morin and fisetin

Quercetin oxidation leads to the formation of a metabolite, 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone, whose antioxidant potency was recently reported to be a 1000-fold higher than that of its precursor. The formation of similar metabolites (BZF) is limited to certain flavonols (FL), among which are myricetin, fisetin, and morin. Here we addressed the consequences of inducing the auto-oxidation of these flavonols in terms of their antioxidant properties (assessed in ROS-exposed Caco-2 cells). The mixtures that result from their oxidation (FLox) exhibited antioxidant activities 10-to-50-fold higher than those of their precursors. Such amplification was fully attributable to the presence of BZF in each FLox (established by HPLC-ESI-MS/MS and chemical subtraction techniques). An identical amplification was also found when the antioxidant activities of BZF, isolated from each FLox, and FL were compared. These findings warrant the search of these BZF in edible plants and their subsequent evaluation as a new type of functional food ingredients.

Topics: Antioxidants; Caco-2 Cells; Flavonoids; Flavonols; Humans; Quercetin; Tandem Mass Spectrometry

Flavonoids are a class of polyphenols that possess diverse properties. The structure-activity relationship of certain flavonoids and resveratrol with ribonuclease A (RNase A) has been investigated. The selected flavonoids have a similar skeleton and the positional preferences of the phenolic moieties toward inhibition of the catalytic activity of RNase A have been studied. The results obtained for RNase A inhibition by flavonoids suggest that the planarity of the molecules is necessary for effective inhibitory potency. Agarose gel electrophoresis and precipitation assay experiments along with kinetic studies reveal K

Topics: Animals; Catalytic Domain; Cattle; Enzyme Inhibitors; Flavanones; Flavonoids; Flavonols; Kaempferols; Kinetics; Models, Molecular; Pancreas; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Structure, Tertiary; Quercetin; Resveratrol; Ribonuclease, Pancreatic; Substrate Specificity; Thermodynamics

The most effective symptomatic treatment of Parkinson's disease remains the metabolic precursor of dopamine, L-dopa. To enhance the efficacy of L-dopa, it is often combined with inhibitors of the enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) B, key metabolic enzymes of L-dopa and dopamine.. This study attempted to discover compounds that exhibit dual inhibition of COMT and MAO-B among a library of 40 structurally diverse natural compounds. Such dual acting inhibitors may be effective as adjuncts to L-dopa and offer enhanced value in the management of Parkinson's disease.. Selected natural compounds were evaluated as in vitro inhibitors of rat liver COMT and recombinant human MAO. Reversibility of MAO inhibition was investigated by dialysis.. Among the natural compounds morin (IC50 = 1.32 µM), chlorogenic acid (IC50 = 6.17 µM), (+)-catechin (IC50 = 0.86 µM), alizarin (IC50 = 0.88 µM), fisetin (IC50 = 5.78 µM) and rutin (IC50 = 25.3 µM) exhibited COMT inhibition. Among these active COMT inhibitors only morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM) and fisetin (IC50 = 7.33 µM) were noteworthy MAO inhibitors, with specificity for MAO-A.. None of the natural products investigated here are dual COMT/MAO-B inhibitors. However, good potency COMT inhibitors have been identified, which may serve as leads for future development of COMT inhibitors.

Topics: Animals; Anthraquinones; Antioxidants; Biological Products; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Flavonoids; Flavonols; Humans; Liver; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Rats; Rats, Sprague-Dawley

Many membrane-associated proteins are involved in various signaling pathways, including the phosphoinositide 3-kinase (PI3K) pathway, which has key roles in diverse cellular processes. Disruption of the activities of these proteins is involved in the development of disease in humans, making these proteins promising targets for drug development. In most cases, the catalytic domain is targeted; however, it is also possible to target membrane associations in order to regulate protein activity. In this study, we established a novel method to study protein-lipid interactions and screened for flavonoid-derived antagonists of PtdIns(3,4,5)P

