Mitochondria-dependent apoptosis in triptolide-induced hepatotoxicity is associated with the Drp1 activation

IF 2.8 4区医学 Q2 TOXICOLOGY

Toxicology Mechanisms and Methods Pub Date : 2020-02-01 DOI:10.1080/15376516.2019.1669247

M. Hasnat, Ziqiao Yuan, Aftab Ullah, M. Naveed, F. Raza, Mirza Muhammad Faran Ashraf Baig, Asifullah Khan, Dengqiu Xu, Yuwen Su, Linxin Sun, Luyong Zhang, Zhenzhou Jiang

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引用次数: 33

Abstract

Abstract How triptolide is associated with mitochondrial dysfunction and apoptosis in connection with its hepatotoxicity remains unclear. The objective of our study was to find out the link between mitochondrial dynamics and cell death in triptolide induced hepatotoxicity. We treated L02 cells with 25 nM concentration of triptolide. The results demonstrated that triptolide treatment caused an increase in apoptotic cell death, mitochondrial depolarization, ROS overproduction, a decrease in ATP production, and mitochondrial fragmentation which in turn is associated with the activation of Drp1 fission protein. Triptolide treatment led to the translocation of Drp1 from the cytosol into outer mitochondrial membrane where it started mitochondrial fission. This fission event is coupled with the mitochondrial release of cytochrome c into the cytosol and subsequently caspase-3 activation. TEM analysis of rat liver tissues revealed the distortion of mitochondrial morphology in triptolide-treated group. Western blot analysis explained that disruption in mitochondrial morphology was attached with the recruitment of Drp1 to mitochondria, cytochrome c release, and caspase-3 activation. However, Mdivi-1 co-treatment inhibited the activation of Drp1 and caspase-3 and blocked the release of cytochrome c into the cytosol. In short, inhibiting Drp1 protein activation may provide a new potential target for curing Drp1-associated apoptosis in triptolide-induced hepatotoxicity.

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雷公藤甲素诱导的肝毒性中线粒体依赖性凋亡与Drp1激活有关

雷公藤甲素与线粒体功能障碍和细胞凋亡及其肝毒性的关系尚不清楚。本研究旨在探讨雷公藤甲素肝毒性小鼠线粒体动力学与细胞死亡之间的关系。用浓度为25 nM的雷公藤甲素处理L02细胞。结果表明，雷公藤甲素处理导致凋亡细胞死亡增加，线粒体去极化，ROS过度产生，ATP产生减少，线粒体断裂，这反过来又与Drp1裂变蛋白的激活有关。雷公藤甲素处理导致Drp1从细胞质转移到线粒体外膜，在那里它开始线粒体裂变。这个裂变事件伴随着线粒体将细胞色素c释放到细胞质中，随后是半胱天冬酶-3激活。大鼠肝组织透射电镜分析显示雷公藤甲素处理组线粒体形态出现畸变。Western blot分析表明，线粒体形态的破坏与Drp1向线粒体的募集、细胞色素c的释放和caspase-3的激活有关。然而，Mdivi-1共处理抑制了Drp1和caspase-3的激活，阻断了细胞色素c向胞质溶胶的释放。总之，抑制Drp1蛋白激活可能为治疗雷公藤甲素诱导的肝毒性中Drp1相关的细胞凋亡提供了一个新的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology Mechanisms and Methods TOXICOLOGY-

自引率

3.10%

发文量

期刊介绍： Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.