A novel pyrazole-containing indolizine derivative suppresses NF-κB activation and protects against TNBS-induced colitis via a PPAR-γ-dependent pathway.
The nuclear factor-κB (NF-κB)-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-γ (PPAR-γ) exerts satisfactory anti-inflammatory effects in experimental colitis models, mostly by suppressing NF-κB-mediated macrophage activation. Therefore, exploring therapeutic strategies to activate PPAR-γ and inhibit the NF-κB 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-κB-mediated production of the pro-inflammatory cytokine TNF-α 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-γ and subsequently suppressed NF-κB activation. Conversely, the addition of the PPAR-γ antagonist GW9662 abrogated the anti-inflammatory effects of compound B4 both in vitro and in vivo. In summary, compound B4 activated the PPAR-γ pathway to inhibit downstream NF-κB signaling, which alleviated experimental colitis. Thus, this compound may serve as a potential therapeutic agent for patients with CD.
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Yong
Y
Fu
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Junting
J
Ma
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Xiafei
X
Shi
College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, PR China.
Xiang-Yun
XY
Song
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Yaping
Y
Yang
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Shuke
S
Xiao
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Jiahuang
J
Li
College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, PR China. Electronic address: gwjchem2012@126.com.
Wei-Jin
WJ
Gu
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China. Electronic address: zhenhuang@nju.edu.cn.
Zhen
Z
Huang
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Junfeng
J
Zhang
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China. Electronic address: jnchen@nju.edu.cn.
Jiangning
J
Chen
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D007212:Indolizines / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014302:Trinitrobenzenesulfonic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D007212:Indolizines; D016328:NF-kappa B; D047495:PPAR gamma; D020011:Protective Agents; D011720:Pyrazoles; C035094:indolizine; C031280:pyrazole; D014302:Trinitrobenzenesulfonic Acid
2,4,6-Trinitrobenzene sulfonic acid (TNBS) (PubChem CID: 11045); 2,4-Dimethylpyridine (PubChem CID: 7936); 2-Methlpyridine (PubChem CID: 7963); 2-Methlpyridine (PubChem CID: 7975); 5-Aminosalicylic acid (PubChem CID: 4075); Colitis; DAPI (PubChem CID: 2954); DMSO (PubChem CID: 679); GW9662 (PubChem CID: 644213); Isoquinoline (PubChem CID: 8405); Lipopolysaccharides (PubChem CID: 53481793); NF-κB; PPAR-γ; Puromycin (PubChem CID:439530); Pyrazole-containing indolizine derivatives; Pyridine (PubChem CID: 1049)