Qiong Luo

Purpose: Recent evidence has shown the involvement of inflammation in the development of diabetic peripheral neuropathy (DPN). MicroRNA-146a (miR-146a) is closely involved in the inflammatory response. However, the role of miR-146a in the inflammatory reaction in DPN has not been clarified. This study was designed to explore the role of miR-146a in the regulation of inflammatory responses in DPN. Methods: Rats were randomly divided into three groups (n=6 per group): control group, type 2 diabetes mellitus (T2DM) group and DPN group. T2DM and DPN rats were intraperitoneally injected with streptozotocin. Sciatic nerve conduction velocity (NCV) was determined at the 6th week and the 12th week in each group. The expression of microRNAs was detected by quantitative real-time polymerase chain reaction in three sciatic nerves for each group of rats. Expression of inflammatory cytokines in nerve tissues and plasma was measured by Western blot and Bio-Plex Pro™ assays. Results: The NCV and expression levels of miR-146a in the DPN group were significantly decreased ( P <0.01) compared to the other two groups. Expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the DPN group was significantly increased compared with the control and T2DM groups ( P <0.01). Pearson’s correlation analysis showed that the expression level of miR-146a was negatively correlated with the levels of IL-1β, TNF-α and NF-κB. Conclusion: miR-146a is involved in the pathogenesis of DPN, and its expression level is closely related to the inflammatory responses that aggravate sciatic nerve injuries. Keywords: type 2 diabetes mellitus, diabetic peripheral neuropathy, microRNA-146a, NF-κB, cytokines

Iguratimod, a novel disease-modifying antirheumatic drug, which is now used in clinics in China and Japan, has been confirmed as a highly efficacious and safe drug for rheumatoid arthritis therapy. The antiarthritic mechanism of iguratimod, especially compared with that of the classical disease-modifying antirheumatic drugs, has not been elucidated. In this study, we conducted a comparative analysis of the antiarthritic effects of iguratimod and two reference drugs, methotrexate and leflunomide. We found that iguratimod dose dependently and potently inhibited arthritic inflammation of the synovium in collagen-induced arthritis and predominantly targeted IL-17 signaling. Consistent with its effects in vivo, iguratimod significantly suppressed the expression of various proinflammatory factors triggered by IL-17 in the cultured fibroblast-like synoviocytes. The inhibition of IL-17 signaling by iguratimod was further linked to a decrease in the mRNA stability of related genes and a reduction in phosphorylation of MAPKs. Iguratimod mainly targets Act1 to disrupt the interaction between Act1 and TRAF5 and IKKi in the IL-17 pathway of synoviocytes. Together, our results suggest that iguratimod yields a strong improvement in arthritis via its unique suppression of IL-17 signaling in fibroblast-like synoviocytes. This feature of iguratimod is different from those of methotrexate and leflunomide. This study may be helpful for further understanding the unique antiarthritic mechanism of iguratimod in patients with rheumatoid arthritis.