A novel benzo[d]imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome.

NLRP3 inflammasome has been reported to be associated with various kinds of immunological diseases including colitis. However, there are few drug candidates targeting inflammasomes for the treatment of colitis. In the present study, we aimed at examining the effect of 1-ethyl-5-methyl-2-phenyl-1H-benzo[d]imidazole, a synthetic small molecular compound also named Fc11a-2, for the treatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice via targeting NLRP3 inflammasome. Treatment with Fc11a-2 dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. In addition, the disease activity index, histopathologic scores and myeloperoxidase activity were also significantly reduced by Fc11a-2 treatment. Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF-α, IL-1β, IL-18, IL-17A and IFN-γ, were markedly suppressed by Fc11a-2. Furthermore, a decreased CD11c⁺ macrophage infiltration in colons and inactivation of caspase-1 in peritoneal macrophages were detected in Fc11a-2-treated mice. The mechanism of action of Fc11a-2 was related to the inhibition of the cleavage of pro-caspase-1, pro-IL-1β and pro-IL-18 which in turn suppressed the activation of NLRP3 inflammasome. Taken together, our results demonstrate the ability of Fc11a-2 to inhibit NLRP3 inflammasome activation and its potential use in the treatment of inflammatory bowel diseases.

Liu W ，Guo W ，Wu J ，Luo Q ，Tao F ，Gu Y ，Shen Y ，Li J ，Tan R ，Xu Q ，Sun Y ... -  《-》

Asiatic acid ameliorates dextran sulfate sodium-induced murine experimental colitis via suppressing mitochondria-mediated NLRP3 inflammasome activation.

In the present study, the effect of asiatic acid, a natural triterpenoid compound, on murine experimental colitis induced by dextran sulfate sodium (DSS) and its possible mechanism were examined in vivo and vitro. Oral administration of asiatic acid dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic scores of musco and myeloperoxidase activity were also significantly reduced by asiatic acid treatment. Protein and mRNA levels of DSS-induced pro-inflammatory cytokines in colon, including TNF-α, IL-1β, IL-6 and IFN-γ, were markedly suppressed by asiatic acid. At the same time, decreased activation of caspase-1 in peritoneal macrophages was detected in asiatic acid-treated mice, which suggested that the NLRP3 inflammasome activation was suppressed. In addition, we also found that asiatic acid dose-dependently inhibited IL-1β secretion, caspase-1 activation as well as inflammasome assembling in vitro. Furthermore, the mechanism of asiatic acid was related to the inhibition of mitochondrial reactive oxygen species generation and prevention of mitochondrial membrane potential collapse. Taken together, our results demonstrate the ability of asiatic acid to inhibit NLRP3 inflammasome activation and its potential usage in the treatment of inflammatory bowel diseases.

Guo W ，Liu W ，Jin B ，Geng J ，Li J ，Ding H ，Wu X ，Xu Q ，Sun Y ，Gao J ... -  《-》

Fumigaclavine C ameliorates dextran sulfate sodium-induced murine experimental colitis via NLRP3 inflammasome inhibition.

In the present study, the effect of Fumigaclavine C, a fungal metabolite, on murine experimental colitis induced by dextran sulfate sodium (DSS) and its possible mechanism were examined in vivo and vitro. Oral administration of Fumigaclavine C dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic scores of musco was also significantly reduced by Fumigaclavine C treatment. Protein and mRNA levels of DSS-induced pro-inflammatory cytokines in colon, including TNF-α, IL-1β and IL-17A, were markedly suppressed by Fumigaclavine C. At the same time, decreased activation of caspase-1 in peritoneal macrophages was detected in Fumigaclavine C -treated mice which suggested that the NLRP3 inflammasome activation was suppressed. Furthermore, in the LPS plus ATP cell model, we found that Fumigaclavine C dose-dependent inhibited IL-1β release and caspase-1 activation. Taken together, our results demonstrate the ability of Fumigaclavine C to inhibit NLRP3 inflammasome activation and give some evidence for its potential use in the treatment of inflammatory bowel diseases.

