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Chemical Structures of Quercetin and Its Glycosides (A) Quercetin, (B) quercetin-3-O-rhamnoside (Rham1), (C) rutin and (D) quercetin3-(2 G-rhamnosylrutinoside) (Rham2).
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Quercetin, one of the flavonoids, is a compound of low molecular weight found in various plants and shows a wide range of diverse neuropharmacological actions. In fruits and vegetables, quercetin exists as monomer- (quercetin-3-O-rhamnoside) (Rham1), dimer- (Rutin), or trimer-glycosides [quercetin-3-(2G-rhamnosylrutinoside)] (Rham2) at carbon-3. In...
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Context 1
... has been known that dietary quercetin and its glycosides are metabolized into three ways. First is to remain in intact quercetin or conjugated with glucoses or sulfates to produce quercetin glucuronides or quercetin sulfates in blood stream; second way is to deglycosylate quercetin to quercetin agly- cone; third way is to remain with quercetin glycosides with- out further metabolisms. 8,9) Interestingly, quercetin glu- curonides or quercetin sulfates maintain their biological ac- tivities as antioxidants if they are conjugated with carbon-3 but not carbon-4. These results indicate that the antioxidant effects of quercetin and its metabolites are due to catechol 3A Receptor by Quercetin and Its Glycosides ring of quercetin backbone structure (Fig. 1). 8) However, it is unknown whether catechol ring of quercetin is also involved in ligand-gated ion channel activity regulations. In future, further investigations using flavonoids, which are conjugated at carbon-4, will be required to evaluate whether intact cate- chol ring of flavonoids is also necessary for the regulation of ligand-gated ion channel ...
Context 2
... one of the flavonoids, and its glycosides are substances of low molecular weight mainly found in apple, tomato, gingko and other red fruits (Fig. 1A). 12) Quercetin shows a wide range of biological activities, [13][14][15] with neu- ropharmacological actions such as analgesia, motility and sleep, 16,17) neuronal oxidative modulations, 18) proconvulsant, anticonvulsant, sedative and anxiolytic effects. [19][20][21] The cel- lular mechanisms underlying quercetin, especially on synap- tic transmissions are not well studied. In the previous studies, we could demonstrate that quercetin regulates glycine and 5- HT 3A receptor channel activities. 6,7) However, although most of quercetin in fruits and vegetables exist as quercetin glyco- sides, the pharmacological and physiological roles of those quercetin glycosides are relatively unknown in nervous sys- ...
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The inhibitory glycine receptor (GlyR) is a pentameric transmembrane protein composed of homologous alpha and beta subunits. Single expression of alpha subunits generates functional homo-oligomeric GlyRs, whereas the beta subunit requires a co-expressed alpha subunit to assemble into hetero-oligomeric channels of invariant stoichiometry (alpha(3)be...
Citations
... However, it is cost-effective and not economically feasible to use these expensive NDP-sugars in large-scale production. The use of microbial synthesis, therefore, seems to be the most viable and efficient option for the biosynthesis of glycosylated products by the use of cell factory manipulations or heterologous expressions of genetic materials [11,35]. Nonetheless, the use of microbes such as an E. coli cell factory for in vivo synthesis of diverse sugar conjugated products, is limited due to lesser conversion of substrates, low substrate susceptibility, and production of endotoxins [36,37]. ...
Corynebacterium glutamicum is traditionally known as a food-grade microorganism due to its high ability to produce amino acids and its endotoxin-free recombinant protein expression factory. In recent years, studies to improve the activities of useful therapeutics and pharmaceutical compounds have led to the engineering of the therapeutically advantageous C. glutamicum cell factory system. One of the well-studied ways to improve the activities of useful compounds is glucosylation with glycosyltransferases. In this study, we successfully and efficiently glycosylated therapeutic butyl-4-aminobenzoate and other N-linked compounds in C. glutamicum using a promiscuous YdhE, which is a glycosyltransferase from Bacillus lichenformis. For efficient glucosylation, components, such as promoter, codons sequence, expression temperatures, and substrate and glucose concentrations were optimized. With glucose as the sole carbon source, we achieved a conversion rate of almost 96% of the glycosylated products in the culture medium. The glycosylated product of high concentration was successfully purified by a simple purification method, and subjected to further analysis. This is a report of the in vivo cultivation and glucosylation of N-linked compounds in C. glutamicum.
