Li Wan-He, Xiang Zheng-Ting-Yan, Lu An-Xin, Wang Su-Su, Yan Chong-Huai
Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Pubilc Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Pubilc Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ecotoxicol Environ Saf. 2023 Aug 7;262:115326. doi: 10.1016/j.ecoenv.2023.115326.
Manganese (Mn) is an essential trace element that maintains many normal physiological functions. However, multi-system disorders would occur once overexposure to Mn, especially neurotoxicity. Despite evidence demonstrating the critical role of ROS-activated JNK/FOXO3a signaling pathway in neuronal survival, the specific mechanisms by which it contributes to Mn-induced neurotoxicity are still unclear. The objectives of this study was to examine the modulation of the JNK/FOXO3a signaling pathway, which is activated by ROS, in Mn-induced apoptosis, using a rat brain astrocyte cell line (CTX cells). This study found that a dose-dependent decrease in cell viability of CTX cells was observed with 150, 200, 250, 300 μmol/L Mn. The results of apoptosis-related protein assay showed that Mn decreased the expression of anti-apoptotic protein Bcl-2 and enhanced the expression of apoptosis-related proteins like Bax and Cleaved-Caspase3. In addition, treatment with Mn resulted in elevated ROS levels and increased phosphorylation levels of JNK. Conversely, phosphorylation of nuclear transcription factors FOXO3a, which regulates expression of transcription factors including Bim and PUMA, was decreased. Depletion of ROS by N-acetyl-L-cysteine (NAC) and inhibition of the JNK pathway by SP600125 prevented Mn-induced JNK/FOXO3a pathway activation and, more importantly, the level of apoptosis was also significantly reduced. Confirmation of Mn-induced apoptosis in CTX cells through ROS generation and activation of the JNK/FOXO3a signaling pathway was the outcome of this study. These findings offer fresh insights into the neurotoxic mechanisms of Mn and therapeutic targets following Mn exposure.
锰（Mn）是一种维持多种正常生理功能的必需微量元素。然而，一旦过度暴露于锰，尤其是神经毒性，就会发生多系统紊乱。尽管有证据表明ROS激活的JNK/FOXO3a信号通路在神经元存活中起关键作用，但其导致锰诱导神经毒性的具体机制仍不清楚。本研究的目的是使用大鼠脑星形胶质细胞系（CTX细胞），研究由ROS激活的JNK/FOXO3a信号通路在锰诱导的细胞凋亡中的调节作用。本研究发现，当锰浓度为150、200、250、300 μmol/L时，CTX细胞的细胞活力呈剂量依赖性下降。凋亡相关蛋白检测结果表明，锰降低了抗凋亡蛋白Bcl-2的表达，并增强了Bax和Cleaved-Caspase3等凋亡相关蛋白的表达。此外，锰处理导致ROS水平升高和JNK磷酸化水平增加。相反，调节包括Bim和PUMA在内的转录因子表达的核转录因子FOXO3a的磷酸化水平降低。N-乙酰-L-半胱氨酸（NAC）清除ROS和SP600125抑制JNK通路可阻止锰诱导的JNK/FOXO3a通路激活，更重要的是，细胞凋亡水平也显著降低。本研究的结果证实了通过ROS生成和JNK/FOXO3a信号通路激活在CTX细胞中诱导锰凋亡。这些发现为锰的神经毒性机制和锰暴露后的治疗靶点提供了新的见解。
