Role of Exogenous Melatonin in Skin Biology

外源性褪黑激素在皮肤生物学中的作用

• 批准号: 8874110
• 负责人: ANDRZEJ T SLOMINSKI
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874110
• 关键词: Affinity; Aging; Agonist; Algae; Antioxidants; Apoptotic; Attenuated; Bacteria; Behavior; Binding; Biochemical; Biological; Biological Response Modifiers; Biology; Buffers; Cells; Chemicals; Circadian Rhythms; Cosmetics; Cutaneous; Degradation Pathway; Disease; Dissection; Dose; Epidermis; Eukaryota; Exhibits; Gene Silencing; Genome; Homeostasis; Hormones; Human; Hyperpigmentation; In Vitro; Inflammatory; Invertebrates; Malignant Neoplasms; Measures; Mediating; Melanogenesis; Melatonin; Membrane; Metabolism; Mitochondria; Molecular; Nature; Neurotransmitters; Nuclear; Nuclear Receptors; Oxidative Stress; Pathology; Pathway interactions; Phenotype; Pigmentation physiologic function; Pineal gland; Plants; Precancerous Conditions; Process; Production; Property; Proteins; Quinone Reductases; Radiation induced damage; Reactive Oxygen Species; Receptor, Melatonin, MT2; Regulation; Retina; Role; Serotonin; Skin; Skin Aging; Specificity; Stress; Structure; Sunscreening Agents; System; Technology; Testing; Therapeutic; Tryptophan; UV Radiation Exposure; Ultraviolet B Radiation; Vertebrates; Vitiligo; autocrine; biological adaptation to stress; clinical application; cytokine; keratinocyte; melanocyte; melanoma; methoxyindole; novel therapeutics; paracrine; pleiotropism; receptor; skin disorder; stressor

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.

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，褪黑激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皮肤产生和代谢的，在那里它可以渗透到所有细胞区室，包括线粒体。褪黑激素（Melatonin）是一种两亲性甲氧基吲哚类化合物，具有多种生物活性，如神经递质、激素、细胞因子和生物反应调节剂等，这些活性是通过与高亲和力受体的相互作用来介导的。褪黑激素也是一种广谱抗氧化剂，通过受体非依赖性方式起作用，它激活细胞保护途径，并在高浓度下减弱或抵消氧化应激。这些抗氧化作用也被其代谢物N1-乙酰基-N2-甲酰基-5-甲氧基犬尿胺（AFMK）所共享，AFMK是褪黑激素代谢的最古老产物。因此，褪黑激素表现出许多对皮肤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能系统通过内分泌、自分泌或旁分泌机制实现细胞特异性选择性，其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，而不依赖于昼夜松果体褪黑激素分泌。这些功能应包括激活细胞保护和抗凋亡途径，以及抗突变、抗基因毒性和抗癌活性。褪黑激素生物活性将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，褪黑激素可以通过活性氧或UVB的作用非酶促转化为AFMK。因此，我们建议：1。采用体外培养的人表皮角质形成细胞和黑素细胞以及组织培养的人皮肤组织块，研究褪黑素对人表皮的保护作用。明确褪黑激素在黑素生成中的调节作用; 3.表征培养的人角质形成细胞和黑素细胞中褪黑激素降解的途径。这些目标的实现将确定褪黑激素是否可以在治疗上被利用，作为具有抗遗传毒性特性的一般“皮肤存活因子”或作为基因组和细胞完整性的“监护人”。因此，它可以用作防晒剂的组分或用于治疗色素沉着病（例如白癜风或色素沉着过度）、增殖过程（包括癌前状态、表皮癌或甚至黑素瘤）、UVB诱导的病理、炎性皮肤病和皮肤老化。