of redox-active 5-lipoxygenase inhibitors with built-in selectivityoral activity Synthesis and protein-tyrosine kinase inhibitory activities of fl avonoid analogues Discovering novel quercetin-3-O-amino acid-esters as a new class of Src tyrosine kinase inhibitors Assessment of solvation effects on calculated binding affi nity differences: trypsin inhibition by fl avonoids as a model system for congeneric series A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening Natural PTP1B inhibitors from Broussonetia papyrifera Novel, highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl) acetic acid derivatives Synthesis, activity, and molecular modeling of a new series of tricyclic pyridazinones as selective aldose reductase inhibitors Effects of natural fl avones and fl avonols on the kinase activity of Cdk5 Serotonin receptors Alkaloids from Eschscholzia californica and their capacity to inhibit binding of [ 3 H]8-Hydroxy-2-(di-N-propylamino)tetralin to 5-HT1A receptors in vitro Structure-activity relationship of human GLO Ⅰ inhibitory natural flavonoids and their growth inhibitory effects Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries Discovery of novel trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase inhibitors Investigation of the pharmacophore space of severe acute respiratory syndrome coronavirus (SARS-CoV) NTPase/ helicase by dihydroxychromone derivatives Quercetin as the active principle of Hypericum hircinum exerts a selective inhibitory activity against MAO-A: extraction, biological analysis, and computational study A new series of fl avones, thiofl avones, and flavanones as selective monoamine oxidase-B inhibitors Structure-based virtual screening approach to the discovery of novel inhibitors of factor-inhibiting HIF-1: identification of new chelating groups for the active-site ferrous ion Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19) Small-molecule inhibitors of NADPH oxidase Vasorelaxant effect of flavonoids through calmodulin inhibition: Ex vivo, in vitro, and in silico approaches Structure-activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP) Biological evaluation and structural determinants of p38alpha mitogenactivated-protein kinase and c-Jun-N-terminal kinase 3 inhibition by fl avonoids immunological, and immunocytochemical evidence for the association of chalcone synthase with endoplasmic reticulum membranes The metabolism of aromatic compounds in higher plants. Ⅳ. Purifi cation and properties of the phenylalanine deaminase of Hordeum vulgare Enzymology of aurone biosynthesis Purifi cation and characterization of chalcone isomerase from soybeans Mechanistic studies on three 2-oxoglutaratedependent oxygenases of flavonoid biosynthesis: anthocyanidin synthase, fl avonol synthase, and fl avanone 3beta-hydroxylase Functional analysis of a predicted flavonol synthase gene family in Arabidopsis Phylogenetic analysis of the UDP-glycosyltransferase multigene family of Arabidopsis thaliana Medicinal plant informatics-an insight The authors acknowledge the library facilities extended by both Pondicherry University and Karunya University.