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识别子痫前期合体滋养细胞衍生细胞外囊泡中的铁死亡相关基因。

Identification of ferroptosis-related genes in syncytiotrophoblast-derived extracellular vesicles of preeclampsia.

机构信息

Department of Obstetrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.

Department of Gynecology and Obstetrics, Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China.

出版信息

Medicine (Baltimore). 2022 Nov 4;101(44):e31583. doi: 10.1097/MD.0000000000031583.

Abstract

Preeclampsia (PE), defined as new-onset hypertension and multi-organ systemic complication during pregnancy, is the leading cause of maternal and neonatal mortality and morbidity. With extracellular vesicles research progresses, current data refers to the possibility that ferroptosis may play a role in exosomal effects. Evidence has suggested that ferroptosis may contribute to the pathogenesis of preeclampsia by bioinformatics analyses. The purpose of the current study is to identify the potential ferroptosis-related genes in syncytiotrophoblast-derived extracellular vesicles (STB-EVs) of preeclampsia using bioinformatics analyses. Clinical characteristics and gene expression data of all samples were obtained from the NCBI GEO database. The differentially expressed mRNAs (DE-mRNAs) in STB-EVs of preeclampsia were screened and then were intersected with ferroptosis genes. Functional and pathway enrichment analyses of ferroptosis-related DE-mRNAs in STB-EVs were performed. Ferroptosis-related hub genes in STB-EVs were identified by Cytoscape plugin CytoHubba with a Degree algorithm using a protein-protein interaction network built constructed from the STRING database. The predictive performance of ferroptosis-related hub genes was determined by a univariate analysis of receiver operating characteristic (ROC). The miRNA-hub gene regulatory network was constructed using the miRwalk database. A total of 1976 DE-mRNAs in STB-EVs were identified and the most enriched item identified by gene set enrichment analysis was signaling by G Protein-Coupled Receptors (normalized enrichment score = 1.238). These DE-mRNAs obtained 26 ferroptosis-related DE-mRNAs. Ferroptosis-related DE-mRNAs of gene ontology terms and Encyclopedia of Genes and Genomes pathway enrichment analysis were enriched significantly in response to oxidative stress and ferroptosis. Five hub genes (ALB, NOX4, CDKN2A, TXNRD1, and CAV1) were found in the constructed protein-protein interaction network with ferroptosis-related DE-mRNAs and the areas under the ROC curves for ALB, NOX4, CDKN2A, TXNRD1, and CAV1 were 0.938 (CI: 0.815-1.000), 0.833 (CI: 0.612-1.000), 0.875 (CI: 0.704-1.000), 0.958 (CI: 0.862-1.000), and 0.854 (CI: 0.652-1.000) in univariate analysis of ROC. We constructed a regulatory network of miRNA-hub gene and the findings demonstrate that hsa-miR-26b-5p, hsa-miR-192-5p, hsa-miR-124-3p, hsa-miR-492, hsa-miR-34a-5p and hsa-miR-155-5p could regulate most hub genes. In this study, we identified several central genes closely related to ferroptosis in STB-EVs (ALB, NOX4, CDKN2A, TXNRD1, and CAV1) that are potential biomarkers related to ferroptosis in preeclampsia. Our findings will provide evidence for the involvement of ferroptosis in preeclampsia and improve the understanding of ferroptosis-related molecular pathways in the pathogenesis of preeclampsia.

摘要

子痫前期(PE)定义为妊娠期间新发生的高血压和多器官系统并发症,是孕产妇和新生儿发病率和死亡率的主要原因。随着细胞外囊泡研究的进展,目前的数据表明铁死亡可能在细胞外囊泡的作用中发挥作用。有证据表明,铁死亡可能通过生物信息学分析参与子痫前期的发病机制。本研究旨在通过生物信息学分析,确定子痫前期合体滋养层衍生细胞外囊泡(STB-EVs)中潜在的铁死亡相关基因。从 NCBI GEO 数据库中获取所有样本的临床特征和基因表达数据。筛选子痫前期 STB-EVs 中的差异表达 mRNA(DE-mRNAs),然后与铁死亡基因相交。对 STB-EVs 中与铁死亡相关的 DE-mRNAs 进行功能和通路富集分析。使用 Cytoscape 插件 CytoHubba 中的 Degree 算法,基于从 STRING 数据库构建的蛋白质-蛋白质相互作用网络,确定 STB-EVs 中与铁死亡相关的枢纽基因。使用单变量分析接收器操作特征(ROC)确定铁死亡相关枢纽基因的预测性能。使用 miRWalk 数据库构建 miRNA-枢纽基因调控网络。确定了 1976 个在 STB-EVs 中差异表达的 mRNAs,基因集富集分析中最富集的项目是 G 蛋白偶联受体信号(归一化富集得分=1.238)。这些 DE-mRNAs 获得了 26 个与铁死亡相关的 DE-mRNAs。GO 术语和基因和基因组百科全书途径富集分析的铁死亡相关 DE-mRNAs 在氧化应激和铁死亡反应中显著富集。在与铁死亡相关的 DE-mRNAs 的构建的蛋白质-蛋白质相互作用网络中发现了 5 个枢纽基因(ALB、NOX4、CDKN2A、TXNRD1 和 CAV1),ALB、NOX4、CDKN2A、TXNRD1 和 CAV1 的 ROC 曲线下面积在 ROC 的单变量分析中分别为 0.938(CI:0.815-1.000)、0.833(CI:0.612-1.000)、0.875(CI:0.704-1.000)、0.958(CI:0.862-1.000)和 0.854(CI:0.652-1.000)。我们构建了 miRNA-枢纽基因的调控网络,研究结果表明 hsa-miR-26b-5p、hsa-miR-192-5p、hsa-miR-124-3p、hsa-miR-492、hsa-miR-34a-5p 和 hsa-miR-155-5p 可以调节大多数枢纽基因。在这项研究中,我们确定了 STB-EVs(ALB、NOX4、CDKN2A、TXNRD1 和 CAV1)中与铁死亡密切相关的几个核心基因,这些基因可能是子痫前期铁死亡相关的潜在生物标志物。我们的研究结果将为铁死亡参与子痫前期提供证据,并提高对子痫前期发病机制中与铁死亡相关分子途径的认识。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bd0/9646584/599d40356f5a/medi-101-e31583-g001.jpg

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