BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury
BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury
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DOI：
10.1016/j.taap.2009.11.017
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发表时间：
2010-02-15
影响因子：
3.8
通讯作者：
Mandl, Jozsef
中科院分区：
文献类型：
--
作者：
Nagy, Gabor;Szarka, Andras;Mandl, Jozsef
最近的研究表明，急性对乙酰氨基酚毒性导致内质网氧化还原应激和肝脏细胞凋亡表型的增加。由于效应半胱天冬酶的激活缺失，因此研究了半胱天冬酶非依赖性机制在对乙酰氨基酚诱导的程序性细胞死亡中的相关性。bp -15，一种已知在氧化还原失衡条件下具有保护作用的药物。与一次亚致死剂量的对乙酰氨基酚同时服用。观察损伤后的促凋亡事件及预后。对乙酰氨基酚诱导内质网氧化还原改变和早期内质网应激相关信号事件，如内质网谷胱甘肽耗竭。与bp -15共处理后，eIF2 α和JNK的磷酸化以及转录因子GADD153的诱导均未被抵消。然而，bp -15阻止了AIF线粒体到核的易位和线粒体去极化。通过凋亡指数和血清酶释放评估，bp -15联合处理降低了对乙酰氨基酚诱导的细胞死亡率。这些结果重申，急性对乙酰氨基酚毒性涉及氧化应激诱导的caspase非依赖性细胞死亡。此外，药物抑制AIF易位可以有效防止或至少延缓对乙酰氨基酚诱导的程序性细胞死亡。(C) 2009爱思唯尔公司版权所有。
It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance. has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion. phosphorylation of eIF2 alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death. (C) 2009 Elsevier Inc. All rights reserved.