Isobavachin, isolated from Psoralea corylifolia L. exhibits therapeutic potential for osteoporosis or skin disease. Here, we evaluated the pharmacological effects of isobavachin on IgE-dependent inflammatory allergic reactions, as well as the underlying mechanisms, in bone marrow-derived mast cells and a mouse model of passive cutaneous anaphylaxis (PCA). Isobavachin reduced IgE/Ag-stimulated degranulation, eicosanoid (leukotriene C₄ and prostaglandin D₂) generation, and release of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin (IL)-6). Mechanistic studies revealed that isobavachin suppressed activation of Fyn, Lyn, spleen tyrosine kinase (Syk), and lymphocyte-specific-protein-kinase (Lck), receptor-proximal tyrosine kinases that initiate and play a central role in FcɛRI-mediated mast cell activation, as well as their common downstream signaling molecules including linker for activation of T cells, phospholipase Cγ1, AKT, mitogen-activated protein kinases (MAPKs), and intracellular Ca²⁺. Additionally, isobavachin increased phosphorylation of Src homology region 2 domain-containing phosphatase-1 (SHP-1), thereby strengthening its interaction with Syk and Lck as well as Fyn and Lyn, resulting in de-phosphorylation of these proximal tyrosine kinases. Genetic knockdown of SHP-1 reversed the inhibitory effects of isobavachin on mast cell activation, as well as the related signaling pathways, indicating that the inhibitory effects of isobavachin are mediated by negative regulation of SHP-1-dependent Fyn, Lyn, Syk and Lck. The anti-inflammatory properties of isobavachin were also examined in macrophages. Isobavachin suppressed production of lipopolysaccharide-stimulated production of pro-inflammatory cytokines and nitric oxide. Furthermore, oral administration of isobavachin attenuated mast cell-mediated PCA reactions in mice. These results suggest that isobavachin is a potential treatment for mast cell-mediated allergic inflammatory diseases.

2024-11-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, synthesis and bioactivity evaluation of isobavachin derivatives as hURAT1 inhibitors for hyperuricemia agents

Article

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

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

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.

100 项与 isobavachin 相关的药物交易

登录后查看更多信息