... Finally, LA inhibited 5-HT3 receptors, which are crucial mediators of nausea. Licorice has been used to treat stomach ulcers, gastrointestinal inflammation, and respiratory diseases (Lee et al., 2008). LA may be involved in regulating peristalsis and digestion to improve symptoms of functional dyspepsia and irritable bowel syndrome. ...
Licochalcone A (LA), a useful and valuable flavonoid, is isolated from Glycyrrhiza uralensis Fisch. ex DC. and widely used clinically in traditional Chinese medicine. We systematically updated the latest information on the pharmacology of LA over the past decade from several authoritative internet databases, including Web of Science, Elsevier, Europe PMC, Wiley Online Library, and PubMed. A combination of keywords containing “Licochalcone A,” “Flavonoid,” and “Pharmacological Therapy” was used to help ensure a comprehensive review. Collected information demonstrates a wide range of pharmacological properties for LA, including anticancer, anti-inflammatory, antioxidant, antibacterial, anti-parasitic, bone protection, blood glucose and lipid regulation, neuroprotection, and skin protection. LA activity is mediated through several signaling pathways, such as PI3K/Akt/mTOR, P53, NF-κB, and P38. Caspase-3 apoptosis, MAPK inflammatory, and Nrf2 oxidative stress signaling pathways are also involved with multiple therapeutic targets, such as TNF-α, VEGF, Fas, FasL, PI3K, AKT, and caspases. Recent studies mainly focus on the anticancer properties of LA, which suggests that the pharmacology of other aspects of LA will need additional study. At the end of this review, current challenges and future research directions on LA are discussed. This review is divided into three parts based on the pharmacological effects of LA for the convenience of readers. We anticipate that this review will inspire further research.
... There are different approaches for the biosynthesis of quercetin rhamnoside, like microbial biotransformation using different microorganisms (Lee et al. 2008;Xiao et al. 2014). E. coli is also becoming popular in synthetic biology for the efficient cell factories designed by genetic manipulation, or recombining heterologous genetic materials (Shiloach and Fass 2005). ...
Two sustainable and cost-effective cascade enzymatic systems were developed to regenerate uridine diphosphate (UDP)-α-d-glucose and UDP-β-l-rhamnose from sucrose. The systems were coupled with the UDP generating glycosylation reactions of UDP sugar–dependent glycosyltransferase (UGT) enzymes mediated reactions. As a result, the UDP generated as a by-product of the GT-mediated reactions was recycled. In the first system, YjiC, a UGT from Bacillus licheniformis DSM 13, was used for transferring glucose from UDP-α-d-glucose to naringenin, in which AtSUS1 from Arabidopsis thaliana was used to synthesize UDP-α-d-glucose and fructose as a by-product from sucrose. In the second system, flavonol 7-O-rhamnosyltransferase (AtUGT89C1) from A. thaliana was used to transfer rhamnose from UDP-β-l-rhamnose to quercetin, in which AtSUS1 along with UDP-β-l-rhamnose synthase (AtRHM1), also from A. thaliana, were used to produce UDP-β-l-rhamnose from the same starter sucrose. The established UDP recycling system for the production of naringenin glucosides was engineered and optimized for several reaction parameters that included temperature, metal ions, NDPs, pH, substrate ratio, and enzymes ratio, to develop a highly feasible system for large-scale production of different derivatives of naringenin and other natural products glucosides, using inexpensive starting materials. The developed system showed the conversion of about 37 mM of naringenin into three different glucosides, namely naringenin, 7-O-β-d-glucoside, naringenin, 4′-O-β-d-glucoside, and naringenin, 4′,7-O-β-d-diglucoside. The UDP recycling (RCmax) was 20.10 for naringenin glucosides. Similarly, the conversion of quercetin to quercetin 7-O-α-l-rhamnoside reached a RCmax value of 10.0.
