基于网络药理学探讨白芍总苷治疗类风湿关节炎肺间质纤维化的机制研究

doi:10.16431/j.cnki.1671-7236.2024.02.041

摘要/Abstract

摘要： 【目的】通过网络药理学结合动物试验探究白芍总苷(TGP)主要药物成分与类风湿关节炎(RA)肺间质纤维化之间的作用靶点,揭示白芍总苷治疗RA肺间质纤维化的分子机制。【方法】通过检索多个数据库,根据2个ADEM参数口服生物利用度(oral bioavailability,OB)＞30%、类药性(drug likeness,DL)＞0.18,筛选出白芍总苷中的主要活性成分及作用的基因靶点;检索DrugBank、GeneCards、OMIM、TTD、DisGenet等数据库筛选RA和肺间质纤维化的基因靶点,通过UniProt数据库进行靶点蛋白的基因名转换,收集白芍总苷治疗RA和肺间质纤维化的作用靶点。获取化合物和疾病靶点取交集,制作韦恩图;将靶点交集导入到STRING数据库绘制PPI网络图,利用DAVID数据库进行GO功能和KEGG信号通路富集分析,深入分析其治疗类风湿关节炎合并肺间质纤维化的机制。将 Wistar大鼠分为空白组、模型组、白芍总苷组和托法替布组,通过测定肺脏指数反映肺脏组织的水肿炎症反应,HE染色观察各组肺组织和踝关节滑膜租住的炎症反应,Masson染色观察肺脏组织的胶原沉积状况。【结果】检索TCMSP数据库,筛选得到85种白芍总苷的药物成分,根据OB＞30%、类药性＞0.18,共筛选9种主要成分;从DrugBank、DisGenet、OMIM、TTD和GeneCards等数据库筛选RA疾病靶点1 625个,肺间质纤维化的疾病靶点1 930个。通过GO功能和KEGG信号通路富集分析共获得分子功能65条目,细胞组分37条目,生物过程350条目和141个富集通路。通过中药-靶点-通路网络图,将Degree排名前十的肿瘤坏死因子(TNF)、白细胞介素-6(IL6)、AKT丝氨酸/苏氨酸激酶1(AKT1)、血管内皮生长因子A(VEGFA)、基质金属蛋白酶9 (MMP9)、转录因子Jun(JUN)、过氧化物酶体增殖物激活受体γ(PPARG)、胱天蛋白酶3(CASP3)、前列腺素内过氧化物合酶2(PTGS2)、细胞间黏附分子-1(ICAM1)作为白芍总苷治疗RA肺间质纤维化的关键作用靶点。动物试验结果显示,与模型组相比,治疗组的关节炎评分和肺脏指数降低;HE染色发现,白芍总苷组的关节和肺脏组织炎性细胞的浸润减少;Masson染色发现,白芍总苷可减少条索状的纤维化灶,表明白芍总苷不但可治疗RA,还能延缓肺间质纤维化的胶原沉积和减少炎症反应。【结论】白芍总苷通过多种成分作用于炎症反应、免疫调节和细胞分化增殖等方面的多靶点和多通路,通过靶点和通路间的协同相互作用来延缓RA肺间质纤维化疾病的发展进程。

关键词: 网络药理学; 白芍总苷; 类风湿关节炎; 肺间质纤维化; 作用机制

Abstract: 【Objective】 The aim of this experiment was to explore the targets and mechanisms between the main drug components of total glucosides of paeony (TGP) and pulmonary interstitial fibrosis in rheumatoid arthritis (RA) through network pharmacology.【Method】 By searching multiple databases, according to two ADEM parameters of oral bioavailability (OB)＞30% and drug likeness (DL)＞0.18, the main active ingredients and gene targets of total glucosides of paeony were screened out.The gene targets of RA and pulmonary interstitial fibrosis were screened by searching DrugBank, GeneCards, OMIM, TTD, DisGenet and other databases.The gene names of target proteins were converted by UniProt database, and the targets of total glucosides of paeony in the treatment of RA and pulmonary fibrosis were collected.The intersection of ingredients and disease targets were obtained, Venn diagram was made.The target intersection was imported into the STRING database to draw the PPI network diagram, and the intersection was copied and pasted into the DAVID database for GO function and KEGG signaling pathway analysis, and the mechanism of its treatment of RA with pulmonary interstitial fibrosis was analyzed in depth. Wistar rats were divided into blank group, model group, total glycosides of peony group, and tofacitinib group. The lung index was measured to reflect the edema and inflammatory response of lung tissue, HE staining was used to observe the inflammatory response of lung tissue and ankle joint synovium in each group, and Masson staining was used to observe the collagen deposition in lung tissue.【Result】 A total of 85 components of total glucosides of paeony were screened by searching the TCMSP database.According to OB＞30% and DL＞0.18, 9 main components were screened.A total of 1 625 RA gene targets and 1 930 pulmonary interstitial fibrosis gene targets were screened from DrugBank, DisGenet, OMIM, TTD and GeneCards databases.A total of 65 terms of molecular functions, 37 terms of cell components, 350 terms of biological processes and 141 enrichment pathways were obtained by GO function and KEGG signaling pathway enrichment analysis.Through the Chinese medicine-target-pathway network diagram, TNF, IL6, AKT1, VEGFA, MMP9, JUN, PPARG, CASP3, PTGS2, and ICAM1 in the top 10 of Degree were used as the key targets for the treatment of RA pulmonary interstitial fibrosis.The results of animal experiments showed that compared with model group, the arthritis score and lung index of the treatment group decreased. HE staining revealed a decrease in the infiltration of inflammatory cells in the joint and lung tissues of the total glycosides of peony group. Masson staining found that total glycosides of peony ccould reduce fibrous lesions in the form of strips. It indicated that total glucosides of paeony could not only treat RA, but also delay collagen deposition and inflammation of pulmonary interstitial fibrosis.【Conclusion】 Total glucosides of paeony acted on multiple targets and pathways in inflammatory response, immunoregulation, cell differentiation and proliferation through various components, and delayed the development of pulmonary interstitial fibrosis in RA through the synergistic interaction between targets and pathways.

Key words: network pharmacology; total glucosides of paeony; rheumatoid arthritis; pulmonary interstitial fibrosis; mechanism

中图分类号:

S853.74

邢清桦, 李松伟, 龚晓红, 胡文盈, 陆超群. 基于网络药理学探讨白芍总苷治疗类风湿关节炎肺间质纤维化的机制研究[J]. 中国畜牧兽医, 2024, 51(2): 850-863.

XING Qinghua, LI Songwei, GONG Xiaohong, HU Wenying, LU Chaoqun. Study on the Mechanism of Total Glucosides of Paeony in the Treatment of Pulmonary Interstitial Fibrosis in Rheumatoid Arthritis Based on Network Pharmacology[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(2): 850-863.

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