gossypetin and myricetin

Abelmoschus manihot (L.) Medic., a folk herbal medicine in China, is a flowering plant belonging\ to Abelmoschus L. genus and Malvaceae family, which has been reported with an antidepressant activity. The\ study was designed to isolate flavonoids from Abelmoschus manihot corolla and explore the action mechanism\ of antidepressant activities. The flavonoids were isolated and purified by D101 macroporous resin column,\ polyamide column and Sephadex LH-20 sequentially and identified as myricetin-3-O-β-D-glucoside (1),\ gossypetin-8-O-β-D-glucuronide (2, G-8-G), gossypetin-3'-O-β-D-glucoside (3), quercetin-3'-glucoside (4, Q-3-G),\ isoquercitrin (5, IQT), hyperoside (6, HY), myricetin (7), quercetin (8, QT). Compounds 2, 4, 5, 6 and 8\ (15, 30 and 60 mg·kg−1) were orally administered to mice and the reaction was observed in tail suspension\ test (TST) and forced swimming test (FST). Western blot analysis was used in determination of the protein\ expressions of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB) and phosphorylation\ eukaryotic elongation factor 2 (p-eEF2). The results revealed that only Q-3-G and G-8-G (15, 30, 60 mg ·kg−1)\ significantly reduced the immobility time in FST and TST. Furthermore, Q-3-G and G-8-G remarkably increased\ the expression of BDNF and TrkB, and decreased the expression of p-eEF2. These results suggest that\ Q-3-G and G-8-G had an obvious antidepressant activity via up-regulation of BDNF expression. The\ new observation will provide a new direction in the development of antidepressant in the treatment of major depressive\ disorder (MDD).

Topics: Abelmoschus; Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; China; Depressive Disorder, Major; Drugs, Chinese Herbal; Ethanol; Flavonoids; Hindlimb Suspension; Hippocampus; Mice; Plant Extracts; Quercetin; Swimming; Up-Regulation

Flos Abelmoschus manihot is a traditional herbal medicine widely used in clinical practice to tackle chronic kidney disease (CKD) for thousands of years. Nowadays, many studies indicate that gut bacteria are closely related to the progression of CKD and CKD-related complications. In this study, a UPLC-Q-TOF/MS method coupled with the MetaboLynx™ software was established and successfully applied to investigate the metabolites and metabolic profile of Flos A. manihot extract by intestinal bacteria from normal and CKD rats. Eight parent components and eight metabolites were characterized by their protonated ions. Among these compounds, 15 were detected in the two group samples while M16 was only determined in the CKD model samples. Compared with the quercetin-type glycosides, fewer myricetin-type and gossypetin-type metabolites were obtained in the two group samples. These metabolites suggested that deglycosylation and methylation are the major metabolic pathways of Flos A. manihot extract. Few differences of metabolite classes were observed in the two group samples. However, the concentrations of aglycones such as quercetin, myricetin and gossypetin in the normal samples were notably higher than those in the CKD model samples. The results are important in unravelling the pharmacological effects of A. manihot and clarifying its mechanism of action in vivo.

Topics: Abelmoschus; Animals; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Flavonoids; Intestinal Mucosa; Intestines; Male; Malvaceae; Mass Spectrometry; Metabolome; Quercetin; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic

Random Forest screening of the phytochemical constituents of 240 herbs used in traditional Chinese medicine identified a number of compounds as potential inhibitors of the human aromatase enzyme (CYP19). Molecular modelling/docking studies indicated that three of these compounds (myricetin, liquiritigenin and gossypetin) would be likely to form stable complexes with the enzyme. The results of the virtual screening studies were subsequently confirmed experimentally, by in vitro (fluorimetric) assay of the compounds' inhibitory activity. The IC-50s for the flavones, myricetin and gossypetin were determined as 10 and 11 microM, respectively, whilst the flavanone, liquiritigenin, gave an IC-50 of 0.34 microM--showing about a 10-fold increase in potency, therefore, over the first generation aromatase inhibitor, aminoglutethimide.

