A novel pyrazole-containing indolizine derivative suppresses NF-κB activation and protects against TNBS-induced colitis via a PPAR-γ-dependent pathway.
Biochem Pharmacol
; 135: 126-138, 2017 07 01.
Article
em En
| MEDLINE
| ID: mdl-28336257
ABSTRACT
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.
Palavras-chave
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)
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Ácido Trinitrobenzenossulfônico
/
NF-kappa B
/
Colite
/
PPAR gama
/
Indolizinas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2017
Tipo de documento:
Article