Rheumatoid arthritis is a chronic autoimmune disease characterized by persistent hyperplasia of the synovial membrane and progressive erosion of articular cartilage. Disequilibrium between the proliferation and death of RA fibroblast-like synoviocytes (RA-FLSs) is the critical factor in progression of RA. Naringin has been reported to exert anti-inflammatory and antioxidant effect in acute and chronic animal models of RA. However, the therapeutic effect and underlying mechanisms of naringin in human RA-FLS remain unclear. Based on network pharmacology, the corresponding targets of naringin were identified using SwissTargetPrediction database, STITCH database, and Comparative Toxicogenomics Database. Deferentially expressed genes (DEGs) in RA were obtained from the GEO database. The protein–protein interaction (PPI) networks of intersected targets were constructed using the STRING database and visualized using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and the pathways directly related to pathogenesis of RA were integrated manually. Further, in vitro studies were carried out based on network pharmacology. 99 target genes were intersected between targets of naringin and DEGs. The PPI network and topological analysis indicated that IL-6, MAPK8, MMP-9, TNF, and MAPK1 shared the highest centrality among all. GO analysis and KEGG analysis indicated that target genes were mostly enriched in (hsa05200) pathways in cancer, (hsa05161) hepatitis B, (hsa04380) osteoclast differentiation, (hsa04151) PI3K-Akt signaling pathway, and (hsa05142) Chagas disease (American trypanosomiasis). In vitro studies revealed that naringin exposure was found to promote apoptosis of RA-FLS, increased the activation of caspase-3, and increased the ratio of Bax/Bcl-2 in a dose-dependent manner. Furthermore, treatment of naringin attenuated the production of inflammatory cytokines and matrix metalloproteinases (MMPs) in TNF-ɑ–induced RA-FLS. Moreover, treatment of naringin inhibited the phosphorylation of Akt and ERK in RA-FLS. Network pharmacology provides a predicative strategy to investigate the therapeutic effects and mechanisms of herbs and compounds. Naringin inhibits inflammation and MMPs production and promotes apoptosis in RA-FLS via PI3K/Akt and MAPK/ERK signaling pathways.

rheumatoid arthritis (ra) and osteoarthritis (oa) are the two most common debilitating joint disorders and although both share similar clinical manifestations, the pathogenesis of each is different and remains relatively unclear. The present study aimed to use bioinformatic analysis to identify pivotal genes and pathways involved in the pathogenesis of ra. Microarray datasets from patients with ra and oa were obtained from the Gene expression omnibus (Geo) database and differentially expressed genes (deGs) were identified using GEO2R software; Gene Ontology analysis and pathway enrichment were analyzed using the database for annotation, Visualization and integrated discovery and the Kyoto Encylopedia for Genes and Genomes, respectively; and protein-protein interaction networks of deGs were constructed using the Search Tool for the retrieval of interacting Genes database, and module analysis and pathway crosstalk of the PPi network was visualized using plugins of cytoscape. in addition, the prediction of target mrnas for differentially expressed micrornas (deMs) was performing using the star-Base database and the identified pivotal genes were verified using reverse-transcription quantitative Pcr in synovial tissue from patients with RA. A total of 566 DEGs were identified in GSe55457, GSe55235 while 23 DEMs were identified in the GSe72564 dataset. upregulated deGs were found to be mostly enriched in the 'cytokine-cytokine receptor interaction' pathway, whereas downregulated deGs were discovered to be enriched in the 'PPar signaling pathway'. The top 25 deGs were mostly enriched in the 'chemokine signaling pathway'. in addition, six of the mirna target genes were selected as potential biomarkers and a total of 24 genes were selected as potential hub genes. experimental validation demonstrated that the expression levels of cytotoxic T-lymphocyte associated Protein 4 (CTLA4), Zeta-chain-associated protein kinase 70 (ZAP70) and lcK proto-oncogene (LCK) were significantly increased, whereas HGF expression levels were decreased in RA synovial tissue. In conclusion, these findings suggest that the identified deGs and pivotal genes in the present study may further enhance our knowledge of the underlying pathways in the pathogenesis of ra. These genes may also serve as diagnostic biomarkers and therapeutic targets for RA; however, further experimental validation is necessary following the bioinformatic analysis to determine our conclusions.

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