... There are a few reports regarding their effects on α7, specifically showing that genistein and quercetin enhance the macroscopic currents of α7 elicited by ACh (Grønlien et al., 2007;Lee et al., 2010). Interestingly, the positive modulatory effects of flavonoids seems to be specific for α7 among pLGICs since genistein inhibits GABA A (Huang et al., 1999), glycine (Huang and Dillon, 2000), 5-HT 3 A, α4β2 and α3β4 receptors (Grønlien et al., 2007); and quercetin inhibits 5-HT 3 A (Lee et al., 2008(Lee et al., , 2005, glycine , GABA A (Goutman et al., 2003;Kim et al., 2015), muscle nAChR (Lee et al., 2011c), α3β4 (Lee et al., 2011b), α4β2 (Goutman et al., 2003), and α9α10 receptors (Lee et al., 2011a). ...
... (Andersen et al., 2016;Bouzat et al., 2004;Rayes et al., 2005). Whereas Gen and Que were shown to negatively modulate 5-HT 3 A receptors (Goutman et al., 2003;Grønlien et al., 2010;Lee et al., 2008Lee et al., , 2005, both flavonoids exert the opposite effect on α7 receptors. Thus, the use of the chimeric receptor constitutes a good approach to identify the structural determinants of potentiation. ...
The use of positive allosteric modulators (PAM) of α7 nicotinic receptors is a promising therapy for neurodegenerative, inflammatory and cognitive disorders. Flavonoids are polyphenolic compounds showing neuroprotective, anti-inflammatory and pro-cognitive actions. Besides their well-known antioxidant activity, flavonoids trigger intracellular pathways and interact with receptors, including α7. To reveal how the beneficial actions of flavonoids are linked to α7 function, we evaluated the effects of three representative flavonoids -genistein, quercetin and the neoflavonoid 5,7-dihydroxy-4-phenylcoumarin- on whole-cell and single-channel currents. All flavonoids increase the maximal currents elicited by acetylcholine with minimal effects on desensitization and do not reactivate desensitized receptors, a behaviour consistent with type I PAMs. At the single-channel level, they increase the duration of the open state and produce activation in long-duration episodes with a rank order of efficacy of genistein > quercetin ≥ neoflavonoid. By using mutant and chimeric α7 receptors, we demonstrated that flavonoids share transmembrane structural determinants with other PAMs. The α7-PAM activity of flavonoids results in decreased cell levels of reactive oxygen species. Thus, allosteric potentiation of α7 may be an additional mechanism underlying neuroprotective actions of flavonoids, which may be used as scaffolds for designing new therapeutic agents.
... Salvia miltiorrhiza and Astragalus propinquus are compounds in a two-ingredient intermixture called myelophil. This mixture has been shown to reduce chemotherapy-correlated adverse side effects, including myelosuppression and anemia, from the cytostatic drug fluorouracil ( Shin et al., 2008) and possesses no described side effects itself ( Jung et al., 2009). Furthermore, myelophil reduced fatigue in patients suffering from chronic fatigue ( Cho et al., 2009) and exhibited anti-amnesic effects in scopolamine-treated mice ( Lee et al., 2014). ...
Kampo medicine is a form of Japanese phytotherapy originating from traditional Chinese medicine (TCM). During the last several decades, much attention has been paid to the pharmacological effects of these medical plants and their constituents. However, in many cases, a systematic screening of Kampo remedies to determine pharmacologically relevant targets is still lacking. In this study, a broad screening of Kampo remedies was performed to look for pharmacologically relevant 5-HT3A and GABAA receptor ligands. Several of the Kampo remedies are currently used for symptoms such as nausea, emesis, gastrointestinal motility disorders, anxiety, restlessness, or insomnia. Therefore, the pharmacological effects of 121 herbal drugs from Kampo medicine were analyzed as ethanol tinctures on heterologously expressed 5-HT3A and GABAA receptors, due to the involvement of these receptors in such pathophysiological processes. The tinctures of Lindera aggregata (radix) and Leonurus japonicus (herba) were the most effective inhibitory compounds on the 5-HT3A receptor. Further investigation of known ingredients in these compounds led to the identification of leonurine from Leonurus as a new natural 5-HT3A receptor antagonist. Several potentiating herbs (e.g., Magnolia officinalis (cortex), Syzygium aromaticum (flos), and Panax ginseng (radix)) were also identified for the GABAA receptor, which are all traditionally used for their sedative or anxiolytic effects. A variety of tinctures with antagonistic effects Salvia miltiorrhiza (radix) were also detected. Therefore, this study reveals new insights into the pharmacological action of a broad spectrum of herbal drugs from Kampo, allowing for a better understanding of their physiological effects and clinical applications.
