Methyl cinnamate protects against dextran sulfate sodium-induced colitis in mice by inhibiting the MAPK signaling pathway.

Effective and non-toxic therapeutic agents are lacking for the prevention and treatment of colitis. Previous studies found that methyl cinnamate (MC), extracted from galangal ( Alpinia officinarum Hance), has anti-inflammatory properties. However, whether MC is effective as anti-colitis therapy remains unknown. In this study, we investigate the therapeutic effects of MC on dextran sulfate sodium (DSS)-induced colitis in mice and further explore its potential mechanism of action. MC treatment relieves symptoms associated with DSS-induced colitis, including the recovery of DSS-induced weight loss, decreases the disease activity index score, and increases the colon length without toxic side effects. MC treatment protects the integrity of the intestinal barrier in mice with DSS-induced colitis and inhibits the overexpression of pro-inflammatory cytokines in vivo and in vitro. Moreover, the MAPK signaling pathway is found to be closely related to the treatment with MC of colitis. Western blot analysis show that phosphorylation of the p38 protein in colon tissues treated with MC is markedly reduced and phosphorylation levels of the p38, JNK and ERK proteins are significantly decreased in RAW 264.7 cells treated with MC, indicating that the mechanism of MC in treating DSS-induced colitis could be achieved by inhibiting the MAPK signaling pathway. Furthermore, 16S RNA sequencing analysis show that MC can improve intestinal microbial dysbiosis in mice with DSS-induced colitis. Altogether, these findings suggest that MC may be a novel therapeutic candidate with anti-colitis efficacy. Furthermore, MC treatment relieves the symptoms of colitis by inhibiting the MAPK signaling pathway and improving the intestinal microbiota.

Attenuated Toxoplasma gondii enhances the antitumor efficacy of anti-PD1 antibody by altering the tumor microenvironment in a pancreatic cancer mouse model.

PURPOSE: To investigate whether attenuated Toxoplasma is efficacious against solid tumors of pancreatic cancer and whether attenuated Toxoplasma improves the antitumor activity of αPD-1 antibody on pancreatic cancer. METHODS: The therapeutic effects of attenuated Toxoplasma NRTUA strain monotherapy and combination therapy of NRTUA with anti-PD-1 antibody on PDAC tumor volume and tumor weight of Pan02 tumor-bearing mice were investigated. We characterized the effects of combination therapy of NRTUA with anti-PD-1 antibody on tumor-infiltrating lymphocytes and tumor-specific IFN-γ by using immunohistochemistry, flow cytometry and ELISA. The antitumor mechanisms of combination therapy of NRTUA with anti-PD-1 antibody were investigated via depletion of CD8+ T cells and IL-12. RESULTS: NRTUA strain treatment inhibited tumor growth in a subcutaneous mouse model of PDAC through activating dendritic cells and increasing CD8+ T cell infiltration in the tumor microenvironment. More importantly, combination therapy of NRTUA with anti-PD-1 antibody elicited a significant antitumor immune response and synergistically controlled tumor growth in Pan02 tumor-bearing mice. Specifically, the combination treatment led to elevation of CD8+ T cell infiltration mediated by dendritic cell-secreted IL-12 and to tumor-specific IFN-γ production in the PDAC tumor microenvironment. Also, the combination treatment markedly reduced the immunosuppressive myeloid-derived suppressor cell population in PDAC mice. CONCLUSION: These findings could provide a novel immunotherapy approach to treating solid tumors of PDAC and overcoming resistance to anti-PD-1 agents in PDAC tumors.