Project description:Obesity drives the development of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis. Several bone morphogenetic proteins (BMPs) except BMP9 were reported related to metabolic syndrome. This study demonstrates that liver cytokine BMP9 is decreased in the liver and serum of NAFLD model mice and patients. BMP9 knockdown induces lipid accumulation in Hepa 1-6 cells. BMP9-knockout mice exhibit hepatosteatosis due to down-regulated peroxisome proliferator-activated receptor α (PPARα) expression and reduced fatty acid oxidation. In vitro, recombinant BMP9 treatment attenuates triglyceride accumulation by enhancing PPARα promoter activity via the activation of p-smad. PPARα-specific antagonist GW6471 abolishes the effect of BMP9 knockdown. Furthermore, adeno-associated virus-mediated BMP9 overexpression in mouse liver markedly relieves liver steatosis and obesity-related metabolic syndrome. These findings indicate that BMP9 plays a critical role in regulating hepatic lipid metabolism in a PPARα-dependent manner and may provide a previously unknown insight into NAFLD therapeutic approaches.

| S-EPMC7695473 | biostudies-literature

Dibenzazecine compounds with a novel dopamine/5HT2A receptor profile and 3D-QSAR analysis.

Project description:BackgroundAntipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at human dopamine D1-D5 and 5HT2A receptors and to assign them to different classes according to their dopamine/5HT2A receptor profile.ResultsRegardless of using affinity data (pKi values at D1-D5 and 5HT2A) or selectivity data (15 log (Ki ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT2A ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of Ki ratios used for principal component analysis from 15 to two (the D1/D2 and D2/5HT2A Ki ratios) obtained the same three groups of compounds. The most potent dibenzazecine clustering in the same group as clozapine was the non-hydroxylated LE410 which shows a slightly different D2-like receptor profile (D2L > D3 > D4.4) than clozapine (D4.4 > D2L > D3). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D1 selectivity.ConclusionIn conclusion, two compounds with a novel dopamine/5HT2A receptor profile, LE404 and LE410, with some differences in their respective D1/D2 receptor affinities including a validated pharmacophore-based 3D-QSAR model for D1 antagonists are presented.

| S-EPMC1586004 | biostudies-literature

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