基于网络药理学探究布地奈德治疗IgA肾病的作用机制

Study on the Mechanism of Budesonide in the Treatment of IgA Nephropathy Based on Network Pharmacology

背景IgA肾病是我国及世界范围最常见的原发性肾小球肾炎,25%~30%的患者在确诊后20年内会进展至终末期肾病。目前尚无针对IgA肾病有效且安全的治疗方案。近年来针对IgA肾病治疗的新药研究进展迅速,其中靶向迟释布地奈德胶囊是全球首个IgA肾病对因治疗药物。目的基于网络药理学探究皮质类固醇布地奈德肠溶胶囊治疗IgA肾病的作用机制。方法通过Chemical Book平台筛选布地奈德的作用靶点;并利用GeneCards和CTD数据库获取IgA肾病的相关靶点。通过韦恩图取交集获得布地奈德-IgAN共同靶点。构建蛋白质-蛋白质相互作用(PPI)网络图,对交集靶点进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。结果筛选出布地奈德作用靶点242个,IgA肾病候选靶点1443个,交集靶点146个。PPI网络核心靶点15个:白介素6(IL-6)、肿瘤坏死因子(TNF)、白介素10(IL-10)、血管内皮生长因子A(VEGFA)、表皮生长因子受体(EGFR)、白介素1B(IL-1B)、白介素4(IL-4)、白介素8(CXCL8)、1号染色体的基因(JUN)、白介素13(IL-13)、白介素2(IL-2)、趋化因子2(CCL2)、TOLL样受体4(TLR4)、集落刺激因子2(CSF2)、白蛋白(ALB)。富集分析共获得1646个GO富集结果,174条KEGG信号通路,其中生物过程(BP)主要涉及磷酸化的正向调节、炎症反应、细胞运动的正向调节等,细胞组成(CC)主要涉及细胞质囊泡腔、囊腔、分泌颗粒腔等,分子过程(MF)主要涉及信号受体激活活性、信号受体调节活性、受体配体活性等。KEGG信号通路主要涉及白介素17信号通路、细胞因子-细胞因子受体相互作用、癌症中的通路、肿瘤坏死因子信号通路等。结论本研究初步验证布地奈德可通过IL-6、TNF、IL-10、VEGFA、EGFR等靶点作用于细胞因子-细胞因子受体相互作用通路、白介素17信号通路、癌症中的通路、肿瘤坏死因子信号通路等多条信号通路治疗IgA肾病,为布地奈德的进一步研究及临床实践提供理论依据。

Background IgA nephropathy(IgAN)is the most common primary glomerulonephritis in China and worldwide,approximately 25%-30%of patients will progress to end-stage renal disease within 20 years after diagnosis.Currently,there is no effective and safe treatment specifically for IgAN.In recent years,there has been a rapid progress in the research of new drugs for IgAN,among which the targeted delayed-release budesonide capsules is the first allopathic drug for IgAN globally.Objective To investigate the mechanism of corticosteroid budesonide capsules in the treatment of IgAN based on pharmacology.Methods Chemical Book platform was used to screen the targets of budesonide;GeneCards and CTD databases were utilized to obtain the relevant targets of IgAN.The intersection of budesonide targets and IgAN targets was obtained through a Venn diagram.A protein-protein interaction(PPI)network map was constructed,and gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were performed on the intersecting targets.Results A total of 242 targets for budesonide,1443 candidate targets for IgAN,and 146 intersecting targets were selected.The 15 core targets in the PPI network included interleukin-6(IL-6),tumor necrosis factor(TNF),interleukin-10(IL-10),vascular endothelial growth factor A(VEGFA),epidermal growth factor receptor(EGFR),interleukin-1B(IL-1B),interleukin-4(IL-4),interleukin-8(CXCL8),gene on chromosome 1(JUN),interleukin-13(IL-13),interleukin-2(IL-2),chemokine 2(CCL2),toll-like receptor 4(TLR4),colony-stimulating factors(CSF2),and albumin(ALB).Enrichment analysis revealed 1646 GO enrichment results and 174 KEGG signaling pathways.The biological processes(BP)mainly involved positive regulation of phosphorylation,inflammatory response,and positive regulation of cell movement.The cellular components(CC)mainly involved cytoplasmic vesicle lumen,cyst cavity,and secretory granule lumen.The molecular functions(MF)mainly involved receptor signaling activity,receptor regulator activity,and receptor ligand activity.The KEGG signaling pathways mainly included interleukin 17 signaling pathway,cytokine-cytokine receptor interaction,pathways in cancer,and tumor necrosis factor signaling pathway.Conclusion This study provides preliminary verified that budesonide can treat IgAN by targeting IL-6,TNF,IL-10,VEGFA,EGFR,and other targets,through multiple signaling pathways,like cytokine-cytokine receptor interaction,interleukin-17 signaling pathway,pathways in cancer,and tumor necrosis factor signaling pathway,providing a theoretical basis for further research and clinical practice of budesonide.