Topics: 3-Phosphoinositide-Dependent Protein Kinases; Binding Sites; Flavones; Flavonoids; Flavonols; Liposomes; Molecular Docking Simulation; Phosphatidylinositol Phosphates; Pleckstrin Homology Domains; Protein Binding; Quantitative Structure-Activity Relationship

Organic anion transporter 1 (OAT1) has been reported to be involved in the nephrotoxicity of many anionic xenobiotics. As current clinically used OAT1 inhibitors are often associated with safety issues, identifying potent OAT1 inhibitors with little toxicity is of great value in reducing OAT1-mediated drug nephrotoxicity. Flavonoids are a class of polyphenolic compounds with exceptional safety records. Our objective was to evaluate the effects of 18 naturally occurring flavonoids, and some of their glycosides, on the uptake of para-aminohippuric acid (PAH) in both OAT1-expressing and OAT1-negative LLC-PK1 cells. Most flavonoid aglycones produced substantial decreases in PAH uptake in OAT1-expressing cells. Among the flavonoids screened, fisetin, luteolin, morin, and quercetin exhibited the strongest effect and produced complete inhibition of OAT1-mediated PAH uptake at a concentration of 50 μM. Further concentration-dependent studies revealed that both morin and luteolin are potent OAT1 inhibitors, with IC50 values of <0.3 and 0.47 μM, respectively. In contrast to the tested flavonoid aglycones, all flavonoid glycosides had negligible or small effects on OAT1. In addition, the role of OAT1 in the uptake of fisetin, luteolin, morin, and quercetin was investigated and fisetin was found to be a substrate of OAT1. Taken together, our results indicate that flavonoids are a novel class of OAT1 modulators. Considering the high consumption of flavonoids in the diet and in herbal products, OAT1-mediated flavonoid-drug interactions may be clinically relevant. Further investigation is warranted to evaluate the nephroprotective role of flavonoids in relation to drug-induced nephrotoxicity mediated by the OAT1 pathway.

Topics: Animals; Biological Transport; Cell Line; Drug Interactions; Flavonoids; Flavonols; Glycosides; Humans; LLC-PK1 Cells; Luteolin; Organic Anion Transport Protein 1; p-Aminohippuric Acid; Quercetin; Swine

In this article, results of (time-dependent) density functional theory (DFT and TDDFT) calculations are combined with experimental absorption and fluorescence measurements to explain fluorescence properties of a series of flavonols. The well-understood fluorescence properties of 3- and 5-hydroxyflavone are revisited and validate our combined experimental and theoretical approach. The accuracy of the computational data (energy differences for selected points at the PES, excitation energies and oscillator strengths) allows us to understand quite different experimentally observed fluorescence spectra in the presence of only subtle structural differences. We show that for flavonols with additional hydroxyl groups not the neutral molecule but rather anions lead to fluorescence and that solvation molecules need to be included explicitly in the theoretical calculations to obtain a sufficient accuracy-enabling the understanding and prediction of experimental data for flavonols belonging to different sub-classes.

Topics: Apigenin; Flavonoids; Flavonols; Hydrogen-Ion Concentration; Kaempferols; Models, Molecular; Quantum Theory; Quercetin; Spectrophotometry

Even hydroxyflavones show diverse biological functions, they have two common features such as showing antioxidative effects and containing hydroxyl groups. The authors tested the antioxidative effects of thirty hydroxyflavones using 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. While the scavenging activity of galangin, 3,5,7-trihydroxyflavone was 52.5%, fisetin, 3,7,3',4'-tetrahydroxyflavone showed 85.2%. To investigate the relationships between the structures of hydroxyflavones and their antioxidative effects, the three-dimensional quantitative structure-activity relationships were examined.

