Department of Pharmacology, University of Seville, Seville, Spain.
J Pineal Res. 2011 Aug;51(1):44-60. doi: 10.1111/j.1600-079X.2011.00915.x.
In intestinal bowel disease (IBD), immune-mediated conditions exert their effects through various cells and proinflammatory mediators. Recent data support a participation of the endoplasmic reticulum stress and mitochondrial dysfunctions in IBD. Moreover, it is evident that chronic degenerative pathologies, including IBD, share comparable disease mechanisms with alteration in the autophagy mechanisms. Chronic inflammation in IBD exposes these patients to a number of signals known to have tumorigenic effects. This circuitry of inflammation and cancer modifies apoptosis and autophagy, and promotes cellular cycle progression, invasion, and angiogenesis. Melatonin has been shown as a specific antioxidant reducing oxidative damage in both lipid and aqueous cell environments. However, several studies provide further insight into the molecular mechanisms of melatonin action in the colon. In this line, recent data suggest that melatonin modulates autophagy and sirtuin activity. An anti-autophagic property of melatonin has been demonstrated, and it could contribute to its anti-oncogenic activity. Nevertheless, there is no information about whether antitumoral effects of melatonin on colon cancer are dependent on autophagy. Sirtuins have pleiotropic effects on cancer development, being reported both as facilitator and as suppressor of colon cancer development. Sirtuins and melatonin are connected through the circadian clock machinery, and melatonin seems able to correct the alterations in sirtuin activity associated with several pathological conditions. Autophagy and sirtuin activities are linked through 5'AMP-activated protein kinase (AMPK) activation, which switches on autophagy and increases sirtuin. The effect of melatonin on AMPK and the impact of this effect on IBD and colon cancer remain an open question.
在炎症性肠病（IBD）中，免疫介导的疾病通过各种细胞和促炎介质发挥作用。最近的数据支持内质网应激和线粒体功能障碍参与 IBD。此外，很明显，包括 IBD 在内的慢性退行性病变与自噬机制的改变具有相似的疾病机制。IBD 的慢性炎症使这些患者暴露于许多已知具有致癌作用的信号。这种炎症和癌症的循环改变了细胞凋亡和自噬，并促进了细胞周期的进展、侵袭和血管生成。褪黑素已被证明是一种特殊的抗氧化剂，可以减少脂质和水相细胞环境中的氧化损伤。然而，一些研究进一步深入了解了褪黑素在结肠中的作用机制。在这方面，最近的数据表明褪黑素调节自噬和沉默信息调节因子 2 相关酶 1（SIRT1）活性。已经证明褪黑素具有抗自噬特性，并且它可能有助于其抗癌活性。然而，关于褪黑素对结肠癌的抗肿瘤作用是否依赖于自噬，目前尚无信息。沉默信息调节因子 2 相关酶 1（SIRT1）在癌症发展中具有多效性作用，被报道既是结肠癌发展的促进剂，也是抑制剂。SIRT1 和褪黑素通过生物钟机制相互联系，并且褪黑素似乎能够纠正与几种病理状况相关的 SIRT1 活性改变。自噬和 SIRT1 活性通过 5'AMP 激活的蛋白激酶（AMPK）的激活而联系在一起，AMPK 激活自噬并增加 SIRT1。褪黑素对 AMPK 的影响以及这种影响对 IBD 和结肠癌的影响仍然是一个悬而未决的问题。
