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| 基于生物信息学探究mTOR抑制剂KU-0063794对缺血性脑卒中的神经保护作用 |
| Neuroprotective effect of mTOR inhibitor KU0063794 on ischemic stroke nerve injury based on bioinformatics analysis |
| 投稿时间：2024-12-23 修订日期：2024-12-23 |
| DOI： |
| 中文关键词: 生物信息学分析 缺血性脑卒中 mTOR抑制剂 KU-0063794 神经保护 |
| 英文关键词: Bioinformatics analysis Ischemic stroke mTOR inhibitor KU-0063794 Neuroprotective |
| 基金项目: |
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| 中文摘要: |
| 目的：本研究采用生物信息学筛选治疗脑缺血的神经保护药物并在动物 tMCAO 模型中进行评价。方法： ① 从Gene Expression Omnibus (GEO) 数据库中获得MCAO 6 h 与12 h 两组数据集后进行差异基因分析。② 使用DAVID和Metascape对差异基因进行生物过程与信号通路富集分析。③ 使用Cytoscape筛选出关键基因并在小鼠tMCAO模型中进行验证。④ 采用Connectivity Map (Cmap) 在线工具预测潜在的脑缺血治疗药物，并选取自噬抑制剂KU-0063794探讨对tMCAO小鼠的神经保护作用。结果： ①两组数据集共鉴定出289个共同差异基因。② 富集分析结果表明，差异基因在缺血性脑卒中急性期主要富集于突触传递调控、脂质生物合成、细胞凋亡等生物学过程。③ Real-time PCR结果显示，tMCAO后12 h 梗死周围皮层中Hmox1、Serpine1、Ptgs2、Timp1 的mRNA水平均升高；Western blotting结果表明在缺血损伤后6 h 至24 h，Hmox1的表达水平增加。④ KU-0063794可显著减少tMCAO小鼠脑梗死体积、并通过激活Nrf2/Hmox1通路减少氧化应激反应和神经细胞凋亡水平；行为学测试表明，KU-0063794显著改善tMCAO小鼠的运动功能障碍。结论： KU-0063794通过减少氧化应激反应和神经细胞凋亡发挥神经保护作用。 |
| 英文摘要: |
| Objective: This study aimed to identify neuroprotective drugs for ischemic stroke using bioinformatics analysis and to assess their efficacy in an animal tMCAO model. Methods: (1) Differential gene expression analysis was performed on datasets from MCAO groups at 6 and 12 hours, obtained from the Gene Expression Omnibus (GEO) database. (2) Enrichment analysis of biological processes and pathways associated with the differentially expressed genes was conducted using DAVID and Metascape. (3) Key genes were identified with Cytoscape and validated in a mouse tMCAO model. (4) Connectivity Map (Cmap) was used to predict potential therapeutic agents for ischemic stroke, with the autophagy inhibitor KU-0063794 selected to investigate its neuroprotective effects in tMCAO mice. Results: (1) A total of 289 common differentially expressed genes were identified from both datasets. (2) Enrichment analysis revealed that these genes were primarily involved in synaptic transmission regulation, lipid biosynthesis, and apoptosis during the acute phase of ischemic stroke. (3) Real-time PCR analysis showed elevated mRNA levels of Hmox1, Serpine1, Ptgs2, and Timp1 in the peri-infarct cortex 12 hours after tMCAO. Western blot analysis demonstrated increased Hmox1 expression from 6 to 24 hours post-ischemia. (4) KU0063794 significantly reduced infarct volume in tMCAO mice, reducing oxidative stress and neuronal apoptosis through activation of the Nrf2/Hmox1 pathway. Behavioral tests showed significant improvements in motor function in tMCAO mice treated with KU-0063794. Conclusion: KU0063794 demonstrates neuroprotective effects by reducing oxidative stress and neuronal apoptosis. |
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