A novel pyrazole-containing indolizine derivative suppresses NF-κB activation and protects against TNBS-induced colitis via a PPAR-γ-dependent pathway

被引:29
作者
Fu, Yong [1 ,2 ]
Ma, Junting [1 ,2 ]
Shi, Xiafei [1 ,2 ]
Song, Xiang-Yun [3 ]
Yang, Yaping [1 ,2 ]
Xiao, Shuke [1 ,2 ]
Li, Jiahuang [1 ,2 ]
Gu, Wei-Jin [3 ]
Huang, Zhen [1 ,2 ]
Zhang, Junfeng [1 ,2 ]
Chen, Jiangning [1 ,2 ]
机构
[1] Nanjing Univ, Sch Life Sci, State Key Lab Analyt Chem Life Sci, Nanjing 210023, Jiangsu, Peoples R China
[2] Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Collaborat Innovat Ctr Chem Life Sci, Nanjing 210023, Jiangsu, Peoples R China
[3] Nanjing Normal Univ, Coll Chem & Mat Sci, Nanjing 210023, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
Pyrazole-containing indolizine derivatives; PPAR-gamma; NF-kappa B; Colitis; INFLAMMATORY-BOWEL-DISEASE; RECEPTOR-GAMMA; ULCERATIVE-COLITIS; EPITHELIAL-CELLS; MICE; MACROPHAGES; ACID; ROSIGLITAZONE; AGONIST; MUCOSA;
D O I
10.1016/j.bcp.2017.03.013
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
The nuclear factor-kappa B (NF-kappa B)-mediated activation of macrophages plays a key role in mucosal immune responses in Crohn's disease (CD). Moreover, increasing evidence shows that the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exerts satisfactory anti-inflammatory effects in experimental colitis models, mostly by suppressing NF-kappa B-mediated macrophage activation. Therefore, exploring therapeutic strategies to activate PPAR-gamma and inhibit the NF-kappa B pathway in colonic macrophages holds great promise for the treatment of CD. In this study, five novel pyrazole-containing indolizine derivatives (B1, B2, B3, B4 and B5) were successfully synthesized and characterized, and their anti-inflammatory activities for CD treatment were also investigated. Among the five compounds, compound B4 effectively decreased the NF-kappa B-mediated production of the pro-inflammatory cytokine TNF-alpha in LPS-stimulated peritoneal macrophages. Moreover, compound B4 significantly ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis symptoms, including body weight loss, colonic pathological damage and inflammatory cell infiltration. The results of western blotting and luciferase reporter assays indicated that compound B4 activated PPAR-gamma and subsequently suppressed NF-kappa B activation. Conversely, the addition of the PPAR-gamma antagonist GW9662 abrogated the anti-inflammatory effects of compound B4 both in vitro and in vivo. In summary, compound B4 activated the PPAR-gamma pathway to inhibit downstream NF-kappa B signaling, which alleviated experimental colitis. Thus, this compound may serve as a potential therapeutic agent for patients with CD. (C) 2017 Elsevier Inc. All rights reserved.
引用
收藏
页码:126 / 138
页数:13
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