Activating the pregnane X receptor by imperatorin attenuates dextran sulphate sodium‐induced colitis in mice

Liu, Meijing; Zhang, Guohui; Zheng, Chunge; Song, Meng; Liu, Fangle; Huang, Xuan; Bai, Shasha; Huang, Xinan; Lin, Chaozhan; Chang, Zhu; Hu, Yingjie; Mi, Suiqing; Liu, Changhui

doi:10.1111/bph.14424

Cited by 37 publications

(19 citation statements)

References 63 publications

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“…Recently, PXR was shown to inhibit NF-κB p65 from nuclear translocation, which is a basic step for NF-κB activation 31 . Additionally, activation of PXR suppresses the expression of NF-κB target genes including iNOS, IL-1α, IL-1β, IL-6 and TNF-α in the colon of DSS colitis mice 7 .…”

Section: Discussionmentioning

confidence: 99%

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

Ren

Yue

Ren

et al. 2019

Sci Rep

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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-κB) activation. In vitro, ALA inhibited NF-κB 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-κB-reporter activity and in this setting, ALA further enhanced the hPXR-mediated inhibition of NF-κB-reporter activity. Furthermore, silencing hPXR gene demonstrated the necessity for hPXR in downregulation of NF-κB 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-κB inflammatory signaling.

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Section: Discussionmentioning

confidence: 99%

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

Ren

Yue

Ren

et al. 2019

Sci Rep

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“…It has been proven that IMP possesses various pharmacological effects such as anticancer, anti-inflammatory, and antidiabetic activities [16,17]. Our previous study found that IMP can attenuate DSS-induced colitis through activating PXR/NF-κB and inhibition of NF-κB signaling in mice [18]. However, its effect on ALI remains unknown.…”

Section: Introductionmentioning

confidence: 98%

The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury

Gao

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.

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“…Pregnane X Receptor (PXR) is a transcription factor that can bind to specific PXR response elements such as CYP3A4 on the promoter of the PXR target gene after activation (Liu et al, 2018). PXR plays a protective role in IBD, and identifying reliable PXR agonists has become a potential IBD treatment strategy (Liu et al, 2018).…”

Section: Cytochrome P450 3a4 (Cyp3a4) Mrna and Its Regulation By Phtomentioning

confidence: 99%

Phytochemical Regulation of RNA in Treating Inflammatory Bowel Disease and Colon Cancer: Inspirations from Cell and Animal Studies

Zhang¹,

Zhang²,

Sun³

et al. 2021

J Pharmacol Exp Ther

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Activating the pregnane X receptor by imperatorin attenuates dextran sulphate sodium‐induced colitis in mice

Abstract: IMP acts as a PXR agonist to attenuate DSS-induced colitis by suppression of the NF-κB-mediated pro-inflammatory response in a PXR/NF-κB-dependent manner.

Cited by 37 publications

References 63 publications

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

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

The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury

Phytochemical Regulation of RNA in Treating Inflammatory Bowel Disease and Colon Cancer: Inspirations from Cell and Animal Studies

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