Department of Anesthesiology, Shanghai Sixth People's Hospital affiliated to Shanghai University of Medicine and Health Sciences, No. 222 Huanhuxisan Road, Pudong, 201306, Shanghai, China.
Department of Intensive Care Medicine, Shanghai Sixth People's Hospital affiliated to Shanghai University of Medicine and Health Sciences, No. 222 Huanhuxisan Road, Pudong, 201306, Shanghai, China.
J Physiol Sci. 2019 May;69(3):489-502. doi: 10.1007/s12576-019-00666-9. Epub 2019 Feb 15.
An uncontrolled inflammatory response has been implicated in the progression of acute liver failure through poorly understood mechanisms. The aim of our study was to investigate whether suramin attenuates inflammation-mediated hepatocyte apoptosis by modulating mitochondrial homeostasis. Primary hepatocytes were isolated from mice and treated with LPS in vitro in the presence or absence of suramin. Western blotting, immunofluorescence staining, and ELISAs were used to evaluate the mitochondrial stress. The LPS treatment caused hepatocyte death via apoptosis. Interestingly, suramin supplementation attenuated LPS-mediated hepatocyte death by reducing Mst1 expression; the overexpression of Mst1 abolished the anti-apoptotic effects of suramin on LPS-treated hepatocytes. At the molecular level, suramin treatment repressed mitochondrial oxidative stress, sustained mitochondrial dynamics and blocked the caspase-9-mediated mitochondrial apoptosis pathway; these effects of suramin were achieved by reversing Mst1 expression. Furthermore, our study found that suramin modulated Mst1 expression via the JNK signaling pathway. Activation of JNK prevented the suramin-mediated Mst1 downregulation and concomitantly increased hepatocyte apoptosis and mitochondrial dysfunction. Taken together, our results confirmed the anti-apoptotic and anti-inflammatory effects of suramin on LPS-challenged hepatocytes. Suramin sustained hepatocyte viability and attenuated mitochondrial stress via repressing the JNK-Mst1 signaling pathway.
未受控制的炎症反应被认为与急性肝衰竭的进展有关，但其机制尚不清楚。本研究旨在探讨苏拉明是否通过调节线粒体稳态来减轻炎症介导的肝细胞凋亡。从小鼠中分离原代肝细胞，并在存在或不存在苏拉明的情况下在体外用 LPS 处理。使用 Western blot、免疫荧光染色和 ELISA 来评估线粒体应激。LPS 处理通过凋亡导致肝细胞死亡。有趣的是，苏拉明通过降低 Mst1 表达来减轻 LPS 介导的肝细胞死亡；Mst1 的过表达消除了苏拉明对 LPS 处理的肝细胞的抗凋亡作用。在分子水平上，苏拉明处理抑制了线粒体氧化应激，维持了线粒体动力学，并阻断了 caspase-9 介导的线粒体凋亡途径；苏拉明的这些作用是通过逆转 Mst1 表达来实现的。此外，我们的研究发现苏拉明通过 JNK 信号通路调节 Mst1 表达。JNK 的激活阻止了苏拉明介导的 Mst1 下调，并同时增加了肝细胞凋亡和线粒体功能障碍。总之，我们的结果证实了苏拉明对 LPS 刺激的肝细胞具有抗凋亡和抗炎作用。苏拉明通过抑制 JNK-Mst1 信号通路来维持肝细胞活力并减轻线粒体应激。
