title: A novel benzo[d]imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome.
abstract: 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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Luo
authors.forename: Feifei
authors.initials: F
authors.lastname: Tao
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles; D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016264:Dextran Sulfate; D009195:Peroxidase; D020170:Caspase 1