... Similarly to that, the other terpen trialactones from Ginkgo biloba extract (ginkgolide A, C, and bilobalide) block GlyR channels though with weak subunit discrimination (Hawthorne et al., 2006;Lynch, 2009). Quercetin, belonging to the flavanoid group, also inhibits α1 GlyR activity (Lee et al., 2008) in a non-competitive manner, with an IC 50 of about 45 μM (Raafat et al., 2010). This compound also inhibits GABA A and GABA C receptors (Kim et al., 2015), causing seizures in animal models (Nassiri-Asl et al., 2014). ...
Glycine receptors (GlyRs) belong to the superfamily of pentameric cys-loop receptor-operated channels and are involved in numerous physiological functions, including movement, vision, and pain. In search for compounds performing subunit-specific modulation of GlyRs we studied action of ginkgolic acid, an abundant Ginkgo biloba product. Using patch-clamp recordings, we analyzed the effects of ginkgolic acid in concentrations from 30 nM to 25 μM on α1–α3 and α1/β, α2/β configurations of GlyR and on GABAARs expressed in cultured CHO-K1 cells and mouse neuroblastoma (N2a) cells. Ginkgolic acid caused an increase in the amplitude of currents mediated by homomeric α1 and heteromeric α1/β GlyRs and provoked a left-shift of the concentration-dependent curves for glycine. Even at high concentrations (10–25 μM) ginkgolic acid was not able to augment ionic currents mediated by α2, α2/β, and α3 GlyRs, or by GABAAR consisting of α1/β2/γ2 subunits. Mutation of three residues (T59A/A261G/A303S) in the α2 GlyR subunit to the corresponding ones from the α1 converted the action of ginkgolic acid to potentiation with a distinct decrease in EC50 for glycine, suggesting an important role for these residues in modulation by ginkgolic acid. Our results suggest that ginkgolic acid is a novel selective enhancer of α1 GlyRs.
... Moreover, quercetin was found to inhibit Na + channels in hippocampal pyramidal neurons [136]. Quercetin and its dimer glycoside rutin were found to inhibit GABA C , glycine, and 5-HT3A receptor channels [137,138]. ...
... Similarly to that, the other terpen trialactones from Ginkgo biloba extract (ginkgolide A, C, and bilobalide) block GlyR channels though with weak subunit discrimination (Hawthorne et al., 2006;Lynch, 2009). Quercetin, belonging to the flavanoid group, also inhibits α1 GlyR activity (Lee et al., 2008) in a non-competitive manner, with an IC 50 of about 45 μM (Raafat et al., 2010). This compound also inhibits GABA A and GABA C receptors (Kim et al., 2015), causing seizures in animal models (Nassiri-Asl et al., 2014). ...
Glycine receptors (GlyRs) belong to the superfamily of pentameric cys-loop receptor-operated channels and are involved in numerous physiological functions, including movement, vision, and pain. In search for compounds performing subunit-specific modulation of GlyRs we studied action of ginkgolic acid, an abundant Ginkgo biloba product. Using patch-clamp recordings, we analyzed the effects of ginkgolic acid in concentrations from 30 nM to 25 μM on α1–α3 and α1/β, α2/β configurations of GlyR and on GABA A Rs expressed in cultured CHO-K1 cells and mouse neuroblastoma (N2a) cells. Ginkgolic acid caused an increase in the amplitude of currents mediated by homomeric α1 and heteromeric α1/β GlyRs and provoked a left-shift of the concentration-dependent curves for glycine. Even at high concentrations (10–25 μM) ginkgolic acid was not able to augment ionic currents mediated by α2, α2/β, and α3 GlyRs, or by GABA A R consisting of α1/β2/γ2 subunits. Mutation of three residues (T59A/A261G/A303S) in the α2 GlyR subunit to the corresponding ones from the α1 converted the action of ginkgolic acid to potentiation with a distinct decrease in EC 50 for glycine, suggesting an important role for these residues in modulation by ginkgolic acid. Our results suggest that ginkgolic acid is a novel selective enhancer of α1 GlyRs.
