isoquercitrin and gossypetin

AL amyloidosis is a life-threatening disease characterized by the deposition of amyloidogenic immunoglobulin light chain secreted from clonal plasma cells. Here we established an in-vitro screening system of amyloid inhibition of a variable domain in λ6 light chain mutant (Vλ6), Wil, and screened a food-additive compound library to identify compounds inhibiting the fibril formation. We found gossypetin and isoquercitrin as novel inhibitors. NMR analysis showed that both compounds directly interacted with natively-folded Wil, and proteolysis experiments demonstrated that these compounds conferred proteolytic resistance, suggesting that the compounds enhance the kinetic stability of Wil. Since gossypetin and isoquercitrin specifically interacted with the protein at micromolar concentrations, these compounds could be used as lead to further develop inhibitors against AL amyloidosis.

Topics: Amyloid; Antioxidants; Catechin; Dose-Response Relationship, Drug; Flavonoids; Humans; Immunoglobulin lambda-Chains; Immunoglobulin Light-chain Amyloidosis; Kinetics; Magnetic Resonance Spectroscopy; Molecular Structure; Mutation; Protein Binding; Protein Stability; Quercetin; Time Factors

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