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