title: Chrysin ameliorates chemically induced colitis in the mouse through modulation of a PXR/NF-κB signaling pathway.
abstract: Targeted activation of pregnane X receptor (PXR) in recent years has become a therapeutic strategy for inflammatory bowel disease. Chrysin is a naturally occurring flavonoid with anti-inflammation activity. The current study investigated the role of chrysin as a putative mouse PXR agonist in preventing experimental colitis. Pre-administration of chrysin ameliorated inflammatory symptoms in mouse models of colitis (dextran sodium sulfate- and 2,4,6-trinitrobenzene sulfonic acid-induced) and resulted in down-regulation of nuclear transcription factor κB (NF-κB) target genes (inducible NO synthase, intercellular adhesion molecule-1, monocyte chemotactic protein-1, cyclooxygenase 2, tumor necrosis factor-α, and interleukin 6) in the colon mucosa. Chrysin inhibited the phosphorylation/degradation of inhibitor κBα (IκBα), which correlated with the decrease in the activity of myeloperoxidase and the levels of tumor necrosis factor-α and interleukin 6 in the colon. Consistent with the in vivo results, chrysin blocked lipopolysaccharide -stimulated nuclear translocation of NF-κB p65 in mouse macrophage RAW264.7. Furthermore, chrysin dose-dependently activated human/mouse PXR in reporter gene assays and up-regulated xenobiotic detoxification genes in the colon mucosa, but not in the liver. Silencing of PXR by RNA interference demonstrated necessity of PXR in mediating chrysin's ability to induce xenobiotic detoxification genes and NF-κB inactivation. The repression of NF-κB transcription activity by chrysin was confirmed by in vitro PXR transduction. These findings suggest that the effect of chrysin in preventing chemically induced colitis is mediated in large part by a PXR/NF-κB pathway. The data also suggest that chrysin or chrysin-like flavonoids could be further developed as intestine-specific PXR activators.
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, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dou
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.forename: Eryun
authors.initials: E
authors.lastname: Zhang
authors.forename: Aning
authors.initials: A
authors.lastname: Sun
authors.forename: Lili
authors.initials: L
authors.lastname: Ding
authors.forename: Guixin
authors.initials: G
authors.lastname: Chou
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D000077297:Pregnane X Receptor; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005419:Flavonoids; D015850:Interleukin-6; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014409:Tumor Necrosis Factor-alpha; C043561:chrysin; D012313:RNA; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase
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