... It is possible that biological actions of flavonoids, including anticonvulsant effects of rutin and quercetin, might be attributed to their antioxidant properties (Dajas et al., 2013;Nassiri-Asl et al., 2013b). Other possible mechanisms are interactions with GABA (Goutman et al., 2003;Kambe et al., 2010), glycine (Lee et al., 2007(Lee et al., , 2008, acetylcholine (Lee et al., 2011), serotonin (Lee et al., 2005(Lee et al., , 2008 and adenosine (Alexander, 2006) receptors. Flavonoids might also influence excitatory glutamatergic neurotransmission (Spencer, 2007). ...
... It is possible that biological actions of flavonoids, including anticonvulsant effects of rutin and quercetin, might be attributed to their antioxidant properties (Dajas et al., 2013;Nassiri-Asl et al., 2013b). Other possible mechanisms are interactions with GABA (Goutman et al., 2003;Kambe et al., 2010), glycine (Lee et al., 2007(Lee et al., , 2008, acetylcholine (Lee et al., 2011), serotonin (Lee et al., 2005(Lee et al., , 2008 and adenosine (Alexander, 2006) receptors. Flavonoids might also influence excitatory glutamatergic neurotransmission (Spencer, 2007). ...
... These include neuropharmacological actions such as analgesia, mild sedation (Picq et al., 1991), and modulation of oxidative metabolism in neurons (Oyama et al., 1994). Quercetin was found to be a tyrosine kinase inhibitor (Huang et al., 1999;Lee et al., 2002), as well as an inhibitor of glycine-and serotonin 5-HT 3 receptor-mediated currents (Lee et al., 2007;Lee et al., 2008). Genistein (Fig. 1B), a tyrosine kinase inhibitor, is a naturally occurring polyphenol from soybean. ...
... The flavonoids quercetin and genistein ( Fig. 1) have been shown to modulate GlyR function (Huang and Dillon, 2000;Lee et al., 2007;Lee et al., 2008). It was assumed that both compounds bind to a site on the receptor that is also targeted by alcohols and local anesthetics. ...
... It has been shown previously that quercetin and genistein are inhibitors of spinal cord GlyRs (Huang and Dillon, 2000;Lee et al., 2007;Lee et al., 2008), but their detailed mode of inhibition was not studied so far. Here, we illustrate that quercetin and genistein act as noncompetitive inhibitors on GlyR a1-mediated currents, both targeting the same site on the receptor. ...
The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signaling in spinal cord, brain stem, and higher central
nervous system regions. The flavonoids quercetin and genistein have been identified previously as promising GlyR antagonists
in vitro, but their detailed mechanism of action was not known. Here, inhibition of recombinant human α1 GlyRs in HEK 293 cells by
genistein, quercetin, and strychnine was studied using whole-cell recording techniques. The interaction of several inhibitors
applied alone or in combination was analyzed using a minimum mechanism of receptor activation and inhibition. Receptor inhibition
in vivo was studied in a mouse model of strychnine toxicity. Genistein, quercetin, and strychnine were noncompetitive GlyR inhibitors.
The inhibitory potency of one flavonoid (either genistein or quercetin) was not affected by simultaneous application of the
other, suggesting that both flavonoids target the same site on the receptor. In combination with strychnine, flavonoid inhibition
was augmented, indicating that strychnine binds to a position on the receptor physically distant from the flavonoid site.
Potentiation of strychnine inhibition by flavonoids was also observed in vivo, where harmless doses of flavonoids enhanced strychnine toxicity in mice. Thus, in vitro and in vivo studies demonstrated a true synergism between flavonoids and strychnine for GlyR inhibition. The mechanism-based approach
used here allows a rapid analysis of the effects of single drugs versus drug combinations.
