Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Oxid Med Cell Longev. 2021 Apr 22;2021:8865813. doi: 10.1155/2021/8865813. eCollection 2021.
Cassiae Semen is a widely used herbal medicine and a popular edible variety in many dietary or health beverage. Emerging evidence disclosed that improper administration of Cassiae Semen could induce obvious liver injury, which is possibly attributed to emodin, one of the bioactive anthraquinone compounds in Cassiae Semen, which caused hepatotoxicity, but the underlying mechanisms are not completely understood. Hence, the present study firstly explored the possible role of oxidative stress-mediated mitochondrial dysfunction and ER stress in emodin-cause apoptosis of L02 cells, aiming to elaborate possible toxic mechanisms involved in emodin-induced hepatotoxicity. Our results showed that emodin-induced ROS activated ER stress and the UPR via the BiP/IRE1/CHOP signaling pathway, followed by ER Ca release and cytoplasmic Ca overloading. At the same time, emodin-caused redox imbalance increased mtROS while decreased MMP and mitochondrial function, resulting in the leaks of mitochondrial-related proapoptotic factors. Interestingly, blocking Ca release from ER by 2-APB could inhibit emodin-induced apoptosis of L02, but the restored mitochondrial function did not reduce the apoptosis rates of emodin-treated cells. Besides, tunicamycin (TM) and doxorubicin (DOX) were used to activate ER stress and mitochondrial injury at a dosage where obvious apoptosis was not observed, respectively. We found that cotreatment with TM and DOX significantly induced apoptosis of L02 cells. Thus, all the results indicated that emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction. Altogether, this finding has implicated that redox imbalance-mediated ER stress could be an alternative target for the treatment of Cassiae Semen or other medicine-food homologous varieties containing emodin-induced liver injury.
决明子是一种广泛使用的草药，也是许多饮食或保健饮料中常见的可食用品种。新出现的证据表明，决明子的不当使用可能会导致明显的肝损伤，这可能归因于大黄素，它是决明子中一种生物活性蒽醌化合物，可引起肝毒性，但潜在机制尚不完全清楚。因此，本研究首先探讨了氧化应激介导的线粒体功能障碍和内质网应激在大黄素诱导 L02 细胞凋亡中的可能作用，旨在阐述大黄素诱导肝毒性涉及的可能毒性机制。我们的结果表明，大黄素诱导的 ROS 通过 BiP/IRE1/CHOP 信号通路激活内质网应激和 UPR，随后是内质网 Ca 释放和细胞质 Ca 超载。同时，大黄素引起的氧化还原失衡增加了 mtROS，同时降低了 MMP 和线粒体功能，导致线粒体相关促凋亡因子的渗漏。有趣的是，用 2-APB 阻断内质网 Ca 释放可以抑制大黄素诱导的 L02 细胞凋亡，但恢复线粒体功能并不能降低大黄素处理细胞的凋亡率。此外，分别使用衣霉素 (TM) 和多柔比星 (DOX) 激活内质网应激和线粒体损伤，剂量下不会观察到明显的凋亡。我们发现，TM 和 DOX 联合处理可显著诱导 L02 细胞凋亡。因此，所有结果表明，大黄素诱导的过量 ROS 生成和氧化还原失衡促进了细胞凋亡，这主要与 BiP/IRE1/CHOP 信号转导介导的内质网应激有关，并且会受到氧化应激介导的线粒体功能障碍的增强。总之，这一发现表明，氧化还原失衡介导的内质网应激可能是治疗决明子或其他含有大黄素引起肝损伤的药食同源品种的替代靶点。
