Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway

Wei Dou, Jingjing Zhang, Hao Li, Sandhya Kortagere, Katherine Sun, Lili Ding, Gaiyan Ren, Zhengtao Wang, Sridhar Mani

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Isorhamnetin is an O-methylated flavonol present in fruit and vegetables. We recently reported the identification of isorhamnetin as an activator of the human pregnane X receptor (PXR), a known target for abrogating inflammation in inflammatory bowel disease (IBD). The current study investigated the role of isorhamnetin as a putative mouse PXR activator in ameliorating chemically induced IBD. Using two different models (ulcerative colitis like and Crohn's disease like) of experimental IBD in mice, we demonstrated that isorhamnetin abrogated inflammation through inhibiting the activity of myeloperoxidase, the levels of TNF-α and IL-6, the mRNA expression of proinflammatory mediators (iNOS, ICAM-1, COX2, TNF-α, IL-2 and IL-6) and the phosphorylation of IκBα and NF-κB p65. PXR gene overexpression inhibited NF-κB luciferase activity, and the inhibition was potentiated by isorhamnetin treatment. PXR knockdown by siRNA demonstrated the necessity for PXR in isorhamnetin-mediated up-regulation of xenobiotic metabolism genes. Ligand pocket-filling mutants (S247W/C284W and S247W/C284W/S208W) of human PXR weakened the effect of isorhamnetin on PXR activation. Molecular docking studies and time-resolved fluorescence resonance energy transfer competitive binding assays confirmed the ligand (isorhamnetin)-binding affinity. These results clearly demonstrated the ameliorating effect of isorhamnetin on experimental IBD via PXR-mediated up-regulation of xenobiotic metabolism and down-regulation of NF-κB signaling. The novel findings may contribute to the effective utilization of isorhamnetin or its derivatives as a PXR ligand in the treatment of human IBD.

Original languageEnglish (US)
Pages (from-to)923-933
Number of pages11
JournalJournal of Nutritional Biochemistry
Volume25
Issue number9
DOIs
StatePublished - 2014

Fingerprint

Inflammatory Bowel Diseases
Xenobiotics
Ligands
Metabolism
Interleukin-6
Up-Regulation
Genes
3-hydroxyflavone
3-methylquercetin
pregnane X receptor
Inflammation
Fluorescence Resonance Energy Transfer
Phosphorylation
Competitive Binding
Vegetables
Intercellular Adhesion Molecule-1
Fruits
Luciferases
Ulcerative Colitis
Crohn Disease

Keywords

  • Inflammatory bowel disease
  • Isorhamnetin
  • NF-κB
  • Pregnane X receptor
  • Xenobiotic metabolism

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

Cite this

Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway. / Dou, Wei; Zhang, Jingjing; Li, Hao; Kortagere, Sandhya; Sun, Katherine; Ding, Lili; Ren, Gaiyan; Wang, Zhengtao; Mani, Sridhar.

In: Journal of Nutritional Biochemistry, Vol. 25, No. 9, 2014, p. 923-933.

Research output: Contribution to journalArticle

Dou, Wei ; Zhang, Jingjing ; Li, Hao ; Kortagere, Sandhya ; Sun, Katherine ; Ding, Lili ; Ren, Gaiyan ; Wang, Zhengtao ; Mani, Sridhar. / Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway. In: Journal of Nutritional Biochemistry. 2014 ; Vol. 25, No. 9. pp. 923-933.
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T1 - Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway

AU - Dou, Wei

AU - Zhang, Jingjing

AU - Li, Hao

AU - Kortagere, Sandhya

AU - Sun, Katherine

AU - Ding, Lili

AU - Ren, Gaiyan

AU - Wang, Zhengtao

AU - Mani, Sridhar

PY - 2014

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AB - Isorhamnetin is an O-methylated flavonol present in fruit and vegetables. We recently reported the identification of isorhamnetin as an activator of the human pregnane X receptor (PXR), a known target for abrogating inflammation in inflammatory bowel disease (IBD). The current study investigated the role of isorhamnetin as a putative mouse PXR activator in ameliorating chemically induced IBD. Using two different models (ulcerative colitis like and Crohn's disease like) of experimental IBD in mice, we demonstrated that isorhamnetin abrogated inflammation through inhibiting the activity of myeloperoxidase, the levels of TNF-α and IL-6, the mRNA expression of proinflammatory mediators (iNOS, ICAM-1, COX2, TNF-α, IL-2 and IL-6) and the phosphorylation of IκBα and NF-κB p65. PXR gene overexpression inhibited NF-κB luciferase activity, and the inhibition was potentiated by isorhamnetin treatment. PXR knockdown by siRNA demonstrated the necessity for PXR in isorhamnetin-mediated up-regulation of xenobiotic metabolism genes. Ligand pocket-filling mutants (S247W/C284W and S247W/C284W/S208W) of human PXR weakened the effect of isorhamnetin on PXR activation. Molecular docking studies and time-resolved fluorescence resonance energy transfer competitive binding assays confirmed the ligand (isorhamnetin)-binding affinity. These results clearly demonstrated the ameliorating effect of isorhamnetin on experimental IBD via PXR-mediated up-regulation of xenobiotic metabolism and down-regulation of NF-κB signaling. The novel findings may contribute to the effective utilization of isorhamnetin or its derivatives as a PXR ligand in the treatment of human IBD.

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