背景:狼疮性肾炎是一种自身免疫性疾病,其发病机制涉及炎症和自噬障碍。研究表明,黄芪可以有效抑制LN的进展,但潜在的治疗靶点仍不清楚.
目的:本研究旨在研究AM改善LN的治疗靶点。
方法:我们从TCMSP和GEO数据库下载了与AM和LN相关的芯片,分别。我们通过WGCNA选择了两个化合物靶标进行后续分析,构建了复合靶标的蛋白质相互作用网络并确定了核心靶标。GO,对化合物靶标进行KEGG分析以鉴定富集的功能和基因组途径。在临床和外部数据集中进一步验证了核心基因。使用AutoDock软件进行AS与核心靶标的分子对接,并利用Gromacs2020.6软件对分子对接得到的最优核心蛋白配体进行分子动力学模拟。
结果:我们获得了10个核心目标,即IL-1β,EGF,CCND1,CASP3,STAT1,PTGS2,PPARγ,AR,CXCL10和KDR,从确定的24个复合目标中。GO富集分析的结果主要包括细胞生长调节。KEGG富集分析结果显示23个有效靶标中有7个在丝裂原活化蛋白激酶途径中显著富集(p<0.01)。结合临床数据集,我们发现IL-1β,EGF,CCND1、CASP3、STAT1、PTGS2和PPARγ对LN有较高的诊断价值。在验证数据集中,所有核心目标都有显著差异表达,除了EGF删除。分子对接和分子动力学模拟结果表明,AM和IL-1β,CASP3、STAT1和PPARγ的结合能均<-5kJ·mol-1,具有良好的结合性能。
结论:IL-1β,CASP3、STAT1和PPARγ可能是AM改善LN的潜在生物标志物和治疗靶点。
BACKGROUND: Lupus nephritis is an autoimmune disease, and its pathogenesis involves inflammation and autophagy disorders. Studies have demonstrated that Astragalus membranaceus can effectively suppress the progression of LN, but the underlying therapeutic target is still unclear.
OBJECTIVE: This study aimed to investigate the therapeutic target whereby AM ameliorates LN.
METHODS: We downloaded AM and LN-related chips from the TCMSP and GEO databases, respectively. We selected the two compound targets for the subsequent analysis via WGCNA, and constructed protein interaction networks of compound targets and determined the core targets. GO, KEGG analyses were conducted on compound targets to identify enriched functional and genomic pathways. The core genes were further validated in clinical and external datasets. Molecular docking of AS with the core targets was performed using the AutoDock software, and molecular dynamics simulation was conducted for the optimal core protein ligand obtained by molecular docking by Gromacs 2020.6 software.
RESULTS: We obtained 10 core targets, namely IL-1β, EGF, CCND1, CASP3, STAT1, PTGS2, PPARγ, AR, CXCL10, and KDR, from the 24 compound targets identified. The results of the GO enrichment analysis mainly included cell growth regulation. The results of the KEGG enrichment analysis showed that 7 out of 23 valid targets were significantly enriched in the mitogen-activated protein kinase pathway (p < 0.01). Combined with the clinical datasets, we found that IL-1β, EGF, CCND1, CASP3, STAT1, PTGS2, and PPARγ have high diagnostic values for LN. In the validation dataset, all the core targets were significantly differentially expressed, except for EGF deletion. The molecular docking and molecular dynamics simulation results showed that AM and IL- 1β, CASP3, STAT1, and PPARγ all had binding energies < -5 kJ·mol-1 and good binding properties.
CONCLUSIONS: IL-1β, CASP3, STAT1, and PPARγ could be potential biomarkers and therapeutic targets in AM ameliorates LN.