5-((7-Chloro-6-fluoro-1h-indol-3-yl)methyl)-3-methylimidazolidine-2,4-di one as a RIP1 inhibitor protects LPS/D-galactosamine-induced liver failure
5-((7-Chloro-6-fluoro-1h-indol-3-yl)methyl)-3-methylimidazolidine-2,4-di one as a RIP1 inhibitor protects LPS/D-galactosamine-induced liver failure
复制标题
5-((7-Chloro-6-氟-1h-indol-3-yl)methyl)-3-methylimidazolidine-2,4-di one作为RIP1抑制剂可保护LPS/D-半乳糖胺诱导的肝衰竭
DOI：
10.1016/j.lfs.2021.119304
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发表时间：
2021
期刊：
影响因子：
6.1
通讯作者：
Chen Zhi
中科院分区：
文献类型：
--
作者：
Li Aichun;Yang Qin;Lou Guohua;Liu Yanning;Xia Hongguang;Chen Zhi
坏死性凋亡是一种由受体相互作用激酶1（RIP 1）、RIP 3和假激酶混合谱系激酶结构域样蛋白（MLKL）介导的炎症性调节性坏死，广泛参与肝脏炎症性疾病。因此，鉴定坏死性凋亡的小分子抑制剂已成为预防肝损伤的潜在治疗策略。本研究以5-（（7-氯-6-氟-1h-吲哚-3-基）甲基）-3-甲基咪唑烷-2，4-二酮（F-nec）为新的坏死性凋亡抑制剂，以肿瘤坏死因子α（TNFα）和泛半胱天冬酶抑制剂z-VAD-fnec联合作用于人单核细胞U937细胞，观察其对细胞凋亡的抑制作用。进一步采用LPS和D-氨基半乳糖（LPS/GalN）模拟急性肝衰竭，探讨F-nec的体内治疗作用。此外，c-Jun NH（2）-末端激酶（JNK）的特异性抑制剂SP 600125及其激活剂茴香霉素用于阐明其在急性肝衰竭治疗中的机制。在本研究中，我们鉴定了F-nec作为一种新的有效的RIP 1抑制剂，其有效地阻断TNFα诱导的人和小鼠细胞的坏死性凋亡。此外，F-nec预处理可以通过减少RIP 1介导的坏死性凋亡来防止肝坏死，还可以通过减弱细胞死亡信号刺激的JNK通路激活，然后抑制JNK触发的炎症，有效地改善LPS/GalN诱导的急性肝衰竭。这项研究表明，F-nec是一种有效的RIP 1抑制剂，并强调了其在RIP 1治疗中的巨大潜力。导致炎症性肝病。
AimsNecroptosis, an inflammatory form of regulated necrosis mediated by receptor-interacting kinase 1 (RIP1), RIP3, and pseudokinase mixed lineage kinase domain-like protein (MLKL) is extensively implicated in liver inflammatory disease. Thus identification small-molecule inhibitor of necroptosis has emerged as a potential therapeutic strategy to prevent liver damage. In this study, we identified 5-((7-chloro-6-fluoro-1 h-indol-3-yl) methyl)-3-methylimidazolidine-2,4-dione (F-nec) as a novel potent necroptosis inhibitor.Main methodsTo find out the potent chemical inhibitors of necroptosis, human monocytic U937 cells were treated with a combination of tumor necrosis factor alpha (TNFα) and a pan-caspase inhibitor z-VAD-fmk. LPS and D-galactosamine (LPS/GalN) were further employed to simulate acute liver failure to explore therapeutic potency of F-nec in vivo. In addition, a specific inhibitor of c-Jun NH (2)-terminal kinases (JNK) SP600125 and its activator anisomycin are used to elucidate its mechanisms in acute liver failure therapy. Necroptosis pathway related proteins were tested by western blot.Key findingsIn this study, we identified F-nec as a novel potent RIP1 inhibitor which efficiently blocked TNFα-induced necroptosis in human and mice cells. Furthermore, pre-treatment of F-nec could prevent hepatic necrosis by reducing RIP1-mediated necroptosis also effectively ameliorated LPS/GalN induced acute liver failure by attenuating cell death signaling-stimulated JNK pathway activation and then suppressing JNK-triggered inflammation.SignificanceAltogether, this study demonstrates that F-nec is a potent inhibitor of RIP1 and highlights its great potential for use in the treatment of RIP1-driven inflammatory liver diseases.