脑出血神经炎症诱发脑损伤潜在发病机制和风险基因的生物信息学分析

IF 1.3 Q4 CLINICAL NEUROLOGY

Brain Hemorrhages Pub Date : 2025-02-01 DOI:10.1016/j.hest.2024.07.007

Ilgiz Gareev , Ozal Beylerli , Elmar Musaev , Chunlei Wang , Valentin Pavlov

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引用次数: 0

摘要

目的自发性（非外伤性）脑出血（ICH）是全球死亡的主要原因之一。我们的生物信息学分析的目的是检测可行的病理生理靶点和小分子候选药物，并确定脑出血脑损伤的精确继发机制。方法从Gene Expression Omnibus （GEO）数据库下载GSE24265数据集，包括4个血肿周围脑组织和7个对侧脑组织的数据，筛选ICH中差异表达基因（differential Expression genes, DEGs）。使用在线分析工具GEO2R和ACBI生物信息工具中的药敏评估模块进行数据差异表达分析。TargetScan、miRDB和RNA22被用来研究调控deg的mirna。使用基因本体（Gene Ontology， GO）资源对DEGs进行功能注释，使用京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes， KEGG）对DEGs进行细胞信号通路分析。使用DAVID对候选靶基因进行GO功能富集分析和KEGG通路分析。通过富集分析探究DEGs的分子机制，利用蛋白-蛋白相互作用（PPI）网络和microRNA -信使RNA （mRNA）网络揭示枢纽节点及其相互作用关系。利用STRING version 12.0在线软件和Cytoscape对PPI网络的枢纽基因和miRNA-mRNA相互作用进行鉴定。接下来，使用L1000CDS2数据库分析deg，以鉴定具有潜在治疗作用的小分子化合物。结果共鉴定出与脑出血相关的325个上调基因和103个下调基因。与脑出血相关的DEGs的生物学功能主要涉及炎症反应、趋化因子活性和免疫反应。KEGG分析确定了几种与脑出血显著相关的途径，包括但不限于细胞因子-细胞因子受体相互作用和MAPK信号通路。利用STRING构建了包含188个节点和563条边的PPI网络，利用Cytoscape软件鉴定了27个枢纽基因。高连通性的miRNA-mRNA网络包含27个关键mrna(来自C-C基序趋化因子配体5 (CCL5)， C-C基序趋化因子配体8 (CCL8), ....包括：形态发生1的凌乱相关激活因子（DAAM1）、WNT信号通路1的FRAT调节因子（FRAT1）)和135个候选mirna。这些基因和mirna与脑出血所致继发性脑损伤密切相关。此外，六种小分子化合物的L1000CDS2分析揭示了它们的治疗潜力。结论sour研究揭示了脑出血患者神经炎症所致脑组织损伤的发病机制，拓展了其关键基因的临床应用。同时，我们构建了一个可能在脑出血发病机制中起关键作用的miRNA-mRNA网络。此外，我们获得了六种对脑出血具有抗炎作用的小分子化合物，包括格尔达那霉素、达沙替尼、BMS-345541、萨拉卡替尼和阿法替尼。

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Bioinformatics analysis of potential pathogenesis and risk genes of neuroinflammation-promoted brain injury in intracerebral hemorrhage

Objective

Spontaneous (non-traumatic) intracerebral hemorrhage (ICH) is one of the major causes of global death. The purpose of our bioinformatics analysis was to detect viable pathophysiological targets and small-molecule drug candidates and to identify the precise secondary mechanisms of brain injury in ICH.

Methods

The GSE24265 dataset, consisting of data from four perihematomal brain tissues and seven contralateral brain tissues, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs) in ICH. Online analysis tool GEO2R and Drug Susceptibility Assessment Module within the ACBI Bioinformation tool was used for data differential expression analysis. TargetScan, miRDB, and RNA22 were used to investigate the miRNAs regulating the DEGs. The functional annotation of DEGs was performed using Gene Ontology (GO) resources, and the cell signaling pathway analysis of DEGs was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG). DAVID is used to perform GO function enrichment analysis and KEGG pathway analysis of candidate target genes. Enrichment analysis was performed for delving the molecular mechanism of DEGs, and protein–protein interaction (PPI) networks and microRNA (miRNA)-messenger RNA (mRNA) networks were used to reveal the hub nodes and the related interaction relationships. Hub genes and miRNA-mRNA interaction of PPI network were identified by STRING version 12.0 online software and Cytoscape. Next, the DEGs were analyzed using the L1000CDS2 database to identify small-molecule compounds with potential therapeutic effects.

Results

A total of 325 upregulated genes and 103 downregulated genes associated with ICH were identified. The biological functions of DEGs associated with ICH are mainly involved in the inflammatory response, chemokine activity, and immune response. The KEGG analysis identified several pathways significantly associated with ICH, including but not limited to cytokine-cytokine receptor interaction and MAPK signaling pathway. A PPI network consisting of 188 nodes and 563 edges was constructed using STRING, and 27 hub genes were identified with Cytoscape software. The miRNA-mRNA network with high connectivity contained key 27 mRNAs (from C-C motif chemokine ligand 5 (CCL5), C-C motif chemokine ligand 8 (CCL8), …., to dishevelled-associated activator of morphogenesis 1 (DAAM1), and FRAT regulator of WNT signaling pathway 1 (FRAT1)) and 135 candidate miRNAs. These genes and miRNAs are closely related to secondary brain injury induced by ICH. In addition, a L1000CDS² analysis of six small-molecule compounds revealed their therapeutic potential.

Conclusions

Our study explores the pathogenesis of brain tissue injury promoted by neuroinflammation in ICH and extends the clinical utility of its key genes. At the same time, we constructed a miRNA-mRNA network which may play crucial roles in the pathogenesis of ICH. In addition, we obtained six small molecule compounds that will have anti-inflammatory effects on ICH, including Geldanamycin, Dasatinib, BMS-345541, Saracatinib, and Afatinib.

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来源期刊

Brain Hemorrhages Medicine-Surgery

CiteScore

2.90

自引率

0.00%

发文量

审稿时长

22 days