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Activation of PXR by alantolactone ameliorates DSS-induced experimental colitis via suppressing NF-?B signaling pathway.

ABSTRACT: Alantolactone (ALA) is a sesquiterpene lactone with potent anti-inflammatory activity. However, the effect of ALA on intestinal inflammation remains largely unknown. The present study demonstrated that ALA significantly ameliorated the clinical symptoms of dextran sulfate sodium (DSS)-induced mice colitis as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration and histological injury. In mice exposed to DSS, ALA treatment significantly lowered pro-inflammatory mediators, including nuclear factor-kappa B (NF-?B) activation. In vitro, ALA inhibited NF-?B nuclear translocation and dose-dependently activated human/mouse pregnane X receptor (PXR), a key regulator gene in inflammatory bowel disease (IBD) pathogenesis. However, the pocket occluding mutants of the ligand-binding domain (LBD) of hPXR, abrogated ALA-mediated activation of the receptor. Overexpression of hPXR inhibited NF-?B-reporter activity and in this setting, ALA further enhanced the hPXR-mediated inhibition of NF-?B-reporter activity. Furthermore, silencing hPXR gene demonstrated the necessity for hPXR in downregulation of NF-?B activation by ALA. Finally, molecular docking studies confirmed the binding affinity between hPXR-LBD and ALA. Collectively, the current study indicates a beneficial effect of ALA on experimental IBD possibly via PXR-mediated suppression of the NF-?B inflammatory signaling.

SUBMITTER: Ren Y

PROVIDER: S-EPMC6851188 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Activation of PXR by alantolactone ameliorates DSS-induced experimental colitis via suppressing NF-κB signaling pathway.

Ren Yijing Y Yue Bei B Ren Gaiyan G Yu Zhilun Z Luo Xiaoping X Sun Aning A Zhang Jingjing J Han Mengqing M Wang Zhengtao Z Dou Wei W

Scientific reports 20191112 1

Alantolactone (ALA) is a sesquiterpene lactone with potent anti-inflammatory activity. However, the effect of ALA on intestinal inflammation remains largely unknown. The present study demonstrated that ALA significantly ameliorated the clinical symptoms of dextran sulfate sodium (DSS)-induced mice colitis as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration and histological injury. In mice exposed to DSS, ALA treatment significantly lowered pro-inflammatory me ...[more]

PMID: 31719637

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Project description:BACKGROUND AND PURPOSE: Kalopanaxsaponin A, a triterpenoid saponin isolated from Kalopanax pictus (family Araliaceae), potently inhibited nuclear factor-kappa B (NF-?B) activation in lipopolysaccharide (LPS)-stimulated peritoneal macrophages during a screening programme for anti-colitis agents from natural products. Its anti-inflammatory mechanism remains unknown. Therefore, we investigated its anti-inflammatory effects in lipopolysaccharide (LPS)- or peptidoglycan-stimulated murine peritoneal macrophages and trinitrobenzene sulphonic acid (TNBS)-induced colitic mice. EXPERIMENTAL APPROACH: Peritoneal macrophages from male ICR mice were stimulated with LPS or peptidoglycan in vitro and treated with kalopanaxsaponin A. Colitis was induced in vivo by intrarectal administration of TNBS in male ICR mice. Mice were treated daily with kalopanaxsaponin A, sulphasalazine or phosphate-buffered saline. Inflammatory markers, cytokines, enzymes and transcription factors were measured by ELISA, immunoblot, flow cytometry and immunofluorescent confocal microscopy. KEY RESULTS: Kalopanaxsaponin A potently inhibited the expression of the pro-inflammatory cytokines, interleukin (IL)-1?, tumour necrosis factor (TNF)-? and IL-6, induced by LPS, but not that induced by TNF-?, in peritoneal macrophages. However, it potently increased the expression of the anti-inflammatory cytokine IL-10. Kalopanaxsaponin A inhibited activation of the IL-1 receptor-associated kinase (IRAK)-1, inhibitor of ?B kinase-?, NF-?B and mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun NH(2) -terminal kinase, p-38), but LPS/Toll-like receptor-4 interaction and IRAK-4 activation were not affected. Oral administration of kalopanaxsaponin A (10 and 20 mg·kg(-1) ) improved the clinical parameters and histology in vivo. Kalopanaxsaponin A inhibited NF-?B and mitogen-activated protein kinase activation induced by TNBS by suppressing IRAK-1 activation. CONCLUSIONS AND IMPLICATIONS: Kalopanaxsaponin A may improve inflammatory diseases, such as colitis, by inhibiting IRAK-1 activation.

Dataset Information

Activation of PXR by alantolactone ameliorates DSS-induced experimental colitis via suppressing NF-?B signaling pathway.

Publications

Activation of PXR by alantolactone ameliorates DSS-induced experimental colitis via suppressing NF-κB signaling pathway.

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