Zeng Piaoqi, Huang Haohan, Li Dongsheng
Department of Rheumatology, Ganzhou People's Hospital, Hongqi Avenue, Zhanggong District, Ganzhou City, 341000, Jiangxi Province, China.
Department of Orthopaedics, Gongli Hospital of Shanghai Pudong New Area, 219 Miaopu Rd, Shanghai 200011, China.
Heliyon. 2024 Sep 6;10(18):e37371. doi: 10.1016/j.heliyon.2024.e37371. eCollection 2024 Sep 30.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint inflammation and destruction, resulting in significant physical and economic burdens. Finding effective and targeted therapy for RA remains a top priority. Resveratrol is a potential candidate with anti-inflammatory and immunomodulatory properties for RA treatment. This study aims to determine the therapeutic targets and signaling pathways of resveratrol in the treatment of RA.
The GSE205962 dataset downloaded from The Gene Expression Omnibus (GEO) database was used to obtain the differentially expressed genes (DEGs) in blood samples from the patients and the healthy. PharmMapper database and Cytoscape (v3.9.1) were applied to construct the resveratrol pharmacophore target network. Gene functional enrichment analysis, including the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, was based on the BiNGo plug-in of Cytoscape and David's online tool. The intersection of the target genes of resveratrol and the DEGs were considered potential therapeutic genes (PT-genes). The Protein-Protein Interaction (PPI) network of PT-genes was constructed using the STRING tool, and the key therapeutic genes (KT-genes) were determined using the cytoHubba plug-in based on the Maximal Clique Centrality (MCC) algorithms. Molecular docking validation of resveratrol and therapeutic targets was performed based on the protein structure of KT-genes predicted by AlphaFold.
A total of 2202 DEGs and 47PT-genes were identified. GO analysis showed that the three groups of genes, the DEGs, the resveratrol target genes, and the PT-genes, have similar results for the top-five gene functional enrichment. PT-genes were closely related to the pathways of metabolic pathways, pathways in cancer, proteoglycans in cancer, insulin signaling pathway, and chemokine signaling pathway. The common pathway enriched by KEGG for the DEGs, and the resveratrol target genes was up to 36 %. The nine KT-genes were ABL1, ANXA5, CASP3, HSP90AA1, LCK, MAP2K1, MAPK1, PIK3R1, and RAC1, and the lowest free energy indicating the resveratrol/protein affinity were -8.4, -7.4, -6.4, -6.7, -8.0, -7.9, -7.4, -6.7, and -7.9, respectively.
Nine KT-genes were identified and validated as the most potential therapeutic targets in the treatment of RA with resveratrol, which provide new insights into therapeutic mechanisms and may improve the efficiency of drug development.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，可导致关节炎症和破坏，造成巨大的身体和经济负担。寻找有效的RA靶向治疗方法仍然是重中之重。白藜芦醇是一种具有抗炎和免疫调节特性的潜在RA治疗候选药物。本研究旨在确定白藜芦醇治疗RA的治疗靶点和信号通路。
从基因表达综合数据库（GEO）下载的GSE205962数据集用于获取患者和健康人血液样本中的差异表达基因（DEG）。应用PharmMapper数据库和Cytoscape（v3.9.1）构建白藜芦醇药效团靶点网络。基于Cytoscape的BiNGo插件和David在线工具进行基因功能富集分析，包括基因本体（GO）和京都基因与基因组百科全书（KEGG）分析。白藜芦醇的靶基因与DEG的交集被视为潜在治疗基因（PT基因）。使用STRING工具构建PT基因的蛋白质-蛋白质相互作用（PPI）网络，并基于最大团中心性（MCC）算法使用cytoHubba插件确定关键治疗基因（KT基因）。基于AlphaFold预测的KT基因蛋白质结构进行白藜芦醇与治疗靶点的分子对接验证。
共鉴定出2202个DEG和47个PT基因。GO分析表明，DEG、白藜芦醇靶基因和PT基因这三组基因在前五位基因功能富集方面结果相似。PT基因与代谢途径、癌症途径、癌症中的蛋白聚糖、胰岛素信号通路和趋化因子信号通路密切相关。KEGG对白藜芦醇靶基因和DEG富集的共同通路高达36%。九个KT基因分别为ABL1、ANXA5、CASP3、HSP90AA1、LCK、MAP2K1、MAPK1、PIK3R1和RAC1，表明白藜芦醇/蛋白质亲和力的最低自由能分别为-8.4、-7.4、-6.4、-6.
