Abstract

Neurodegenerative diseases all share several common features such as involvement of oxidative damage and mitochondrial dysfunction in pathogenesis. Oxidative stress induced by overproduction of mitochondrial reactive oxygen species (ROS) or impairment of the antioxidant deficiency results in mitochondrial dysfunction and initiation of the cell death cascade. Berberine (BBR), a traditional Chinese medicine, has been reported to exert anti-oxidative stress and anti-apoptosis effect in CNS diseases. However, the mechanism of BBR on regulating mitophagy and protecting mitochondrial function under oxidative stress remains unclear. In present study, we evaluated the beneficial effects of BBR on the tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity. Furthermore, we explored the protective role of BBR in mitochondrial function and mitophagy under oxidative stress in PC-12 cells. Our results demonstrated that BBR effectively inhibited t-BHP-induced apoptosis which is associated with the decreased leakage of lactate dehydrogenase (LDH) and ROS overproduction. Moreover, BBR significantly suppressed cytochrome c expression, upregulated the ratio of Bcl-2/Bax, and ameliorated mitochondrial dysfunction by optimizing mitochondria membrane potential (ΔΨm) status and ATP production. In addition, BBR reduced the expression of autophagy-specific marker LC3, SQTM1/p62, and maintained lysosome normal function which involved the restoration of upstream signaling pathway AKT and mTOR phosphorylation level. Collectively, these findings suggested that BBR protects PC-12 cells from oxidative injury through inhibiting ROS level, mitochondria dysfunction, and mitophagy via PI3K/AKT/mTOR signaling pathways, which suggest a potential therapeutic strategy for oxidative stress and neurotoxic damages.

中文翻译：

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小ber碱通过抑制PC-12细胞中的氧化应激和线粒体功能障碍，减轻了t-BHP诱导的细胞毒性。

摘要

神经退行性疾病均具有几种共同特征，例如在发病机理中涉及氧化损伤和线粒体功能障碍。线粒体活性氧（ROS）的过量产生或抗氧化剂缺乏引起的氧化应激会导致线粒体功能障碍和细胞死亡级联反应的启动。据报道，小ber碱（BBR）在中枢神经系统疾病中发挥抗氧化应激和抗凋亡作用。然而，BBR在氧化应激下调节线粒体和保护线粒体功能的机制仍不清楚。在本研究中，我们评估了BBR对叔丁基氢过氧化物（t-BHP）诱导的细胞毒性的有益作用。此外，我们探讨了BBR在PC-12细胞氧化应激下对线粒体功能和线粒体的保护作用。我们的结果表明，BBR有效抑制t-BHP诱导的凋亡，这与乳酸脱氢酶（LDH）渗漏减少和ROS过量产生有关。此外，BBR通过优化线粒体膜电位（ΔΨm）状态和ATP产生，显着抑制细胞色素c的表达，上调Bcl-2 / Bax的比例，并改善线粒体功能障碍。此外，BBR降低了自噬特异性标志物LC3，SQTM1 / p62的表达，并维持了溶酶体的正常功能，涉及上游信号通路AKT和mTOR磷酸化水平的恢复。总的来说，