Resveratrol (Res) is a polyphenolic compound that has a variety of biological functions and activities. This study aimed to explore the mechanisms of the antioxidant and proapoptotic effects of Res in H2O2‐treated rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLSs) by the Nrf2–Keap1 signaling pathway. We found that 5 µM H2O2 promoted cell proliferation and increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content in RA‐FLSs. However, Res could reverse these effects in 5 µMH2O2‐treated RA‐FLSs by (1) promoting expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1), (2) reducing expression of Kelch‐like ECH–related protein 1 (Keap1), (3) inhibiting production of ROS and MDA, (4) blocking activation of nuclear factor‐κB (NF‐κB) p65, (5) inhibiting cell proliferation and migration, and (6) activating Bcl‐2/Bax to induce apoptosis. After lentiviral silencing of Nrf2 (siNrf2) mRNA expression in RA‐FLSs, Res addition did not increase the expression of Nrf2 or HO‐1 to reduce the production of mitochondrial ROS caused by 5 µM H2O2. Res reduced the Bcl‐2/Bax ratio, but siNrf2 reduced the ability of Res to promote apoptosis. We conclude that Res inhibits ROS production by activating the Nrf2 pathway, thereby inhibiting activation of NF‐κB and proliferation and migration of RA‐FLSs, to induce apoptosis. Targeting the Nrf2–Keap1 pathway may be a relevant aim of using Res in the treatment of RA.
Rheumatoid arthritis (RA) is a refractory systemic autoimmune disease associated with synovial inflammation. Previous studies postulate that paeonol has good anti-arthritis effects on RA. However, its systematic description remains unknown. Herein, we used bioinformatics tools to evaluate the mechanism of paeonol in arthritis systematically. A macrophage model was employed to study the differentially expressed genes between the inflammation and normal group, revealing 169 inflammation-related genes. Another 275 key genes affected by paeonol were identified in the same model. Three key genes, FPR2, Cd83, and Cfb, were obtained after combining the two data sets. Paeonol inhibited the release of inflammatory factors and the proliferation of synovial. However, its inhibitory effect was blocked by Fpr2 blocker WRW4. In summary, paeonol can inhibit the development of arthritis through FPR2. This provides new scope for the design and development of FPR2 ligands.
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