Chronic exposure to arsenic remains a worldwide environmental health issue, affecting hundreds of millions of people. Although, arsenic‐induced oxidative stress and apoptosis have been determined, the underlying apoptosis mechanism has not been fully elucidated yet. Oxidative stress integrated‐ER stress plays an important role in Life‐and‐Death decision of cells. The current study was to investigate whether NaAsO2 utilizes oxidative stress integrated‐ER stress signaling to exert pro‐apoptotic activity in L‐02 cells. Results showed that death receptor 5 (DR5) was a mediator of NaAsO2‐induced apoptosis by enhancing construction of the death‐inducing signaling complex (DISC). NaAsO2‐sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO2 increased expression in biomarker of endoplasmic reticulum (ER) stress and activated the protein kinase R‐like ER kinase (PERK)‐eukaryotic translation initiation 2α (eIF2α)‐activating transcription factor 4 (ATF4) pathway. PERK inhibitor and ATF4 siRNA significantly attenuated NaAsO2‐induced CHOP and DR5 expressions. In addition, the antioxidant N‐acetyl‐l‐cysteine (NAC) treatment led to amelioration of NaAsO2‐induced production of reactive oxygen species (ROS) and some ER stress‐ and apoptosis‐ related protein levels and cell viability. Taken together, the results indicate that ROS‐mediated PERK‐eIF2α‐ATF4 pathway activated by NaAsO2 is the critical upstream event for subsequent apoptosis induction via regulating CHOP‐DR5 signaling in L‐02 cells when chronic exposure to arsenic, and support that antioxidants might be potential therapeutic agents for preventing or delaying the onset and progress of arsenic‐induced hepatotoxicity.

中文翻译：

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ROS介导的PERK-eIF2α-ATF4通路通过调节CHOP-DR5信号在亚砷酸盐诱导的L-02细胞凋亡中起重要作用

长期接触砷仍然是一个全球性的环境健康问题，影响着数亿人。尽管已经确定了砷诱导的氧化应激和细胞凋亡，但潜在的细胞凋亡机制尚未完全阐明。氧化应激综合内质网应激在细胞的生死决策中起重要作用。目前的研究是探讨 NaAsO2 是否利用氧化应激整合的 ER 应激信号在 L-02 细胞中发挥促凋亡活性。结果表明，死亡受体 5 (DR5) 通过增强死亡诱导信号复合物 (DISC) 的构建，是 NaAsO2 诱导细胞凋亡的介质。NaAsO2 致敏的 DR5 升高需要可维持的转录及其转录因子 C/EBP 同源蛋白 (CHOP)。进一步的结果表明，NaAsO2 增加了内质网 (ER) 应激生物标志物的表达，并激活了蛋白激酶 R 样 ER 激酶 (PERK)-真核翻译起始 2α (eIF2α)-激活转录因子 4 (ATF4) 通路。PERK 抑制剂和 ATF4 siRNA 显着减弱了 NaAsO2 诱导的 CHOP 和 DR5 表达。此外，抗氧化剂 N-乙酰-l-半胱氨酸 (NAC) 处理导致 NaAsO2 诱导的活性氧 (ROS) 产生和一些内质网应激和细胞凋亡相关的蛋白质水平和细胞活力的改善。总之，结果表明，当长期暴露于砷时，通过调节 L-02 细胞中的 CHOP-DR5 信号传导，由 NaAsO2 激活的 ROS 介导的 PERK-eIF2α-ATF4 通路是随后诱导凋亡的关键上游事件，