Topics: Algorithms; Aminoglutethimide; Aromatase Inhibitors; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Flavanones; Flavonoids; Fluorometry; Humans; Inhibitory Concentration 50; Models, Molecular; Structure-Activity Relationship

Tau protein is the major component of the intraneuronal filamentous inclusions that constitute defining neuropathological characteristics of Alzheimer's disease and other tauopathies. The discovery of tau gene mutations in familial forms of frontotemporal dementia has established that dysfunction of the tau protein is sufficient to cause neurodegeneration and dementia. Here we have tested 42 compounds belonging to nine different chemical classes for their ability to inhibit heparin-induced assembly of tau into filaments in vitro. Several phenothiazines (methylene blue, azure A, azure B, and quinacrine mustard), polyphenols (myricetin, epicatechin 5-gallate, gossypetin, and 2,3,4,2',4'-pentahydroxybenzophenone), and the porphyrin ferric dehydroporphyrin IX inhibited tau filament formation with IC(50) values in the low micromolar range as assessed by thioflavin S fluorescence, electron microscopy, and Sarkosyl insolubility. Disassembly of tau filaments was observed in the presence of the porphyrin phthalocyanine. Compounds that inhibited tau filament assembly were also found to inhibit the formation of Abeta fibrils. Biochemical analysis revealed the formation of soluble oligomeric tau in the presence of the inhibitory compounds, suggesting that this may be the mechanism by which tau filament formation is inhibited. The compounds investigated did not affect the ability of tau to interact with microtubules. Identification of small molecule inhibitors of heparin-induced assembly of tau will form a starting point for the development of mechanism-based therapies for the tauopathies.

Topics: Antioxidants; Azure Stains; Benzophenones; Brain; Catechin; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Flavonoids; Fluorescent Dyes; Heparin; Humans; Methylene Blue; Microtubules; Models, Chemical; Neurofibrillary Tangles; Phenols; Phenothiazines; Polyphenols; Porphyrins; Protein Binding; Quinacrine Mustard; tau Proteins; Time Factors

Myricetin and gossypetin, two hexahydroxylated flavonoids, are capable of modifying low density lipoprotein (LDL) to increase greatly its uptake by macrophages. When human 125I-labelled LDL was incubated with 100-1000 microM myricetin or gossypetin, it was subsequently endocytosed much faster by mouse peritoneal macrophages. This modification did not occur at a concentration of 10 microM. Nine other flavonoids containing up to five hydroxyl substituents did not modify LDL to any great extent at 100 microM. The modification of LDL by 100 microM myricetin was time-dependent and complete by 6 hr. Flavonoids can sometimes act as pro-oxidants but myricetin did not act by oxidizing the LDL, as the LDL lipid hydroperoxide content was not increased by myricetin, nor did it promote the depletion of the endogenous antioxidant alpha-tocopherol in the LDL. High concentrations of myricetin caused the aggregation of LDL particles, as judged by light microscopy, agarose gel electrophoresis, retention by a membrane filter and sedimentability by centrifugation. SDS-PAGE indicated that the apolipoprotein B-100 molecules of LDL particles were covalently crosslinked. The uptake and degradation by macrophages of myricetin-modified 125I-labelled LDL reached saturation at about 10 micrograms protein/mL, suggesting the existence of a high affinity uptake process for the modified LDL. The uptake of myricetin-modified 125I-labelled LDL was not competed for by a large excess of non-labelled native LDL or acetylated LDL. We conclude that myricetin and gossypetin at high concentrations are capable of modifying LDL by a novel non-oxidative mechanism to a form taken up by macrophages by a high affinity process.

Topics: Animals; Dose-Response Relationship, Drug; Flavonoids; Humans; Lipid Peroxides; Lipoproteins, LDL; Macrophages; Mice; Vitamin E

Low density lipoproteins (LDL) can be oxidatively modified in vitro by macrophages and certain other cell types so that macrophages will take them up much faster. This process may be important in the formation of cholesterol-laden foam cells derived from macrophages in atherosclerotic lesions. In this study, we have shown that certain flavonoids, plant constituents found in the diet, are potent inhibitors of the modification of 125I-labelled LDL by macrophages, with IC50 values in the micromolar range (e.g. morin and fisetin 1 microM; quercetin and gossypetin 2 microM). The potencies of individual flavonoids in inhibiting LDL modification did not correlate with their previously determined potencies as inhibitors of 5-lipoxygenase and cyclo-oxygenase. The modification of LDL by macrophages exhibits a lag period of about 4-6 hr before enhanced uptake is detected. During this time, there is a rapid depletion in its content of alpha-tocopherol (an endogenous antioxidant found in lipoproteins) followed by a large increase in the level of hydroperoxides. The flavonoids conserved the alpha-tocopherol content of LDL and delayed the onset of detectable lipid peroxidation. Flavonoids also inhibited the cell-free oxidation of LDL mediated by CuSO4. These findings raise the possibility that flavonoids may protect LDL against oxidation in atherosclerotic lesions and may therefore be natural anti-atherosclerotic components of the diet, although this will depend to a large extent on their pharmacokinetics.

Topics: Copper; Flavonoids; Humans; Lipoproteins, LDL; Macrophages; Oxidation-Reduction; Quercetin; Time Factors