Nobiletin and its colonic metabolites suppress colitis-associated colon carcinogenesis by down-regulating iNOS, inducing antioxidative enzymes and arresting cell cycle progression
Nobiletin and its colonic metabolites suppress colitis-associated colon carcinogenesis by down-regulating iNOS, inducing antioxidative enzymes and arresting cell cycle progression
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DOI：
10.1016/j.jnutbio.2016.12.020
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发表时间：
2017-04-01
影响因子：
5.6
通讯作者：
Xiao, Hang
中科院分区：
文献类型：
--
作者：
Wu, Xian;Song, Mingyue;Xiao, Hang
诺必列汀（NOB）是柑橘中一种重要的多甲氧基黄酮（PMF），具有多种生物活性。我们以前报道，饮食NOB显着抑制结肠炎相关的结肠癌发生在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）治疗的小鼠，和化学预防作用与NOB代谢产物中发现的小鼠结肠组织。在这项研究中，为了更好地了解NOB的结肠代谢物的作用，我们确定了NOB及其主要代谢物（NOB-Met）的混合物的抗炎和抗癌作用，其浓度相当于NOB喂养小鼠的结肠组织中发现的浓度。结果表明，NOB-Met能有效降低脂多糖（LPS）刺激的巨噬细胞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（NQOI）的表达水平，上调核因子红细胞2相关因子（Nrf 2）信号通路。NOB-Met还在人结肠癌细胞中引起显著的细胞周期停滞。验证研究证实，膳食NOB导致与AOM/DSS处理的小鼠的结肠中的上述作用相似的作用。具体而言，膳食NOB显著降低了iNOS的水平，上调了Nrf 2依赖性酶，并深刻地调节了关键信号蛋白，导致AOM/DSS治疗小鼠结肠组织中细胞周期进展减少。总体而言，我们的研究结果表明，膳食NOB导致NOB及其代谢产物在结肠组织中的存在，其通过下调iNOS、诱导抗氧化酶和阻止细胞周期进展来抑制结肠炎相关的结肠癌发生。(C)2017爱思唯尔公司All rights reserved.
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 (NQOI) 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. (C) 2017 Elsevier Inc. All rights reserved.