A Slominski

..However, it diverges from the HPA organization in its distal step, where CRH and ACTH stimulate production of corticosterone, instead of cortisol...

..We conclude that the expanding list of neuroendocrine elements expressed in the skin supports a strong role for this system in cutaneous biology...

..Ultimately, the skin neuroendocrine system would act to preserve cutaneous structural and functional integrity to maintain systemic homeostasis...

..Thus, skin cells represent a true target for the products of the serotoninergic/melatoninergic cutaneous pathway with their actions modulating cell proliferation or viability...

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..We conclude that while the TPH mRNA and protein are widely expressed in cultured normal and pathological epidermal and dermal skin cells, in vivo TPH expression is predominantly restricted to cells of melanocytic origin...

..The adnexal location of CRH-R2 suggests a role for the receptor in hair growth. The differential interspecies CRH signaling expression pattern probably reflects adaptation to species-specific skin function determinants...

..These endocrine factors would represent an exquisite regulatory layer addressed at restricting maximally the effect of noxious agents in the skin to preserve local and consequently global homeostasis...

..Thus, P450scc can metabolize vitamin D2 to generate novel products, with intrinsic biological activity (at least in keratinocytes)...

..The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis...

..Indeed, the significance of melanogenesis extends beyond the mere assignment of a color trait...

..In conclusion, CRH and related peptides can couple CRH-R1 to any of diverse signal transduction pathways; they also regulate cell viability and proliferation in cell type and growth condition-dependent manners...

..Furthermore, melatonin could have a role in protection against solar radiation or even in the management of skin diseases...

..Mouse skin and hamster melanomas also expressed 5HT2B and 5HT7. We identified two novel isoforms of MT1A and 5HT7...

..Additional vitamin D3 metabolites arise from the action of other enzymes in adrenal mitochondria. These findings appear to define novel metabolic pathways involving vitamin D3 that remain to be characterized...

..This pattern demonstrates the fractal nature of the response to stress with similar activation sequence at the single-cell and whole body levels...

..Melanin itself has a wide range of bioactivities that extend far beyond its determination of hair color...

..Slominski, A. J., Wortsman, J., Tobin, D. J. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun...

..Thus, differential, CRH-driven responses of defined cutaneous cell populations reproduce key features of the central HPA axis at the tissue/single cell levels...

..Direct identification of these peptides is consistent with translation of the corresponding genes, and it also suggests intermediate pituitary lobe-like POMC peptide processing...

..Such capabilities have defined melanocytes as neuroendocrine cells that not only coordinate cutaneous but also can affect a global homeostasis...

..The 5-7 dienal intermediates of the pathway can be a source of biologically active vitamin D3 derivatives after delivery to or production in the skin, an organ intermittently exposed to solar radiation...

..Thus, the inhibition of melanogenesis might represent a valid therapeutic target for the management of advanced melanotic melanomas...

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..This novel pathway has the potential to generate a variety of molecules depending on local steroidogenic activity and access to UVB...

..Therefore, we suggest that the skin neuroendocrine system acts by preserving and maintaining the skin structural and functional integrity and, by inference, systemic homeostasis...

..In this way, melatonin actions may counteract or buffer both environmental and endogenous stressors to maintain skin integrity...

..In such a CRH/POMC system, the CRH-Rs may be a central element...

..NAS identity was confirmed further by LC/MS in keratinocytes. In conclusion, we provide evidence that the human skin expresses intrinsic serotonin and melatonin biosynthetic pathways...

..Thus, this study provides what I believe to be the first mechanistic link between psychological stress and increased susceptibility to microbial infection...

..As distinct from the adrenal cortex, production of A, B, Aldo, 18OHdeoxycorticosterone, or F in keratinocytes was absent or below limits of detectability...

..Thus, human melanoma cells can synthesize and metabolize Ser and Mel...

..The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic techniques and potential therapeutic approaches...

..The intensity of the oncostatic response to melatonin could be related to the cell-line specific pattern of melatonin cellular receptors and cytosolic binding protein expression...

..This is the first demonstration that skin cells (malignant melanocytes) have the capability to synthesize 11-deoxycorticosterone, corticosterone, and 18-hydroxydeoxycorticosterone...

