The mTOR/GCLc/GSH Pathway Mediates the Dose-Dependent Bidirectional Regulation of ROS Induced by TiO2 NPs in Neurogenic Cells
The mTOR/GCLc/GSH Pathway Mediates the Dose-Dependent Bidirectional Regulation of ROS Induced by TiO2 NPs in Neurogenic Cells
复制标题
mTOR/GCLc/GSH 通路介导神经源细胞中 TiO2 NP 诱导的 ROS 剂量依赖性双向调节
DOI：
10.1155/2019/7621561
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发表时间：
2019
影响因子：
--
通讯作者：
Chen Minjian
中科院分区：
文献类型：
--
作者：
Mao Zhilei;Li Shushu;Zhang Lina;Yao Mengmeng;Zhou Zhu;Chen Minjian
目标。TiO2NP暴露对神经系统的影响及其潜在机制尚不清楚。低剂量的纳米二氧化钛具有不同于高剂量的抗氧化作用，这是本研究新发现的。本研究旨在探讨低剂量纳米二氧化钛的抗氧化作用和高剂量纳米二氧化钛诱导神经源性细胞ROS积聚的机制。我们通过免疫印迹、流式细胞仪和商业试剂盒检测ROS调节通路中关键分子的变化，并用TiO2 NPs处理的SH-SY5Y、U251和SK-N-SH细胞进一步验证这些关键分子的相互作用和作用。结果表明，mTOR/GCLC诱导的GSH生成过多和GSH-Px活性降低是小剂量小鼠抗氧化作用较弱的原因。高剂量下ROS的积累是由mTOR/GCLC介导的GSH生成减少、GSH-Px活性受损和ROS生成急剧增加所致。此外，我们还发现，ROS物种主要是O2-⋅，在mTOR蛋白激活之前，超氧化物歧化酶在降低O2-⋅水平方面起着至关重要的作用。我们揭示了不同剂量的纳米二氧化钛对神经源性细胞系中ROS的双向调节机制。我们的研究强调了低剂量NPs的潜在神经毒性作用，这应该引起人们对其安全性的关注。
Objective. The effect of TiO2NP exposure on the nervous system and the underlying mechanism remain unclear. The antioxidant effect of TiO2NPs at a low dose was newly found in our study, which was different from the effect at high dose. This study is aimed at exploring the mechanism underlying the antioxidant effects of TiO2NPs at low dose and the induction of ROS accumulation by TiO2NPs at high dose in neurogenic cell lines.Methods. We measured the changes in key molecules in the ROS regulation pathway by western blotting, flow cytometry, and commercial assay kits, and these key molecules were further evaluated to verify their interactions and roles using SH‐SY5Y, U251, and SK‐N‐SH cell lines treated with TiO2NPs.Results. Our results showed that the weak antioxidant effect at low dose was caused by mTOR/GCLc‐induced GSH overproduction and GSH‐Px activity impairment. ROS accumulation at high dose was caused by a mTOR/GCLc‐mediated decrease in GSH production, GSH‐Px activity impairment, and dramatic ROS production. Furthermore, we found that the ROS species were mainly O2-⋅, and that SOD played a crucial role in reducing O2-⋅levels before the mTOR protein was activated.Conclusion. We revealed the mechanism underlying the bidirectional regulation of ROS induced by TiO2NPs at different doses in neurogenic cell lines. Our study emphasized the potential neurotoxic effects of NPs at low dose, which should arouse concern about their safety.