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Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease

Alpinetin is a naturally occurring flavonoid from the ginger plants. We previously reported the identification of alpinetin as a ligand of human pregnane X receptor (hPXR). The current study investigated the role of alpinetin as a putative PXR activator in ameliorating chemically induced inflammator...

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Autores principales: Yu, Zhilun, Yue, Bei, Ding, Lili, Luo, Xiaoping, Ren, Yijing, Zhang, Jingjing, Mani, Sridhar, Wang, Zhengtao, Dou, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186371/
https://www.ncbi.nlm.nih.gov/pubmed/32372959
http://dx.doi.org/10.3389/fphar.2020.00474
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author Yu, Zhilun
Yue, Bei
Ding, Lili
Luo, Xiaoping
Ren, Yijing
Zhang, Jingjing
Mani, Sridhar
Wang, Zhengtao
Dou, Wei
author_facet Yu, Zhilun
Yue, Bei
Ding, Lili
Luo, Xiaoping
Ren, Yijing
Zhang, Jingjing
Mani, Sridhar
Wang, Zhengtao
Dou, Wei
author_sort Yu, Zhilun
collection PubMed
description Alpinetin is a naturally occurring flavonoid from the ginger plants. We previously reported the identification of alpinetin as a ligand of human pregnane X receptor (hPXR). The current study investigated the role of alpinetin as a putative PXR activator in ameliorating chemically induced inflammatory bowel disease (IBD). We found that oral administration of alpinetin significantly alleviated the severity of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration, the levels of the pro-inflammatory mediators, and the PXR target genes in the colon. In vitro, alpinetin blocked the nuclear translocation of p-p65 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Further, alpinetin significantly upregulated PXR target genes and inhibited TNF-α-induced NF-κB-luciferase activity in LS174T colorectal cells; however, this regulatory effects were lost when cellular PXR gene was knocked down. In PXR transactivation assays, alpinetin increased both mouse and human PXR transactivation in a dose-dependent manner. Ligand occluding mutants, S247W/C284W and S247W/C284W/S208W, in hPXR-reporter assays, abrogated alpinetin-induced hPXR transactivation. Finally, alpinetin bound to the hPXR-ligand-binding domain (LBD) was confirmed by competitive ligand binding assay. The current study significantly extends prior observations by validating a PXR/NF-κB regulatory mechanism governing alpinetin’s anti-inflammatory effects in a murine model of IBD.
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spelling pubmed-71863712020-05-05 Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease Yu, Zhilun Yue, Bei Ding, Lili Luo, Xiaoping Ren, Yijing Zhang, Jingjing Mani, Sridhar Wang, Zhengtao Dou, Wei Front Pharmacol Pharmacology Alpinetin is a naturally occurring flavonoid from the ginger plants. We previously reported the identification of alpinetin as a ligand of human pregnane X receptor (hPXR). The current study investigated the role of alpinetin as a putative PXR activator in ameliorating chemically induced inflammatory bowel disease (IBD). We found that oral administration of alpinetin significantly alleviated the severity of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration, the levels of the pro-inflammatory mediators, and the PXR target genes in the colon. In vitro, alpinetin blocked the nuclear translocation of p-p65 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Further, alpinetin significantly upregulated PXR target genes and inhibited TNF-α-induced NF-κB-luciferase activity in LS174T colorectal cells; however, this regulatory effects were lost when cellular PXR gene was knocked down. In PXR transactivation assays, alpinetin increased both mouse and human PXR transactivation in a dose-dependent manner. Ligand occluding mutants, S247W/C284W and S247W/C284W/S208W, in hPXR-reporter assays, abrogated alpinetin-induced hPXR transactivation. Finally, alpinetin bound to the hPXR-ligand-binding domain (LBD) was confirmed by competitive ligand binding assay. The current study significantly extends prior observations by validating a PXR/NF-κB regulatory mechanism governing alpinetin’s anti-inflammatory effects in a murine model of IBD. Frontiers Media S.A. 2020-04-21 /pmc/articles/PMC7186371/ /pubmed/32372959 http://dx.doi.org/10.3389/fphar.2020.00474 Text en Copyright © 2020 Yu, Yue, Ding, Luo, Ren, Zhang, Mani, Wang and Dou http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Yu, Zhilun
Yue, Bei
Ding, Lili
Luo, Xiaoping
Ren, Yijing
Zhang, Jingjing
Mani, Sridhar
Wang, Zhengtao
Dou, Wei
Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease
title Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease
title_full Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease
title_fullStr Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease
title_full_unstemmed Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease
title_short Activation of PXR by Alpinetin Contributes to Abrogate Chemically Induced Inflammatory Bowel Disease
title_sort activation of pxr by alpinetin contributes to abrogate chemically induced inflammatory bowel disease
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186371/
https://www.ncbi.nlm.nih.gov/pubmed/32372959
http://dx.doi.org/10.3389/fphar.2020.00474
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