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Chrysin Ameliorates Chemically Induced Colitis in the Mouse through Modulation of a PXR/NF-κB Signaling Pathway
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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.
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“administration of synthetic NR1I2 agonists exerts protective effects in mouse models of colitis (Dou et al., 2013; Garg et al., 2016; Shah et al., 2007; Terc et al., 2014; Venkatesh et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Dou et al., 2013
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“Nr1i2−/− mice exhibit impaired epithelial barrier function”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Dou et al., 2013
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Metadata
- Authors
- Dou, W., Zhang, J., Zhang, E., Sun, A., Ding, L., Chou, G., Wang, Z., & Mani, S.
- Affiliations
- Shanghai University of Traditional Chinese Medicine (CN)
- Albert Einstein College of Medicine (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 345
- Issue
- 3
- Pages
- 473-482
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC3657113
- OpenAlex
- W2143953127
- Cited by
- 111
- References
- 26
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 9 · 2020: 7 · 2019: 10 · 2018: 8 · 2017: 17 · 2016: 12 · 2015: 6 · 2014: 11 · 2013: 2
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA161879, R01CA127231)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Flavonoids in Medical Research
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- chrysin, pregnane X receptor, NF-κB signaling, experimental colitis, inflammatory bowel disease, DSS-induced colitis, trinitrobenzene sulfonic acid-induced colitis, flavonoids, IκBα phosphorylation, TNF-α, interleukin-6, macrophages, colonic mucosa, PXR agonists
- MeSH terms
- Pregnane X Receptor, Animals, Colitis, Female, Flavonoids, Fluorescent Antibody Technique, Humans, Mice, Inbred C57BL, Peroxidase, Receptors, Steroid, RNA, Trinitrobenzenesulfonic Acid, Tumor Necrosis Factor-alpha, Blotting, Western, Signal Transduction, Interleukin-6, Up-Regulation, Dextran Sulfate, NF-kappa B, Genes, Reporter, Gene Silencing, Mice
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