Importance of gedunin in antagonizing rheumatoid arthritis via activating the Nrf2/ARE signaling

Objective. This study assessed the anti-arthritic effect and protection of Gedunin (GDN) on joint tissues and revealed the possible mechanism in suppressing rheumatoid arthritis (RA). Methods. LPS-induced macrophages and TNF-alpha-stimulated synovial fibroblasts (MH7A) or IL-1 beta-stimulated primary rheumatoid arthritis synovial fibroblasts (RASFs) were used to evaluate the antiinflammatory effect of GDN. In addition, CIA-induced arthritis was employed here to evaluate the anti-arthritic effect. MTT and BRDU assays were utilized to evaluate the cell viability and proliferation, Q-PCR was conducted to detect the mRNA expression of cytokines, FACS was adopted to monitor ROS production, while western blotting (WB) and siRNA interference were applied in confirming the anti-arthritic effects of GDN via the Nrf2 signaling. Results. In vitro, cell viability was inhibited in macrophages and MH7A cells, but not in RASFs; but the proliferation of RASFs was significantly suppressed in time- and dose-dependent manners. GDN suppressed cytokine levels in LPS-stimulated macrophages and TNF-alpha-stimulated MH7A cells or RASFs. GDN suppressed ROS expression. Furthermore, GDN treatment notably dose-dependently decreased the mRNA and protein expression of iNOS in LPS-induced macrophages. sip62 interference results showed that GDN cause the less expression of HO-1 and Keap1 and also fail to inhibit cytokines after sip62 interference. In vivo, GDN effectively inhibited paw swelling, arthritis score, and arthritis incidence and cytokines. Conclusions. Our study suggested that GDN exhibited strong antagonistic effect on arthritis both in vitro and in vivo via activation of Nrf2 signaling. Our work will provide a promising therapeutic strategy for RA.