Files and links (1)
Accepted (AM)Open Access (License Unspecified), Open
Journal article
Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway
The Journal of nutritional biochemistry, v 25(9), pp 923-933
Sep 2014
PMID: 24913217
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
Metrics
Details
- Title
- Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway
- Creators
- Wei Dou - Shanghai University of Traditional Chinese MedicineJingjing Zhang - Shanghai University of Traditional Chinese MedicineHao Li - Albert Einstein College of MedicineSandhya Kortagere - Drexel UniversityKatherine Sun - Montefiore Medical CenterLili Ding - Shanghai University of Traditional Chinese MedicineGaiyan Ren - Shanghai University of Traditional Chinese MedicineZhengtao Wang - Shanghai University of Traditional Chinese MedicineSridhar Mani - Albert Einstein College of Medicine
- Publication Details
- The Journal of nutritional biochemistry, v 25(9), pp 923-933
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000340510500004
- Scopus ID
- 2-s2.0-84905266822
- Other Identifier
- 991019168110504721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Nutrition & Dietetics