Topics: Antioxidants; Flavones; Flavonoids; Flavonols; Free Radical Scavengers; Models, Molecular; Quantitative Structure-Activity Relationship

We previously reported that quercetin and rutin have potent, anti-asthmatic activity, but the structure-activity relationships of flavonoids and anti-asthmatic agents are still poorly understood. In the current study, the effects of kaempferol, fisetin, and morin on the immediate-phase response (IAR) and late-phase response (LAR) caused by exposure to aerosolized-ovalbumin (OA) in OA-sensitized guinea pigs were evaluated by determining the specific airway resistance (sRaw), recruitment of leukocytes and chemical mediators in bronchoalveolar lavage fluid (BALF), histopathological surveys, and determination of neutrophil chemotaxis. Fisetin and kaempherol (30 mg/kg, p.o.) significantly (P<0.01) inhibited sRaw by 47.93% and 30.05% in IAR, and 54.45% and 40.50% in LAR, when compared to vehicle control, respectively. Furthermore, all three studied flavonols (30 mg/kg, p.o.) significantly (P<0.05) inhibited the recruitment of total, as well as subtypes of, leukocytes into the lung BALF. This recruitment inhibition corresponded to the inhibition of leukocyte infiltration, particularly of eosinophils and neutrophils, into the lung in pathological surveys and formly-methionyl-leucyl-phenylalanine (FMLP)-induced neutrophil chemotaxis studies. Kaempferol inhibited FMLP-induced neutrophil chemotaxis in a concentration-dependent manner in a tested range of 1-100 μM. Fisetin inhibited histamine content and peroxidase (EPO) activity in BALF in a dose-dependent manner. All three tested flavonols significantly (P<0.01) inhibited histamine content at 10 mg/kg, and phospholipase A(2) (PLA(2)) and EPO activities at 30 mg/kg (p.o.) in BALF. Kaempherol had a greater anti-asthmatic effect than other flavonols. Fisetin demonstrated the greatest inhibition of sRaw, whereas morin had lesser effects. These results indicate that the lower the molecular weight, the greater the anti-asthmatic activities of these compounds.

Topics: Administration, Inhalation; Aerosols; Airway Resistance; Animals; Anti-Asthmatic Agents; Bronchoalveolar Lavage; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Eosinophils; Flavonoids; Flavonols; Guinea Pigs; Histamine; Kaempferols; Leukocytes; Lung; Male; Molecular Weight; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Infiltration; Neutrophils; Ovalbumin; Peroxidase; Phospholipases A2; Plant Extracts; Respiratory Mechanics

Zingiber officinale Roscoe. (Family Zingiberaceae) is well known in Asia. The plant is widely cultivated in village gardens in the tropics for its medicinal properties and as a marketable spice in Malaysia. Ginger varieties are rich in physiologically active phenolics and flavonoids with a range of pharmacological activities. Experiments were conducted to determine the feasibility of increasing levels of flavonoids (quercetin, rutin, catechin, epicatechin, kaempferol, naringenin, fisetin and morin) and phenolic acid (gallic acid, vanillic acid, ferulic acid, tannic acid, cinnamic acid and salicylic acid), and antioxidant activities in different parts of Malaysian young ginger varieties (Halia Bentong and Halia Bara) with CO(2) enrichment in a controlled environment system. Both varieties showed an increase in phenolic compounds and flavonoids in response to CO(2) enrichment from 400 to 800 µmol mol-1 CO(2). These increases were greater in rhizomes compared to leaves. High performance liquid chromatography (HPLC) results showed that quercetin and gallic acid were the most abundant flavonoid and phenolic acid in Malaysian young ginger varieties. Under elevated CO(2) conditions, kaempferol and fisetin were among the flavonoid compounds, and gallic acid and vanillic acid were among the phenolic compounds whose levels increased in both varieties. As CO(2) concentration was increased from 400 to 800 µmol mol-1, free radical scavenging power (DPPH) increased about 30% in Halia Bentong and 21.4% in Halia Bara; and the rhizomes exhibited more enhanced free radical scavenging power, with 44.9% in Halia Bentong and 46.2% in Halia Bara. Leaves of both varieties also displayed good levels of flavonoid compounds and antioxidant activities. These results indicate that the yield and pharmaceutical quality of Malaysian young ginger varieties can be enhanced by controlled environment production and CO(2) enrichment.