..In conclusion, we suggest that local production of ACTH may represent a regulatory element in the control of skin functions including hair growth...

..These results support the hypothesis that murine hair growth and attendant melanogenesis can be regulated through coordinated changes in local expression of POMC, MC1-R, and tyrosinase genes...

..CRH mRNA is transcribed in cultured melanocytes but not in keratinocytes. It is proposed that an equivalent of the 'hypothalamus-pituitary axis' composed of the CRH-CRHR-POMC loop is conserved in mammalian skin...

..In conclusion, we now demonstrate that human skin and mouse skin as well as cultured keratinocytes and melanoma cells exhibit functional expression of the urocortin gene with actual production of urocortin peptide...

..In conclusion, these data provide detailed evidence for specific antiapoptotic mechanisms of melatonin in UVR-induced damage of human keratinocytes...

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..Thus, normal rodent skin possesses steroidogenic activity that can be shown using progesterone or DOC as primary substrates...

..Therefore, similar to its central actions, cutaneous CRH may also he involved in the stress response, but at a highly localized level...

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..In conclusion, UVB induces CRH production in human melanocytes through stimulation of the protein kinase A pathway, with sequential involvement of CRH-CRH receptor 1 in the stimulation of POMC expression...

..The CRF production and secretion is markedly stimulated by ultraviolet B (UVB) radiation. This is the first demonstration that cutaneous melanocytes respond to environmental stress (UVB) through the production of CRF...

..These findings suggest that some components of hypothalamo-pituitary axis are operating in mouse skin...

..Thus, molecular elements of the distal loop of the "pituitary-adrenal axis" such as the MC-2, CYP11A1, CYP17 and CYP21A2 genes are expressed in the skin...

..Thus, pretreatment with melatonin led to strong protection against UVB-induced damage in keratinocytes...

..As serotonin has powerful vasodilator, immunomodulator, and growth factor actions, this pathway could be involved in skin physiology and/or pathology...

..This article reviews the current understanding of melanocyte receptors, their agonists and inhibitors, and their potential to treat the melanocytic pathology...

..Whereas the latter implies feedback control of melanogenesis, it is also possible that the two mechanisms operate jointly in hair follicles...

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..In summary, we have developed a microarray chip that can be used for simultaneous testing of transcriptional responses to cutaneous stressors in the context of neuroendocrine-immune functions of the skin...

..This suggests that both protein kinase A and C can be involved in CRF-dependent signal transduction...

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..The latter finding may be the pathogenic connection (lichenoid dermatitis of LS triggering an autoimmune reaction to melanocytes) that underlies the documented association of LS with vitiligo...

..The additional biological activity of these individual melatonin metabolites increases the spectrum of potential actions of the recently identified cutaneous melatoninergic system...

..We review current and potential biomarkers useful for the screening for and prevention, diagnosis, staging, and prognosis of melanoma...

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..Moreover, corticotropin-releasing hormone inhibited the trans-cription of the nuclear factor-kappaB responsive genes, interleukin-2 and heat shock protein 90...

..These data imply that the previously unreported pathway of vitamin D3 metabolism by P450scc may have wider biological implications depending, for example, on the extent of adrenal gland or cutaneous metabolism...

..In conclusion, the results of these cell culture experiments give support to a clinical trial of pharmacologically induced decrease in melanin synthesis to enhance the efficacy of radiotherapy in advanced melanomas...

..g. through activation of POMC. We suggest that induction of POMC by CRH serves as a feedback mechanism to self-restrict inflammatory response in the skin...

..New drugs are urgently needed for improved therapy for melanoma...

..Therefore, we suggest that ocular tissue expresses CRF-driven signalling system that follows organisational structure of the HPA axis...

..CRH-dependent stimulation of NF-kappaB activity is consistent with accumulated data about role of this neuropeptide in the regulation of local epidermal homeostasis...

..Since at the tissue level mast cells integrate stress responses into the neuroimmune regulatory network, it is likely that the POMC system is involved in mast cells' functions in tissue homeostasis...

..The information generated can be used for defining the roles of melanogenesis and of tyrosinase expression in the regulation of melanoma behavior and the effect of their modification on the course of the disease...