Dimethyl fumarate ameliorates dextran sulfate sodium-induced murine experimental colitis by activating Nrf2 and suppressing NLRP3 inflammasome activation.

In the present study, we examined the effects of dimethyl fumarate (DMF) on dextran sulfate sodium (DSS)-induced murine colitis, an animal model which mimics human IBD. Oral administration of DMF dose-dependently attenuated body weight loss, colon length shortening and colonic pathological damage including decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities in DSS-treated mice. Increased glutathione (GSH) induced by DMF demonstrated its potential antioxidant capacity. In addition, Nrf2 and its downstream genes were markedly activated by DMF. Furthermore, protein and mRNA levels of pro-inflammatory cytokines, including IL-1β, TNF-α and IL-6 were markedly suppressed by DMF. At the same time, decreased activation of caspase-1 was detected in DMF-treated mice, indicating that the NLRP3 inflammasome activation was suppressed. The in vitro study verified a negative regulation of DMF and its intestinal metabolite on NLRP3 inflammasome. Moreover, the inhibitory effect was found to be mostly dependent on Nrf2 which decreased mitochondrial ROS (mROS) generation and mitochondrial DNA (mtDNA) release. Taken together, our results demonstrated the ability of DMF to inhibit NLRP3 inflammasome activation and its potential use in the treatment of NLRP3-associated diseases.

Liu X ，Zhou W ，Zhang X ，Lu P ，Du Q ，Tao L ，Ding Y ，Wang Y ，Hu R ... -  《-》

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 ... -  《-》

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 ... -  《-》

Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone.

Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b(+) macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation.

Wu XF ，Ouyang ZJ ，Feng LL ，Chen G ，Guo WJ ，Shen Y ，Wu XD ，Sun Y ，Xu Q ... -  《-》

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 ... -  《-》