Talero Elena, Garcia-Maurino Sofia, Motilva Virginia
Department of Pharmacology, School of Pharmacy, University of Seville, c. Prof. Garcia Gonzalez nº 2, 41012 Seville, Spain.
Curr Pharm Des. 2014;20(30):4816-27. doi: 10.2174/1381612819666131119110835.
The intestinal epithelium forms a barrier against the intestinal contents and the wider environment, allowing entry of selected molecules for nutrition and programming of the mucosal immune system, but excluding toxins and most microorganisms. Many receptors and signalling pathways are coupled and implicated in the epithelial control and significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD) and in the introduction of biologics. However, not all of the patients respond and many lose their response. Data from experimental studies have documented that the pineal secretory product melatonin exerts important inmunoregulatory and antiinflammatory effects in different models of colitis. These actions have been associated to a variety of mechanisms, such as reduction of T cells number, modulation of macrophage activity, suppression of NFκB activity, inhibition of cell adhesion molecules and proinflammatory cytokines , suppression of COX-2 and iNOS levels and the consequent synthesis of PGE2 and NO, reduction of matrix metalloproteinase (MMP) -2 and -9 activity, and modulation of apoptosis. In addition, the beneficial effects of melatonin in IBD are related to its scavenger effect on free radicals and the activation of several antioxidant enzymes. However, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. There is a considerable bulk of information supporting the connection between autophagy and human diseases, including IBD, and although autophagy is actually considered more a pro-survival than a pro-death pathway, these two features of its action are relevant in human diseases, having therapeutic potential for both activators and inhibitors of autophagy. Some of the opposite effects than have been reported for melatonin in IBD could be related to the duality of its effects on autophagy, which itself can be beneficial or detrimental. In this review, new data for melatonin in IBD are discussed, trying to provide recent information of different molecular mechanism including the role of the autophagy regulation.
肠上皮形成一道抵御肠内容物和更广泛环境的屏障，允许特定分子进入以提供营养并对黏膜免疫系统进行编程，但排除毒素和大多数微生物。许多受体和信号通路相互关联并参与上皮控制，在炎症性肠病（IBD）发病机制的理解以及生物制剂的引入方面已取得重大进展。然而，并非所有患者都有反应，许多患者还会失去反应。实验研究数据表明，松果体分泌产物褪黑素在不同的结肠炎模型中发挥重要的免疫调节和抗炎作用。这些作用与多种机制有关，如T细胞数量减少、巨噬细胞活性调节、NFκB活性抑制、细胞黏附分子和促炎细胞因子抑制、COX - 2和iNOS水平抑制以及随后PGE2和NO的合成减少、基质金属蛋白酶（MMP）-2和-9活性降低以及细胞凋亡调节。此外，褪黑素在IBD中的有益作用与其对自由基的清除作用以及几种抗氧化酶的激活有关。然而，只有少数人体研究在病例报告和临床试验中报道了褪黑素可能的有益和有害作用。有大量信息支持自噬与包括IBD在内的人类疾病之间的联系，尽管自噬实际上更多地被认为是一种促生存而非促死亡途径，但其这两个作用特征在人类疾病中具有相关性，自噬激活剂和抑制剂都具有治疗潜力。在IBD中报道的褪黑素一些相反作用可能与其对自噬的双重作用有关，而自噬本身可能有益也可能有害。在本综述中，讨论了褪黑素在IBD中的新数据，试图提供包括自噬调节作用在内的不同分子机制的最新信息。
