MW-9, a chalcones derivative bearing heterocyclic moieties, ameliorates ulcerative colitis via regulating MAPK signaling pathway / 中国药理学通报

Aim To investigate the therapeutic effect of the MW-9 on ulcerative colitis(UC)and reveal the underlying mechanism, so as to provide a scientific guidance for the MW-9 treatment of UC. Methods The model of lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cells was established. The effect of MW-9 on RAW264.7 cells viability was detected by MTT assay. The levels of nitric oxide(NO)in RAW264.7 macrophages were measured by Griess assay. Cell supernatants and serum levels of inflammatory cytokines containing IL-6, TNF-α and IL-1β were determined by ELISA kits. Dextran sulfate sodium(DSS)-induced UC model in mice was established and body weight of mice in each group was measured. The histopathological damage degree of colonic tissue was assessed by HE staining. The protein expression of p-p38, p-ERK1/2 and p-JNK was detected by Western blot. Results MW-9 intervention significantly inhibited NO release in RAW264.7 macrophages with IC50 of 20.47 mg·L-1 and decreased the overproduction of inflammatory factors IL-6, IL-1β and TNF-α(P<0.05). MW-9 had no cytotoxicity at the concentrations below 6 mg·L-1. After MW-9 treatment, mouse body weight was gradually reduced, and the serum IL-6, IL-1β and TNF-α levels were significantly down-regulated. Compared with the model group, MW-9 significantly decreased the expression of p-p38 and p-ERK1/2 protein. Conclusions MW-9 has significant anti-inflammatory activities both in vitro and in vivo, and its underlying mechanism for the treatment of UC may be associated with the inhibition of MAPK signaling pathway.

MW­9, a chalcones derivative bearing heterocyclic moieties, attenuates experimental autoimmune encephalomyelitis via suppressing pathogenic TH17 cells.

Previous studies have indicated that MW­9, a chalcones derivative bearing heterocyclic moieties, has considerable anti­inflammatory activity in vitro. Whether MW­9 may be used to treat inflammation­based diseases, such as multiple sclerosis, remains unknown. The present study was designed to determine the effect and underlying mechanism of MW­9 in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice immunized with MOG35­55 were treated with or without MW­9, then the clinical scores and other relevant parameters were investigated. Production of cytokines and specific antibodies were monitored by ELISA assays. Surface marker, Treg cell, and intracellular cytokines (IL­17A and IFN­Î³) were detected by flow cytometry, and mRNA expression in the helper­T (TH)17 cell­related signaling pathway was examined by reverse transcription­quantitative (RT­q) PCR analysis. TH17 cell differentiation assay was performed. Herein, the present results demonstrated that oral administration of MW­9 reduced the severity of disease in EAE mice through slowing down infiltration process, inhibiting the demyelination, blocking anti­MOG35­55 IgG antibody production (IgG, IgG2a and IgG3), and decreasing accumulation of CD11b+Gr­1+ neutrophils from EAE mice. MW­9 treatments also led to significantly decreased IL­17A production and IL­17 expression in CD4+ T­cells, but had no detectable influence on development of TH1 and T­regulatory cells ex vivo. RT­qPCR analysis showed that within the spinal cords of the mice, MW­9 blocked transcriptional expression of TH17­associated genes, including Il17a, Il17f, Il6 and Ccr6. In TH17 cell differentiation assay, MW­9 inhibited differentiation of 'naïve' CD4+ T­cells into TH17 cells and reduced the IL­17A production. The data demonstrated that MW­9 could attenuate EAE in part through suppressing the formation and activities of pathogenic TH17 cells.