RhoA/ROCK2信号通路调控mn诱导小鼠认知功能障碍的紧密连接蛋白改变。

IF 2.9 Q2 TOXICOLOGY Current Research in Toxicology Pub Date : 2024-12-18 eCollection Date: 2025-01-01 DOI:10.1016/j.crtox.2024.100207
Yan Ma, Honggang Chen, Yuxin Jiang, Diya Wang, Michael Aschner, Wenjing Luo, Peng Su
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引用次数: 0

摘要

锰(Mn)暴露升高与广泛的神经疾病有关,包括运动功能障碍和认知缺陷。先前的研究表明,锰通过破坏血脑屏障(BBB)的完整性来诱导神经毒性,血脑屏障是维持中枢神经系统稳态的关键调节因子,也是许多神经疾病发病的一个因素。然而,mn诱导血脑屏障破坏的精确分子机制及其在促进神经毒性中的作用仍然不完全清楚。本研究的主要目的是阐明锰暴露与血脑屏障紧密连接蛋白(TJPs)之间关系的潜在机制,并进一步研究减轻锰诱导的认知障碍的潜在神经保护策略。在这项研究中,我们利用小鼠和细胞培养系统建立了锰暴露模型,以阐明tjp参与的机制,并评估天麻素(一种从中药中提取的生物活性化合物)的潜在神经保护作用。我们的研究结果显示,在体内和体外,mn诱导的血脑屏障破坏中,TJPs的表达显著降低。Occludin (OCLN)是tjp的一个重要组成部分,过表达可以减轻mn诱导的血脑屏障损伤。GAS有效地减弱了mn诱导的血脑屏障破坏,增强了tjp的表达,并减轻了mn诱导的认知功能障碍,这可能是通过调节RhoA/ROCK2信号通路实现的。本研究旨在促进我们对锰介导的血脑屏障破坏的分子途径的理解,并确定新的治疗方法来减轻锰暴露对认知功能的有害影响。
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RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice.

Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood-brain barrier (BBB), a critical regulator in maintaining central nervous system homeostasis and a contributing factor in the pathogenesis of numerous neurological disorders. However, the precise molecular mechanisms underlying Mn-induced BBB disruption and its role in facilitating neurotoxicity remain incompletely understood. The primary objectives of this study were to elucidate the mechanisms underlying the relationship between Mn exposure and BBB tight junction proteins (TJPs), and to further investigate potential neuroprotective strategies for mitigating Mn-induced cognitive impairments. In this investigation, we developed Mn exposure models utilizing both murine subjects and cell culture systems to elucidate the mechanisms underlying TJPs involvement and to assess the potential neuroprotective effects of gastrodin (GAS), a bioactive compound extracted from traditional Chinese medicine. Our findings revealed a significant reduction in TJPs expression, both in vivo and in vitro, in Mn-induced BBB disruption. The overexpression of Occludin (OCLN), a crucial component of TJPs, mitigated Mn-induced BBB damage. GAS administration effectively attenuated Mn-induced disruption of the BBB, enhanced the expression of TJPs, and mitigated Mn-induced cognitive dysfunctions, potentially through the modulation of the RhoA/ROCK2 signaling pathway. This research sought to advance our understanding of the molecular pathways involved in Mn-mediated BBB disruption and to identify novel therapeutic approaches for mitigating the deleterious effects of Mn exposure on cognitive function.

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来源期刊
Current Research in Toxicology
Current Research in Toxicology Environmental Science-Health, Toxicology and Mutagenesis
CiteScore
4.70
自引率
3.00%
发文量
33
审稿时长
82 days
期刊最新文献
Efficacy of a hydrogen-oxygen generator in treating cigarette smoke-induced chronic obstructive pulmonary disease in rats. A simple, reliable and easily generalizable cell-based assay for screening potential drugs that inhibit lipid accumulation. The role of the gut microbiota and the nicotinate/nicotinamide pathway in rotenone-induced neurotoxicity. L-3-n-butylphthalide alleviates intermittent alcohol exposure-induced hypothalamic cell apoptosis via inhibiting the IRE1α-ASK1-JNK pathway in adolescent rats. RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice.
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