chrysin and Colitis

Inflammatory bowel disease (IBD) is a chronic disease that occurs in the intestinal tract. Phyto-ingredients have been evaluated for their ability to protect against IBD because of their anti-inflammatory activities. In our previous study, we identified a novel derivative of chrysin (HE-chrysin) using irradiation technology, which exhibited stronger anti-cancer activity in human colorectal cancer cells than the original chrysin. Here, to determine whether HE-chrysin is a new therapeutic candidate for IBD, we investigated the anti-inflammatory effects of HE-chrysin on bone marrow-derived dendritic cells (BMDCs) and dextran sodium salt (DSS)-induced colitis in mice. HE-chrysin more effectively inhibited BMDC maturation compared to chrysin, as demonstrated by the decreased levels of pro-inflammatory cytokines, surface molecules, antigen-presenting ability, and T cell proliferation/activation in lipopolysaccharide-stimulated BMDCs. These anti-inflammatory effects of HE-chrysin were regulated by mitogen-activated protein kinases and nuclear factor-κB. Furthermore, oral administration of HE-chrysin attenuated DSS-induced colitis symptoms and clinical signs in the mouse model. The protective effects of HE-chrysin treatment against colitis were mediated by decreasing Th1- and Th17-type cytokine levels. These results indicate that HE-chrysin is attractive candidate for IBD therapy.

Topics: Animals; Anti-Inflammatory Agents; Cell Proliferation; Colitis; Cytokines; Dendritic Cells; Dextran Sulfate; Disease Models, Animal; Female; Flavonoids; Inflammation Mediators; Inflammatory Bowel Diseases; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; Protective Agents; Signal Transduction

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.

Topics: Animals; Blotting, Western; Colitis; Dextran Sulfate; Female; Flavonoids; Fluorescent Antibody Technique; Gene Silencing; Genes, Reporter; Humans; Interleukin-6; Mice; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Pregnane X Receptor; Receptors, Steroid; RNA; Signal Transduction; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Up-Regulation