Abstract
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.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease characterized with chronic synovitis along with progressive cartilage and bone erosion
A total of 256 genes were identified as targets of naringin from SwissTargetPrediction database, Comparative Toxicogenomics database, and STITCH database. 3,687 Deferentially expressed genes (DEGs) were screened from GSE55235 dataset, while 1971 genes were upregulated and 1716 were downregulated (Figure 2B)
Target genes were mostly enriched in response to drug, positive regulation of smooth muscle cell proliferation, and inflammatory response in Biological Process (BP) enrichment analysis; extracellular space, cytosol, and extracellular region in closeness centrality (CC) analysis; and identical protein binding, cytokine activity, and transcription factor binding in Molecular Function (MF) analysis (Figure 3A)
Summary
Rheumatoid arthritis (RA) is an autoimmune disease characterized with chronic synovitis along with progressive cartilage and bone erosion. The average prevalence of RA is estimated to range within 0.5–1.0% globally (Gottenberg et al, 2019). Serological parameters, such as anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), are the distinctive features of RA, and immunological abnormalities precede the development of RA (Veale et al, 2017). The present treatment of RA aims to control the inflammatory reaction and relieve joint pain. Disease-modifying antirheumatic drugs (DMARDs) have the tendency for the inhibition of inflammatory and damaging events in RA patients (Scott et al, 2010). Biological agents that target inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, have been widely used, and these have substantially improved the RA therapy
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