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.
J Pharmacol Exp Ther. 2013 Jun;345(3):473-82. doi: 10.1124/jpet.112.201863. Epub 2013 Mar 27.
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.
近年来，靶向前体激活素 X 受体（PXR）已成为治疗炎症性肠病的一种治疗策略。白杨素是一种具有抗炎活性的天然黄酮类化合物。本研究探讨了白杨素作为一种潜在的小鼠 PXR 激动剂在预防实验性结肠炎中的作用。白杨素预处理可改善结肠炎（葡聚糖硫酸钠和 2,4,6-三硝基苯磺酸诱导）小鼠模型中的炎症症状，并导致核转录因子κB（NF-κB）靶基因（诱导型一氧化氮合酶、细胞间黏附分子-1、单核细胞趋化蛋白-1、环氧合酶 2、肿瘤坏死因子-α和白细胞介素 6）在结肠黏膜中的下调。白杨素抑制了抑制剂κBα（IκBα）的磷酸化/降解，这与髓过氧化物酶活性的降低以及结肠中肿瘤坏死因子-α和白细胞介素 6 的水平降低相关。与体内结果一致，白杨素阻断了脂多糖刺激的 NF-κB p65在小鼠巨噬细胞 RAW264.7 中的核易位。此外，白杨素在报告基因检测中剂量依赖性地激活人/鼠 PXR，并在上皮细胞中上调外源解毒基因，但在肝脏中则没有。RNA 干扰沉默 PXR 证明了 PXR 在介导白杨素诱导外源解毒基因和 NF-κB 失活中的必要性。通过体外 PXR 转导证实了白杨素对 NF-κB 转录活性的抑制作用。这些发现表明，白杨素在预防化学诱导结肠炎中的作用在很大程度上是通过 PXR/NF-κB 途径介导的。数据还表明，白杨素或类白杨素黄酮类化合物可能进一步开发为肠道特异性 PXR 激活剂。
