Wu Xian, Song Mingyue, Gao Zili, Sun Yue, Wang Minqi, Li Fang, Zheng Jinkai, Xiao Hang
Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States.
Department of Food Science, University of Massachusetts Amherst, Amherst, MA, United States.
J Nutr Biochem. 2017 Apr;42:17-25. doi: 10.1016/j.jnutbio.2016.12.020. Epub 2017 Jan 11.
Nobiletin (NOB) is a major citrus polymethoxyflavone (PMF) with various beneficial biological activities. We reported previously that dietary NOB significantly inhibited colitis-associated colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice, and the chemopreventive effects were associated with NOB metabolites found in the mouse colonic tissues. In this study, to better understand the role of colonic metabolites of NOB, we determined the anti-inflammation and anticancer effects of a mixture of NOB and its major metabolites (NOB-Met) at the concentrations equivalent to those found in colonic tissues of NOB-fed mice. The results demonstrated that NOB-Met effectively decreased the expression level of inducible nitric oxide synthase (iNOS), increased the level of heme oxygenase-1 (HO-1) and NADH quinone oxidoreductase 1 (NQO1) and up-regulated nuclear factor erythroid 2-related factor (Nrf2) signaling pathway in lipopolysaccharide (LPS)-stimulated macrophages. NOB-Met also caused a significant cell cycle arrest in human colon cancer cells. Validation study confirmed that dietary NOB led to the effects similar to those described above in the colon of AOM/DSS-treated mice. Specifically, dietary NOB significantly reduced the level of iNOS, up-regulated Nrf2-dependent enzymes and profoundly modulated key signaling proteins resulting in decreased cell cycle progression in the colonic tissue of AOM/DSS-treated mice. Overall, our findings demonstrated that dietary NOB led to the presence of NOB and its metabolites in the colonic tissue, which suppressed colitis-associated colon carcinogenesis via down-regulating iNOS, inducing antioxidative enzymes and arresting cell cycle progression.
川陈皮素（NOB）是一种主要的柑橘类多甲氧基黄酮（PMF），具有多种有益的生物活性。我们之前报道过，在经氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）处理的小鼠中，饮食中的NOB能显著抑制结肠炎相关的结肠癌发生，其化学预防作用与在小鼠结肠组织中发现的NOB代谢产物有关。在本研究中，为了更好地理解NOB结肠代谢产物的作用，我们测定了NOB及其主要代谢产物混合物（NOB-Met）在相当于喂食NOB小鼠结肠组织中发现的浓度下的抗炎和抗癌作用。结果表明，NOB-Met能有效降低脂多糖（LPS）刺激的巨噬细胞中诱导型一氧化氮合酶（iNOS）的表达水平，提高血红素加氧酶-1（HO-1）和NADH醌氧化还原酶1（NQO1）的水平，并上调核因子红细胞2相关因子（Nrf2）信号通路。NOB-Met还能导致人结肠癌细胞出现显著的细胞周期阻滞。验证研究证实，饮食中的NOB在AOM/DSS处理的小鼠结肠中产生了与上述相似的作用。具体而言，饮食中的NOB显著降低了iNOS水平，上调了Nrf2依赖性酶，并深刻调节关键信号蛋白，导致AOM/DSS处理的小鼠结肠组织中的细胞周期进程减缓。总体而言，我们的研究结果表明，饮食中的NOB导致结肠组织中存在NOB及其代谢产物，它们通过下调iNOS、诱导抗氧化酶和阻滞细胞周期进程来抑制结肠炎相关的结肠癌发生。
