Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, 400014, China.
Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, 400014, China.
Free Radic Biol Med. 2024 Mar;213:359-370. doi: 10.1016/j.freeradbiomed.2024.01.045. Epub 2024 Jan 28.
Epidemiological studies have established a robust correlation between exposure to ambient particulate matter (PM) and various neurological disorders, with dysregulation of intracellular redox processes and cell death being key mechanisms involved. Ferroptosis, a cell death form characterized by iron-dependent lipid peroxidation and disruption of antioxidant defenses, may be involved in the neurotoxic effects of PM exposure. However, the relationship between PM-induced neurotoxicity and ferroptosis in nerve cells remains to be elucidated. In this study, we utilized a rat model (exposed to PM at a dose of 10 mg/kg body weight per day for 4 weeks) and an HT-22 cell model (exposed to PM at concentrations of 50, 100, and 200 μg/mL for 24 h) to investigate the potential induction of ferroptosis by PM exposure. Furthermore, RNA sequencing analysis was employed to identify hub genes that potentially contribute to the process of ferroptosis, which was subsequently validated through in vivo and in vitro experiments. The results revealed that PM exposure increased MDA content and Fe levels, and decreased SOD activity and GSH/GSSG ratio in rat hippocampal and HT-22 cells. Through RNA sequencing analysis, bioinformatics analysis, and RT-qPCR experiments, we identified GSK3B as a possible hub gene involved in ferroptosis. Subsequent investigations demonstrated that PM exposure increased GSK3B levels and decreased Nrf2, and GPX4 levels in vivo and in vitro. Furthermore, treatment with LY2090314, a specific inhibitor of GSK3B, was found to mitigate the PM-induced elevation of MDA and ROS and restore SOD activity and GSH/GSSG ratio. The LY2090314 treatment promoted the upregulation of Nrf2 and GPX4 and facilitated the nuclear translocation of Nrf2 in HT-22 cells. Moreover, treatment with LY2090314 resulted in the upregulation of Nrf2 and GPX4, along with the facilitation of nuclear translocation of Nrf2. This study suggested that PM-induced ferroptosis in hippocampal cells may be via the GSK3B/Nrf2/GPX4 pathway.
流行病学研究已经确立了暴露于环境颗粒物（PM）与各种神经紊乱之间的强大相关性，其中细胞内氧化还原过程的失调和细胞死亡是涉及的关键机制。铁死亡是一种细胞死亡形式，其特征是铁依赖性脂质过氧化和抗氧化防御的破坏，可能与 PM 暴露的神经毒性作用有关。然而，PM 诱导的神经毒性与神经细胞中的铁死亡之间的关系仍有待阐明。在这项研究中，我们利用大鼠模型（每天暴露于 10mg/kg 体重的 PM 4 周）和 HT-22 细胞模型（暴露于 50、100 和 200μg/mL 的 PM 24 小时）来研究 PM 暴露对铁死亡的潜在诱导作用。此外，我们还进行了 RNA 测序分析，以鉴定可能有助于铁死亡过程的枢纽基因，随后通过体内和体外实验进行验证。结果表明，PM 暴露增加了大鼠海马和 HT-22 细胞中 MDA 含量和 Fe 水平，降低了 SOD 活性和 GSH/GSSG 比值。通过 RNA 测序分析、生物信息学分析和 RT-qPCR 实验，我们确定 GSK3B 是铁死亡过程中可能的枢纽基因。随后的研究表明，PM 暴露增加了体内和体外的 GSK3B 水平，降低了 Nrf2 和 GPX4 水平。此外，使用 GSK3B 的特异性抑制剂 LY2090314 处理可减轻 PM 诱导的 MDA 和 ROS 升高，并恢复 SOD 活性和 GSH/GSSG 比值。LY2090314 处理促进了 HT-22 细胞中 Nrf2 和 GPX4 的上调，并促进了 Nrf2 的核转位。此外，LY2090314 处理导致 Nrf2 和 GPX4 的上调，并促进了 Nrf2 的核转位。这项研究表明，海马细胞中的 PM 诱导的铁死亡可能是通过 GSK3B/Nrf2/GPX4 途径。
