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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Chrysin Ameliorates Chemically Induced Colitis in the Mouse through Modulation of a PXR/NF-κB Signaling Pathway

Wei Dou, Jingjing Zhang, Eryun Zhang, Aning Sun, Lili Ding, Guixin Chou, Zhengtao Wang and Sridhar Mani
Journal of Pharmacology and Experimental Therapeutics June 2013, 345 (3) 473-482; DOI: https://doi.org/10.1124/jpet.112.201863
Wei Dou
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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Jingjing Zhang
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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Eryun Zhang
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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Aning Sun
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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Lili Ding
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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Guixin Chou
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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Zhengtao Wang
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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Sridhar Mani
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 (W.D., J.Z., E.Z., A.S., L.D., Z.W.); Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (W.D., S.M.); Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, China (G.C., Z.W.)
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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.

Footnotes

    • Received November 14, 2012.
    • Accepted March 21, 2013.
  • Z.W. and S.M. contributed equally to this work.

  • This work was supported by National Natural Science Foundation of China [Grants U1032604 and 81273572]; Natural Science Foundation of Shanghai [Grant 12ZR1431400]; Innovation Program of Shanghai Municipal Education Commission [Grant 13YZ043]; the National Institutes of Health [Grant RO1CA127231]; and the Damon Runyon Foundation Clinical Investigator Award [CI 1502].

  • dx.doi.org/10.1124/jpet.112.201863.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 3
1 Jun 2013
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Chrysin Ameliorates Chemical Colitis via PXR/NF-κB

Wei Dou, Jingjing Zhang, Eryun Zhang, Aning Sun, Lili Ding, Guixin Chou, Zhengtao Wang and Sridhar Mani
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 473-482; DOI: https://doi.org/10.1124/jpet.112.201863

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Chrysin Ameliorates Chemical Colitis via PXR/NF-κB

Wei Dou, Jingjing Zhang, Eryun Zhang, Aning Sun, Lili Ding, Guixin Chou, Zhengtao Wang and Sridhar Mani
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 473-482; DOI: https://doi.org/10.1124/jpet.112.201863
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