Role of exogenous melatonin in skin biology

描述（由申请人提供）：假设在脊椎动物中褪黑激素仅在松果体和视网膜中产生。然而，越来越多的证据表明，褪黑素在自然界中广泛存在，在脊椎动物、无脊椎动物、植物、单细胞真核生物、藻类甚至细菌中都有发现。我们已经证明，褪黑激素是由哺乳动物的皮肤产生和代谢的，它可以渗透到包括线粒体在内的所有细胞区室。褪黑素是一种两亲性甲氧基吲哚，具有多种生物活性，可作为神经递质、激素、细胞因子和生物反应调节剂，与高亲和受体相互作用介导。褪黑素也是一种广谱抗氧化剂，通过受体不依赖的方式激活细胞保护途径，高浓度时可减弱或抵消氧化应激。其代谢物n1 -乙酰- n2 -甲酰基-5-甲氧基nuramine （AFMK）也具有这些抗氧化作用，AFMK是褪黑素代谢的系统发育上最古老的产物。因此，褪黑素显示出许多对被皮应激反应系统非常有用的特性。因此，我们提出皮肤褪黑激素系统通过分泌内、自身或旁分泌机制实现细胞特异性选择性，允许局部抵消或缓冲环境和内源性应激源，以维持皮肤完整性，独立于昼夜松果体褪黑激素分泌。这些功能应该包括细胞保护和抗凋亡途径的激活，以及抗诱变、抗基因毒性和抗癌活性。褪黑素的生物活性取决于预先存在的局部降解途径和暴露于紫外线辐射（UVR）的强度，例如，褪黑素可以通过活性氧或UVB的作用非酶转化为AFMK。因此，我们建议：1。利用体外培养的表皮角质形成细胞和黑色素细胞以及离体组织培养的人皮肤外植体来确定褪黑素对人表皮的保护作用；2. 明确褪黑素在调节黑色素形成中的作用；3. 探讨褪黑激素在体外培养的人角质形成细胞和黑色素细胞中的降解途径。实现这些目标将决定褪黑素是否可以用于治疗，要么作为具有抗基因毒性的一般“皮肤生存因子”，要么作为基因组和细胞完整性的“守护者”。因此，它可以用作防晒霜的成分或用于治疗色素疾病（例如白癜风或色素沉着过多）、增殖过程（包括癌前状态、表皮癌甚至黑色素瘤）、uvb诱导的病理、炎症性皮肤病和皮肤老化。

DESCRIPTION (provided by applicant): It was assumed that in vertebrates melatonin is only produced in the pineal gland and retina. However, evidence has accumulated that melatonin is widely detectable throughout Nature, being found in vertebrates, invertebrates, plants, unicellular eukaryotes, algae and even bacteria. We have documented that melatonin is produced and metabolized by the mammalian skin, where it can permeate to all cellular compartments including mitochondria. Melatonin (an amphilic methoxyindole) has pleiotropic bioactivities, as neurotransmitter, hormone, cytokine and biological response modifier, which are mediated by interactions with high affinity receptors. Melatonin is also a broad-spectrum antioxidant and acting via receptor-independent manner it activates cytoprotective pathways and at high concentrations it attenuates or counteracts the oxidative stress. These antioxidant effects are also shared by its metabolite, N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK), phylogenetically the oldest product of melatonin metabolism. Thus, melatonin exhibits a number of properties that are extremely useful for the integumental stress-response systems. Accordingly, we have proposed that the cutaneous melatoninergic system enables for cell-specific selectivity through intra-, auto- or paracrine mechanisms, which allow locally counteracting or buffering both environmental and endogenous stressors to maintain skin integrity, independent of circadian pineal melatonin secretion. Such functions should include activation of cytoprotective and anti-apoptotic pathways, and antimutagenic, antigenotoxic and anticancerogenic activites. Melatonin bioactivity would depend on preexistent local degradative pathways and the intensity of exposure to ultraviolet radiation (UVR), e.g., melatonin can be converted non-enzymatically to AFMK through action of reactive oxygen species or UVB. Therefore, we are proposing: 1. To define the protective role of melatonin in human epidermis using epidermal keratinocytes and melanocytes cultured in vitro and human skin explants histocultured ex-vivo; 2. To define the role of melatonin in regulation of melanogenesis; 3. To characterize the pathway of melatonin degradation in cultured human keratinocytes and melanocytes. Realization of these aims will define whether melatonin can be exploited therapeutically, either as a general "skin survival factor" with anti- genotoxic properties or as a "guardian" of genome and cellular integrity. Thus, it may be used as a component of sunscreens or in the treatment of pigmentary diseases (e.g. vitiligo or hyperpigmentation), proliferative processes (including precancerous states, epidermal cancer or even melanoma), UVB-induced pathology, inflammatory dermatoses and skin aging. PUBLIC HEALTH RELEVANCE: A long-standing clinically and economically important key question is whether melatonin and its metabolites, that have been shown experimentally to serve as a "guardians" of genome and cellular integrity, can be exploited therapeutically as a general "skin protectants" with anti-genotoxic, anti-oxidant, and/or anti- carcinogenic properties. The systematic dissection of intracutaneous melatonin metabolism and direct melatonin actions will define novel therapeutic strategies for UVB-induced skin pathology and for the exploitation of melatonin as a protective or cosmetic agent.