CDKN1A敲低抑制IL-17途径抑制氧化应激和减轻自闭症谱系障碍

IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wenda Wang, Qiujin Lin, Liru Liu, Hanhui Mai, Hongmei Tang, Kaishou Xu
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引用次数: 0

摘要

自闭症谱系障碍(ASD)是一种复杂的神经发育疾病,其特征是社交障碍、沟通缺陷和重复行为。然而,潜在的分子机制仍然难以捉摸。本研究旨在探讨细胞周期蛋白依赖性激酶抑制剂1a (CDKN1A)在ASD中的作用。本研究结合多组学生物信息学分析,鉴定ASD中与氧化应激相关的差异表达基因(DEGs)。使用机器学习模型筛选枢纽基因。在体内,通过母体脂多糖(LPS)注射建立ASD大鼠模型。行为学测试(野外、三室社交、morris水迷宫)。苏木精-伊红染色观察组织病理学改变。在体外,用IL-17A处理lps刺激的BV2小胶质细胞进行反馈实验。采用酶联免疫吸附法测定炎症因子和氧化应激指标。Western blot检测蛋白表达。生物信息学分析揭示了30个DEGs, CDKN1A作为与氧化应激相关的重要枢纽基因出现。ASD模型大鼠表现出行为缺陷、神经炎症和海马神经变性。CDKN1A基因敲低显著减弱了这些表型,改善了社会互动,减少了焦虑样行为,增强了空间学习和记忆。此外,IL-17通路被筛选为CDKN1A的下游通路。CDKN1A沉默可抑制lps诱导的BV2小胶质细胞凋亡、炎症和氧化应激,而IL-17A可减弱这一作用。CDKN1A通过IL-17通路激活驱动ASD发病机制其抑制可减轻神经炎症、氧化应激和行为障碍,使CDKN1A成为ASD的新治疗靶点。试验注册:临床试验编号:不适用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Knockdown of CDKN1A Suppresses the IL-17 Pathway to Inhibit Oxidative Stress and Alleviate Autism Spectrum Disorder

Knockdown of CDKN1A Suppresses the IL-17 Pathway to Inhibit Oxidative Stress and Alleviate Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social interaction, communication deficits, and repetitive behaviors. However, the underlying molecular mechanisms remain elusive. This study aims to investigate the role of cyclin-dependent kinase inhibitor 1 A (CDKN1A) in ASD. This study integrated multi-omics bioinformatics analysis to identify differentially expressed genes (DEGs) related to oxidative stress in ASD. Hub genes were screened using machine learning models. In vivo, an ASD rat model was established by maternal lipopolysaccharide (LPS) injection. Behavioral tests (open field, three-chamber social, morris water maze) were performed. Histopathology change was observed by hematoxylin-eosin staining. In vitro, LPS-stimulated BV2 microglia were treated with IL-17A for feedback experiments. Enzyme-linked immunosorbent assay was carried out to measure inflammatory factors and oxidative stress indicators. Western blot was used to detect protein expression. Bioinformatics analysis revealed 30 DEGs, with CDKN1A emerging as a prominent hub gene associated with oxidative stress. ASD model rats exhibited behavioral deficits, neuroinflammation, and hippocampal neurodegeneration. CDKN1A knockdown significantly attenuated these phenotypes, improving social interaction, reducing anxiety-like behaviors, and enhancing spatial learning and memory. Moreover, IL-17 pathway was screened as downstream pathway of CDKN1A. CDKN1A silencing suppressed LPS-induced apoptosis, inflammation, and oxidative stress in BV2 microglial cells, which was weakened by IL-17A. CDKN1A drives ASD pathogenesis via IL-17 pathway activation. Its suppression mitigates neuroinflammation, oxidative stress, and behavioral impairments, establishing CDKN1A as a novel therapeutic target for ASD.

Trial Registration: Clinical trial number: Not applicable.

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来源期刊
CiteScore
5.80
自引率
2.80%
发文量
277
审稿时长
6-12 weeks
期刊介绍: The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.
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