MEK1 inhibition ameliorates mitochondrial-dependent apoptosis induced by deltamethrin in mouse hippocampal neuron HT22 cells

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro Pub Date : 2025-03-07 DOI:10.1016/j.tiv.2025.106047

Lexing Wei , Yang Chen , Minjia Wu , Peixuan Ma , Huan Wang , Yueming Jiang , Michael Aschner , Jing Zhou , Guodong Lu , Lina Zhao , Xiaowei Huang

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引用次数: 0

Abstract

Deltamethrin (DM), a widely used pyrethroid insecticide, has been increasingly recognized as a risk factor for neurodegeneration. However, the underlying mechanism is still far from clear. In this study, we investigated whether MEK1 is involved in DM-induced neurotoxicity and mediated mitochondrial-dependent apoptosis. In mouse hippocampal neuron HT22 cells model, DM (2,10,50 μM) dose-dependently increased apoptotic cells rate and impaired mitochondrial membrane potential (MMP), as well as significantly upregulated of apoptotic related proteins Bax, cytochrome c (Cyt-c) and Caspase-3 were observed. RNA-sequencing analysis further revealed that the MEK/ERK signal pathway was remarkably enriched and activated after DM exposure. In particularly, upregulation of MEK1, other than ERK1/2, was detected at both transcriptional and translational levels. Inhibition of MEK1 can effectively result in the recovery of mitochondrial morphology and MMP in DM-treated HT22 cells. And that further alleviated apoptosis by reversing the overexpression of Bax, Cyt-c and Caspase-3. Collectively, these findings demonstrate the critical role of MEK1 in regulating mitochondrial-dependent apoptosis induced by DM, providing a novel understanding of the neurotoxicity of DM.

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抑制 MEK1 可改善溴氰菊酯诱导的小鼠海马神经元 HT22 细胞线粒体依赖性凋亡。

溴氰菊酯（DM）是一种广泛使用的拟除虫菊酯类杀虫剂，越来越被认为是神经退行性疾病的危险因素。然而，其潜在机制仍远不清楚。在这项研究中，我们研究了MEK1是否参与dm诱导的神经毒性和介导的线粒体依赖性细胞凋亡。在小鼠海马神经元HT22细胞模型中，DM（2,10,50 μM）剂量依赖性地增加凋亡细胞率，损害线粒体膜电位（MMP），并显著上调凋亡相关蛋白Bax、细胞色素c （Cyt-c）和Caspase-3。rna测序分析进一步发现，DM暴露后MEK/ERK信号通路显著富集和激活。特别是，除了ERK1/2外，MEK1在转录和翻译水平上都有上调。抑制MEK1可以有效地恢复dm处理的HT22细胞的线粒体形态和MMP。通过逆转Bax、Cyt-c和Caspase-3的过表达，进一步减轻细胞凋亡。总的来说，这些发现证明了MEK1在调节DM诱导的线粒体依赖性细胞凋亡中的关键作用，为DM的神经毒性提供了新的认识。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.