Topics: Antioxidants; Carbon Dioxide; Catechin; Chromatography, High Pressure Liquid; Cinnamates; Coumaric Acids; Flavanones; Flavonoids; Flavonols; Free Radical Scavengers; Gallic Acid; Hydroxybenzoates; Kaempferols; Malaysia; Phenols; Quercetin; Rutin; Salicylic Acid; Tannins; Vanillic Acid; Zingiber officinale

Dietary flavonoid intake has been reported to be inversely associated with the incidence of coronary artery disease. To clarify the possible role of flavonoids in the prevention of atherosclerosis, we investigated the effects of some of these compounds, including fisetin, morin and myricetin, on the susceptibility of low-density lipoprotein (LDL) to oxidative modification and on oxLDL uptake in macrophages. The results demonstrated that fisetin had stronger inhibitory activity than the other two on inhibiting Cu(2+)-mediated LDL oxidation measured by thiobarbituric acid-reactive substances assay (TBARS), conjugated diene formation and electrophoretic mobility. The class B scavenger receptor, CD36, to which oxLDL binds, is present in atherosclerotic lesions. Treatment of U937-derived macrophages with myricetin (20 microM) significantly inhibited CD36 cell surface protein and mRNA expression (p<0.01). Fisetin, morin and myricetin (20 microM) also reduced the feed-forward induction of CD36 mRNA and surface protein expression by PPARgamma. The inhibition of CD36 by flavonols was mediated by interference with PPARgamma activation thus counteracting the deleterious autoamplification loop of CD36 expression stimulated by PPARgamma ligand. All three flavonols (10 and 20 microM) markedly decreased the uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanide perchlorate (DiI)-labeled oxLDL uptake in U937-derived macrophages dose-dependently. Current evidences indicate that fisetin, morin and myricetin not only prevent LDL from oxidation but also block oxLDL uptake by macrophages at least in part through reducing CD36 gene expression on macrophages. In conclusion, flavonols may play a role in ameliorating atherosclerosis.

Topics: Anilides; Antioxidants; Blotting, Western; CD36 Antigens; Copper; Endocytosis; Flavonoids; Flavonols; Gene Expression; Humans; Lipoproteins, LDL; Macrophages; Molecular Structure; PPAR gamma; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; Scavenger Receptors, Class A; Static Electricity; Tetradecanoylphorbol Acetate; Thiobarbituric Acid Reactive Substances; U937 Cells

Flavonoids are food components that appear to have potential beneficial health effects. There is a range of in vitro studies supporting the anti-oxidant and anti-inflammatory properties of flavonoids. Previously, we demonstrated that in vitro flavonoids, including luteolin and apigenin, inhibit proliferation and IFN-gamma production by murine and human autoimmune T cells. In the present study, we examined the effects of oral flavonoids as well as of curcumin on autoimmune T cell reactivity in mice and on the course of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. Continuous oral administration of flavonoids significantly affected antigen-specific proliferation and IFN-gamma production by lymph node-derived T cells following immunization with an EAE-inducing peptide. Both luteolin and apigenin suppress proliferative responses as they did in vitro, whereas IFN-gamma production on the other hand was enhanced. Other flavonoids exerted differential effects on proliferation and IFN-gamma production. The effects of flavonoids and curcumin on EAE were assessed using either passive transfer of autoimmune T cells or active disease induction. In passive EAE, flavonoids led to delayed recovery of clinical symptoms rather than to any reduction in disease. In active EAE, the effects were less pronounced but also, in this case, the flavonoid hesperitin delayed recovery. Oral curcumin had overall mild but beneficial effects. Our results indicate that oral flavonoids fail to beneficially influence the course of EAE in mice but, instead, suppress recovery from acute inflammatory damage.