Guo W ，Hu S ，Elgehama A ，Shao F ，Ren R ，Liu W ，Zhang W ，Wang X ，Tan R ，Xu Q ，Sun Y ，Jiao R ... -  《-》

3-(2-Oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one (compound 1), a novel potent Nrf2/ARE inducer, protects against DSS-induced colitis via inhibiting NLRP3 inflammasome.

NLRP3 inflammasome is a key component of the inflammatory process and its dysregulation contributes to IBD for its ability to induce IL-1β release. Previously, we reported that a novel small molecular activator of Nrf2, 3-(2-oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino-[2,1-a]isoquinolin-4(11bH)-one (compound 1) can prevent the development of colorectal adenomas in AOM-DSS models. Here we further investigated the anti-inflammatory effect of compound 1 in DSS-induced colitis in C57BL/6 and NLRP3(-/-) mice, and revealed the possible modulation by compound 1 of NLRP3 inflammasome-mediated IL-1β release from macrophages. In C57BL/6 mice, oral administration of compound 1 significantly attenuated DSS-induced colonic pathological damage, remarkably inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and IL-1β secretion in colons. In contrast, mice deficient for NLRP3 were less sensitive to DSS-induced acute colitis, and compound 1 treatment exerted no protective effect on DSS-induced intestinal inflammation in NLRP3(-/-) mice. The protective effect of compound 1 may be attributed to its inhibition of NLRP3 inflammasome and Nrf2 activation in colons. Furthermore, compound 1, as a small molecular activator of Nrf2, significantly inhibited NLRP3 inflammasome activation in both THP-1 derived macrophages and bone-marrow derived macrophages, as indicated by reduced expression of NLRP3 and cleaved caspase-1, and lowered IL-1β secretion. Finally, compound 1-induced NLRP3 inflammasome inhibition is through blocking NLRP3 priming step and dependent on Nrf2 activation. Taken together, our findings demonstrate that compound 1 might be a potential agent for the treatment of IBD by targeting Nrf2 and NLRP3 inflammasome.

Wang Y ，Wang H ，Qian C ，Tang J ，Zhou W ，Liu X ，You Q ，Hu R ... -  《-》

Wogonoside protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB and NLRP3 inflammasome activation.

Previous studies have demonstrated that wogonoside, the glucuronide metabolite of wogonin, has anti-inflammatory, anti-angiogenic and anticancer effects. However, the anti-inflammatory mechanism of wogonoside has not been fully elucidated. Recently, NLRP3 inflammasome has been reported to be correlated with inflammatory bowel disease for its ability to induce IL-1β release. Nevertheless, there are few drug candidates targeting NLRP3 inflammasome for this disease. In this study, we investigated the anti-inflammatory effect of wogonoside in dextran sulfate sodium (DSS)-induced murine colitis and further revealed the underlying mechanisms by targeting NF-κB and NLRP3 inflammasome. Wogonoside treatment dose-dependently attenuated DSS-induced body weight loss and colon length shortening. Moreover, wogonoside prevented DSS-induced colonic pathological damage, remarkably inhibited inflammatory cells infiltration and significantly decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities. The production of pro-inflammatory mediators in serum and colon was also significantly reduced by wogonoside. The underlying mechanisms for the protective effect of wogonoside in DSS-induced colitis may be attributed to its inhibition on NF-κB and NLRP3 inflammasome activation in colons. Furthermore, wogonoside markedly decreased production of IL-1β, TNF-α and IL-6 and suppressed mRNA expression of pro-IL-1β and NLRP3 in phorbol myristate acetate (PMA)-differentiated monocytic THP-1 cells via inhibiting the activation of NF-κB and NLRP3 inflammasome. In conclusion, our study demonstrated that wogonoside may exert its anti-inflammatory effect via dual inhibition of NF-κB and NLRP3 inflammasome, suggesting that wogonoside might be a potential effective drug for inflammatory bowel diseases.

Sun Y ，Zhao Y ，Yao J ，Zhao L ，Wu Z ，Wang Y ，Pan D ，Miao H ，Guo Q ，Lu N ... -  《-》