Key Genes Associated with Pyroptosis in Gout and Construction of a miRNA-mRNA Regulatory Network.
Key Genes Associated with Pyroptosis in Gout and Construction of a miRNA-mRNA Regulatory Network.
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DOI：
10.3390/cells11203269
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发表时间：
2022-10-17
期刊：
影响因子：
6
通讯作者：
Sun, Yuping
中科院分区：
文献类型：
--
作者：
Bai, Bing;Liu, Yezhou;Abudukerimu, Azierguli;Tian, Tingting;Liang, Meiting;Li, Rui;Sun, Yuping
本研究旨在通过分析痛风焦亡相关的关键枢纽基因，构建痛风焦亡的miRNA-mRNA调控网络，为阐明痛风的发病机制和开发痛风的靶向治疗策略提供新的思路。方法：从GEO数据库下载GSE 160170数据集。从数据集中提取的表达数据用于筛选差异表达基因（DEG），其与热解相关基因相一致。通过基因本体论（GO）和京都基因和基因组百科全书（KEGG）富集分析来分析这些DEG，并且构建蛋白质-蛋白质相互作用（PPI）网络以鉴定热解相关的枢纽DEG。分析上游miRNAs与hub基因的关系，构建属于痛风疾病的miRNA-mRNA网络，并利用痛风患者样本进行实验验证。使用CTDbase工具分析所鉴定的枢纽基因并构建分子对接模型。结果如下：通过分析GSE 160170数据集中早期痛风患者和健康对照个体的数据，共鉴定出943个DEG（380个上调和563个下调）。对DEG和脓毒症相关基因进行分析，获得17个与痛风相关的脓毒症相关DEG;其中12个上调，5个下调。GO和KEGG分析结果显示DEG在炎症和免疫信号通路中富集。此外，发现DEG调节炎症反应并与细胞凋亡相关。TNF、IL-1β、NLRP 3、CXCL 8、PTGS 2、NFE 2L 2、CASP 8和CD 274被确定为PPI网络中的关键枢纽基因，并构建了具有16条边的miRNA-mRNA网络。实验验证显示，PTGS 2和NFE 2L 2在痛风中显著上调，CASP 8和CD 274在痛风中显著下调。此外，miR-128- 3 p、miR-16- 5 p、miR-155- 5 p和miR-20 a-5 p（与miRNA-mRNA调控网络相关）在痛风中显著下调。选择五种具有稳定PTGS 2结合的潜在治疗药物来开发分子对接模型。结论：痛风患者体内存在与脓毒症相关的DEGs，构建了miRNA-mRNA潜在调控网络。miR-16- 5 p、miR-128- 3 p、miR-20 a-5 p和miR-155- 5 p可通过影响PTGS 2、CASP 8、NFE 2L 2和CD 274基因的表达而潜在地影响焦亡和痛风的发生和发展。筛选塞来昔布与白藜芦醇等具有稳定结合作用的靶向药物。这项研究的发现为痛风的调节机制提供了有价值的见解，并可能有助于识别生物标志物和制定针对痛风的治疗策略。
This study aimed to analyze key hub genes related to pyroptosis in gout and construct a miRNA-mRNA regulatory network using bioinformatic tools to elucidate the pathogenesis of gout and offer novel ideas to develop targeted therapeutic strategies for gout. Methods: The GSE160170 dataset was downloaded from the GEO database. The expression data extracted from the dataset were used to screen for differentially expressed genes (DEGs), which intersected with pyroptosis-related genes. These DEGs were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and a protein–protein interaction (PPI) network was constructed to identify pyroptosis-related hub DEGs. The relationship between upstream miRNAs and the hub genes was analyzed, miRNA-mRNA networks belonging to gout disease were constructed and samples from patients with gout were used for experimental verification. The CTDbase tool was used to analyze the identified hub genes and construct a molecular docking model. Results: A total of 943 DEGs (380 upregulated and 563 downregulated) were identified by analyzing the data of patients with early-stage gout and healthy control individuals in the GSE160170 dataset. DEGs and pyroptosis-related genes were intersected to obtain 17 pyroptosis-related DEGs associated with gout; of which, 12 were upregulated, and five were downregulated. The results of GO and KEGG analyses revealed that the DEGs were enriched in inflammatory and immune signaling pathways. Additionally, the DEGs were found to regulate inflammatory responses and were associated with apoptosis. TNF, IL-1β, NLRP3, CXCL8, PTGS2, NFE2L2, CASP8, and CD274 were identified as key hub genes in the PPI network, and a miRNA-mRNA network was constructed, which had 16 edges. Experimental validation revealed that PTGS2 and NFE2L2 were significantly upregulated, and CASP8 and CD274 were significantly downregulated in gout. In addition, miR-128-3p, miR-16-5p, miR-155-5p, and miR-20a-5p (associated with the miRNA-mRNA regulatory network) were significantly downregulated in gout. Five potential therapeutic drugs with stable PTGS2 binding were selected to develop a molecular docking model. Conclusion: A miRNA-mRNA potential regulatory network was constructed based on pyroptosis-related DEGs associated with gout. miR-16-5p, miR-128-3p, miR-20a-5p, and miR-155-5p can potentially influence pyroptosis and the occurrence and development of gout by affecting the expression of the PTGS2, CASP8, NFE2L2, and CD274 genes. Screening of celecoxib and resveratrol and other targeted drugs with stable binding. The findings of this study offer valuable insights into the regulatory mechanisms of gout and may help to identify Biomarkers and develop targeted therapeutic strategies for gout.
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