作者: Luo, Jiajun ; Zhang, Jiajie ; Chen, Mengyu ; Wu, Ting ; Luo, Jian ; Li, Zhonghuang ; Pang, Jianxin ; Wan, Shanhe ; Zhao, Zean ; Chen, Xinhua ; Tian, Yuanxin ; Chen, Jianjun

Previously, we reported a novel natural scaffold compound, isobavachin (4',7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC₅₀ = 0.24 μM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC₅₀ of 4.47 μM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.

2024-10-01·Toxicology in Vitro

Isobavachin induces autophagy-mediated cytotoxicity in AML12 cells via AMPK and PI3K/Akt/mTOR pathways

Article

作者: Du, Hai-Wei ; Dong, Yu-Tong ; Meng, Zhao-Jun ; Chen, Qing-Hai ; Zhou, Kun ; Shen, Rong ; Xia, Ning ; Ma, Shu-Yue ; Huang, Jia-Li

Isobavachin (IBA) is a dihydroflavonoid compound with various pharmacological effects. However, further investigation into the hepatotoxicity of IBA is necessary. This study aims to identify the hepatotoxic effects of IBA and explore its potential mechanisms. The study assessed the impact of IBA on the viability of AML12, HepG2, LO2, rat, and mouse primary hepatocytes using MTT and LDH assays. Autophagy was detected in AML12 cells after IBA treatment using electron microscopy, MDC, and Ad-mCherry-GFP-LC3B fluorescence. The effect of IBA on autophagy-related proteins was examined using Western blot. The results showed that IBA had dose-dependent inhibitory effects on five cells, induced autophagy in AML12 cells, and promoted autophagic flux. The study found that IBA treatment inhibited phosphorylation of PI3K, Akt, and mTOR, while increasing phosphorylation levels of AMPK and ULK1. Treatment with both AMPK and PI3K inhibitors reversed the expression of AMPK and PI3K-Akt-mTOR signaling pathway proteins. These results suggest that IBA may have hepatocytotoxic effects but can also prevent IBA hepatotoxicity by inhibiting the AMPK and PI3K/Akt/mTOR signaling pathways. This provides a theoretical basis for preventing and treating IBA hepatotoxicity in clinical settings.

2024-07-01·Pulmonary Circulation

Integrated approach of network pharmacology, molecular docking, and clinical observations in evaluating the efficacy and safety of Bufei Huoxue capsules for pulmonary hypertension associated with chronic obstructive pulmonary disease

Article

作者: Chen, Yuqin ; Lu, Wenju ; Chen, Yilin ; Zhou, Dansha ; Wang, Jian ; Xiong, Yuanhui ; Liu, Chunli ; He, Wenjun ; Li, Xuanyi ; Lai, Ning ; Bogaard, Harm Jan ; Aman, Jurjan ; Jiang, Qian ; Li, Defu ; Feng, Weici ; Zhong, Bihua

AbstractChronic obstructive pulmonary disease (COPD) is a persistent and progressive disorder characterized by airway or alveolar abnormalities, commonly leading to pulmonary hypertension (PH). This clinical observational study investigates the therapeutic mechanisms of Bufei Huoxue capsules (BHC) in treating PH in patients with COPD‐linked PH (COPD‐PH) using network pharmacology and molecular docking methods, and assesses the therapeutic efficacy and safety of BHCs. The active compounds and their target proteins in BHCs were sourced from the Traditional Chinese Medicine Systems Pharmacology database, with additional target proteins derived from the GeneCards and OMIM databases. An active network was constructed using Cytoscape 3.7.1, and interaction networks were established. Intersecting targets underwent Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Metascape database. Network pharmacology and molecular docking studies demonstrated favorable binding affinities of BHC active ingredients, such as quercetin, bavachalcone, and isobavachin, for key targets including PTGS1, ESR1, and PTGS2. Gene Ontology enrichment analysis highlighted the involvement of these targets in processes such as the positive regulation of locomotion, the transmembrane receptor protein tyrosine kinase signaling pathway, and peptidyl‐tyrosine phosphorylation. KEGG pathway analysis indicated their roles in pathways related to cancer, AGE‐RAGE signaling in diabetic complications, and prostate cancer. BHCs exhibit therapeutic effects on COPD‐PH through multi‐component, multi‐target, and multi‐pathway interactions. This clinical observational study confirms the efficacy and safety of BHCs in improving cardiac and pulmonary functions, enhancing exercise tolerance, and elevating the quality of life in patients with COPD‐PH.

100 项与 isobavachin 相关的药物交易

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