Topics: Administration, Oral; Animals; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Female; Flavonoids; Flavonols; Glycosides; Growth Inhibitors; Growth Substances; Luteolin; Mice; Mice, Inbred Strains; Quercetin; Recovery of Function; T-Lymphocytes

Mushroom tyrosinase (EC 1.14.18.1) is a copper containing oxidase that catalyzes both the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones, and then forms brown or black pigments. In the present study, the effects of some flavonoids on the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) have been studied. The results show that flavonoids can lead to reversible inhibition of the enzyme. A kinetic analysis showed that the flavonols are competitive inhibitors, whereas luteolin is an uncompetitive inhibitor. The rank order of inhibition was: quercetin > galangin > morin; fisetin > 3,7,4;-trihydroxyflavone; luteolin > apigenin > chrysin.

Topics: Agaricales; Apigenin; Binding, Competitive; Catalysis; Copper; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavonoids; Flavonols; Kinetics; Luteolin; Models, Chemical; Molecular Structure; Monophenol Monooxygenase; Quercetin; Rutin; Structure-Activity Relationship

The protective effect of flavonoids against linoleic acid hydroperoxide (LOOH)-induced cytotoxicity was examined by using cultured endothelial cells. When the cells were incubated with both LOOH and flavonoids, most flavonols protected the cells from injury by LOOH. Flavones bearing an ortho-dihydroxy structure also showed a protective effect against the cytotoxicity of LOOH. However, flavanones had no effect. The structure-activity relationship revealed the presence of either the ortho-di-hydroxy structure in the B ring of the flavonoids or 3-hydroxyl and 4-oxo groups in the C ring to be important for the protective activities. The interaction between flavonoids and a-tocopherol was also examined in this system. Flavonoids that were protective against LOOH-induced cytotoxicity had at least an additive effect on the action of alpha-tocopherol against LOOH-induced damage.

Topics: Antioxidants; Cell Survival; Cells, Cultured; Chromones; Endothelium, Vascular; Enzyme Inhibitors; Flavones; Flavonoids; Flavonols; Humans; Kaempferols; Linoleic Acids; Lipid Peroxides; Luteolin; Mutagens; Quercetin; Structure-Activity Relationship; Umbilical Veins; Vitamin E

Flavonoids are a class of phenolic plant pigments which impair the oxidative burst of neutrophils to an extent dependent on their hydrophobicity. The distribution of quercetin and of morin in nitrogen-cavitated neutrophils paralleled their respective hydrophobic characteristics and respiratory burst inhibition. While both flavonoids were localized primarily in the specific granule membrane of neutrophils, the amount of quercetin was considerably greater than that of morin. We here demonstrate inhibition of the initial stimulation response, depolarization of the membrane potential as monitored by fluorescence of the membrane probe diS-C3-(5), and of the respiratory burst, monitored by following the destruction of diS-C3-(5), a reaction mediated by the H2O2 produced in the burst. The flavonoids kaempferol, morin, quercetin, or fisetin were preincubated with human neutrophils at a concentration of 100 microM per 2 X 10(6) cells/ml for 2-3 min and subsequently stimulated with 1 microgram/ml of the tumor promoter phorbol myristate acetate (PMA) or with 60 micrograms/ml of immune complex. The effect of each compound differed, i.e. depolarization was enhanced by some and inhibited by others, while H2O2 generation was inhibited by each, supporting our previous findings that membrane potential depolarization and the respiratory burst are dissociable events. Concentration-response experiments, performed at flavonoid concentrations between 12.5 and 500 microM to determine the IC50 values of these compounds for depolarization and burst activation, indicated that none of the flavonoids affected the resting potential, while all perturbed the stimulus-coupled response, the direction and extent of the perturbation depending upon the stimulus, and the function assessed. These data show that the effects of flavonoids on human neutrophils are complex and suggest several sites of action depending upon the flavonoid's subcellular distribution and pathway of stimulation.

Topics: Flavonoids; Flavonols; Free Radicals; Humans; Hydrogen Peroxide; Kaempferols; Membrane Potentials; Neutrophils; Oxygen Consumption; Quercetin; Solubility; Superoxides; Tetradecanoylphorbol Acetate