Manganese induces neuronal apoptosis by activating mTOR signaling pathway in vitro and in vivo

IF 3.9 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY Food and Chemical Toxicology Pub Date : 2024-02-07 DOI:10.1016/j.fct.2024.114508

Yuyan Cen , Jianmin Yang , Liyu Su , Feng Wang , Deyu Zhu , Lan Zhao , Yan Li

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Abstract

Manganese (Mn) is a well-known environmental pollutant and occupational toxicant that causes neurotoxicity, which present as neurodegenerative-like symptoms. However, the mechanism of Mn-induced neuronal injury remains unclear. In this research, we explored the mechanism of Mn-induced neurotoxicity, focusing on the mTOR signaling pathway. A plasmid expressing a short hairpin RNA (shRNA) targeting mTOR (shRNA-mTOR) was transfected into N27 cells in vitro, and rapamycin was used as an mTOR inhibitor in vivo to block the mTOR signaling pathway. Cells were treated with different concentrations of manganese (II) chloride (MnCl₂). We found that Mn induced cell injury and apoptosis and markedly upregulated the expression of mTOR pathway-related proteins. The phosphorylation of 4E-BP1, S6K1, Akt and SGK1 was markedly decreased after blocking mTOR, and cell apoptosis was also reduced. Furthermore, the mTOR-specific inhibitor rapamycin restored learning and memory abilities in vivo. This research highlights that inhibiting mTOR might be useful for preventing Mn-induced neurodegenerative-like disorders.

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锰通过激活体外和体内的 mTOR 信号通路诱导神经细胞凋亡。

锰（Mn）是一种众所周知的环境污染物和职业毒物，可导致神经中毒，表现为类似神经退行性病变的症状。然而，锰诱导神经元损伤的机制仍不清楚。在这项研究中，我们以 mTOR 信号通路为重点，探索了锰诱导神经毒性的机制。我们在体外将表达靶向 mTOR 的短发夹 RNA（shRNA）的质粒转染到 N27 细胞中，在体内使用雷帕霉素作为 mTOR 抑制剂阻断 mTOR 信号通路。用不同浓度的氯化锰（MnCl2）处理细胞。我们发现锰能诱导细胞损伤和凋亡，并显著上调 mTOR 通路相关蛋白的表达。阻断 mTOR 后，4E-BP1、S6K1、Akt 和 SGK1 的磷酸化明显降低，细胞凋亡也减少了。此外，mTOR特异性抑制剂雷帕霉素还能恢复体内学习和记忆能力。这项研究强调，抑制 mTOR 可能有助于预防锰诱导的神经退行性疾病。

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.