title: Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway.
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.
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dou
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Departments of Medicine and Genetics, Albert Einstein College of Medicine, NY 10461, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, PA 19129, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kortagere
authors.affiliation: Department of Pathology, Montefiore Medical Center, NY 10467, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sun
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Ding
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Gaiyan
authors.initials: G
authors.lastname: Ren
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: wangzht@shutcm.edu.cn.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Departments of Medicine and Genetics, Albert Einstein College of Medicine, NY 10461, USA. Electronic address: sridhar.mani@einstein.yu.edu.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D010944:Plants / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D000077297:Pregnane X Receptor; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011987:Receptors, Steroid / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C047368:3-methylquercetin; D016264:Dextran Sulfate; D011794:Quercetin
keywords: Inflammatory bowel disease; Isorhamnetin; NF-κB; Pregnane X receptor; Xenobiotic metabolism