2. Academic Validation
  3. Manganese-induced apoptosis through the ROS-activated JNK/FOXO3a signaling pathway in CTX cells, a model of rat astrocytes

Manganese-induced apoptosis through the ROS-activated JNK/FOXO3a signaling pathway in CTX cells, a model of rat astrocytes

  • Ecotoxicol Environ Saf. 2023 Aug 7;262:115326. doi: 10.1016/j.ecoenv.2023.115326.
Wan-He Li 1,  Zheng-Ting-Yan Xiang 2,  An-Xin Lu 3,  Su-Su Wang 4,  Chong-Huai Yan 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 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. Electronic address: 2291885575@qq.com.
  • 5 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. Electronic address: yanchonghuai@xinhuamed.com.cn.
PMID: 37556958 DOI: 10.1016/j.ecoenv.2023.115326
Abstract

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.

Keywords

Apoptosis; JNK/FOXO3a; Manganese; Neurotoxicity; Reactive oxygen species.

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