Cromolyn prevents cerebral vasospasm and dementia by targeting WDR43.
Cromolyn prevents cerebral vasospasm and dementia by targeting WDR43.
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DOI：
10.3389/fnagi.2023.1132733
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发表时间：
2023
影响因子：
4.8
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中科院分区：
文献类型：
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脑血管痉挛（CV）可引起老年人神经细胞炎症和损伤，导致痴呆。本研究旨在探讨老年人CV所致痴呆的遗传机制，确定预防和治疗药物，并评估其治疗神经退行性疾病的疗效。获得与蛛网膜下腔出血和CV相关的基因，并筛选与动脉瘤破裂相关的差异表达的miRNA（DEmiRNAs）。构建DEmiRNAs和mRNA的调控网络，并进行虚拟筛选以评估食品和药物管理局（FDA）批准的药物与核心蛋白之间可能的结合模式。对最佳对接复合物进行了分子动力学模拟。通过细胞实验评估最佳对接药物在治疗神经退行性疾病中的功效。该研究发现了与动脉瘤破裂相关的上调基因（包括WDR 43和THBS1）和一个下调基因。这些基因表达的差异表明更大的疾病风险。鉴定了与破裂主动脉瘤相关的DEmiRNAs，其中两个可与THBS1和WDR 43结合。克罗诺因和羊毛毒素分别与WDR 43和THBS1形成最佳对接复合物。细胞实验表明，克罗埃西亚可提高BV2细胞活力，增强Aβ42摄取，表明其作为炎症相关疾病治疗剂的潜力。研究结果表明，WDR 43和THBS1是预防和治疗老年人CV诱导的痴呆的潜在靶点。克罗埃西亚可能对阿尔茨海默病和痴呆症有治疗价值。
Cerebral vasospasm (CV) can cause inflammation and damage to neuronal cells in the elderly, leading to dementia. This study aimed to investigate the genetic mechanisms underlying dementia caused by CV in the elderly, identify preventive and therapeutic drugs, and evaluate their efficacy in treating neurodegenerative diseases. Genes associated with subarachnoid hemorrhage and CV were acquired and screened for differentially expressed miRNAs (DEmiRNAs) associated with aneurysm rupture. A regulatory network of DEmiRNAs and mRNAs was constructed, and virtual screening was performed to evaluate possible binding patterns between Food and Drug Administration (FDA)-approved drugs and core proteins. Molecular dynamics simulations were performed on the optimal docked complexes. Optimally docked drugs were evaluated for efficacy in the treatment of neurodegenerative diseases through cellular experiments. The study found upregulated genes (including WDR43 and THBS1) and one downregulated gene associated with aneurysm rupture. Differences in the expression of these genes indicate greater disease risk. DEmiRNAs associated with ruptured aortic aneurysm were identified, of which two could bind to THBS1 and WDR43. Cromolyn and lanoxin formed the best docking complexes with WDR43 and THBS1, respectively. Cellular experiments showed that cromolyn improved BV2 cell viability and enhanced Aβ42 uptake, suggesting its potential as a therapeutic agent for inflammation-related disorders. The findings suggest that WDR43 and THBS1 are potential targets for preventing and treating CV-induced dementia in the elderly. Cromolyn may have therapeutic value in the treatment of Alzheimer’s disease and dementia.
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影响因子：
3.4
作者：
Chen X;Zheng C;He Y;Tian L;Li J;Li D;Jin W;Li M;Zheng S
通讯作者：
Zheng S
影响因子：
4.7
作者：
Lin CH;Lin E;Lane HY
通讯作者：
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影响因子：
6.8
作者：
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通讯作者：
Ding YB
影响因子：
4.8
作者：
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影响因子：
5.6
作者：
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通讯作者：
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