Network Pharmacology and Metabolomic Effects in vivo of Fufang Duzhong Jiangu Granules for the Treatment of Kashin-Beck Disease

Abstract

Abstract Background: Fufang Duzhong Jiangu Granules (FDJG) is used clinically for treating swelling, pain and functional impairment caused by osteoarthropathy. However, the potential therapeutic mechanisms of FDJG for Kashin-Beck Disease (KBD) remain unclear. Objective: Our study aims to predict the drug efficacy and molecular mechanisms of FDJG in the treatment of KBD based on network pharmacology, metabolomics and molecular docking. Methods: The active ingredients and target proteins of FDJG were obtained from TCMSP database, and analyzed in conjunction with the differential genes of KBD. GO and KEGG enrichment analysis, PPI network construction and topological characteristics evaluation, molecular docking were performed to explore gene function and potential mechanisms of FDJG in the treatment of KBD. Furthermore, FDJG treatment for one month was administered to patients with KBD, and some differentially expressed genes and metabolic effects before and after treatmentwere measured using qPCR and nontargeted metabolomics methods. Further gene-metabolism joint pathway analysis was conducted. Results: There were 151 genes which are the therapeutic targets of FDJG in the treatment of KBD. 48 core target proteins were mainly enriched in PI3K-Akt signaling pathway, TNF signaling pathway, MAPK signaling pathway, apoptosis and osteoclast differentiation. Quercetin, kaempferol and luteolin in FDJG could strongly bind to TP53, STAT3, HSP90AA1, etc., which had important anti-inflammatory and anti-apoptotic effects in the treatment of KBD. After one-month FDJG treatment, the RNA expression levels of STAT3, FOS and RELA in peripheral blood of KBD patients were significantly down-regulated. A total of 80 differential expressed metabolites were identified in the plasma of KBD patients. Drug targets and differential metabolites were co-enriched in four metabolic pathways: glycerophospholipid metabolism, inositol phosphate metabolism, phosphatidylinositol signaling system, and steroid hormone biosynthesis. Conclusion: FDJG may effectively treat KBD by anti-inflammatory and regulating abnormal lipid metabolism pathway, which has great potential in the treatment of patients with KBD.