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Although recent therapeutic developments raise hope, melanoma remains a devastating disease with a need for new treatment targets. In other tumours prohormone convertases have been shown to be pro-tumourigenic as they are involved in processing preforms of matrix-metalloproteinases, growth factors and adhesion molecules. The aim of this study was to look for new treatment options for melanoma, by investigating the role of the prohormone convertase Paired basic Amino acid-Cleaving Enzyme 4 (PACE4/PCSK6) in melanoma cell lines and human melanoma tissue. PACE4-transfected A375 melanoma cells displayed significantly increased proliferation, MMP-2 production, gelatinase activity and migratory capacity in vitro compared with sham-transfected cells. In vivo, elevated PACE4 expression resulted in significantly increased tumour growth on immunodeficient mice. In the majority of 45 human primary melanomas and melanoma metastases ex vivo PACE4 immunoreactivity was detectable, while it was absent in in situ melanomas. These results indicate PACE4 as a regulator of melanoma cell aggressiveness. [ABSTRACT FROM AUTHOR]

Is Fas-mediated apoptosis of melanocytes indispensable in vitiligo? Genome-wide association studies further disclosed loci in several candidate genes encoding apoptosis-regulating proteins such as I FASLG i , I BCL2L11 i and I CASP7 i .4 It was demonstrated that destruction of melanocytes depends on Fas-mediated apoptosis by tracking autoreactive CD4 SP + sp T cells in a transgenic vitiligo mouse model.5 Our observation challenges the idea that Fas-mediated apoptosis of melanocytes is indispensable in vitiligo. With interest, we have read the article by Jimbo et al. in I Experimental Dermatology i .1 The authors reported that the Fas pathway is involved in CD8+ T-lymphocyte-dependent depigmentation in a vitiligo mouse model. [Extracted from the article]

Background: Little is known about the effect of neuropeptides on basophils, which are important effector cells in immune and allergic responses. Objective: This study aimed at revealing the role of α-melanocyte–stimulating hormone (α-MSH) on basophil function. Methods: Expression of melanocortin receptors and proopiomelanocortin (POMC) was analyzed by means of RT-PCR, Western immunoblotting, fluorescence-activated cell sorting, and double-immunofluorescence analysis. Signal transduction studies included cyclic AMP and Ca2+ mobilization assays. Basophil activity was assessed based on CD63 surface expression and cytokine release. Results: MC-1R expression was detectable in basophils isolated from human peripheral blood, as well as in basophils within nasal tissue. In isolated basophils from human blood, truncated POMC transcripts were present, but there was no POMC protein. Treatment of basophils with α-MSH increased intracellular Ca2+ but not cyclic AMP levels. α-MSH at physiologic doses potently suppressed basophil activation induced by N-formyl-methionyl-leucyl-phenylalanine, phorbol 12-myristate 13-acetate, or grass pollen allergen in whole blood of healthy or allergic subjects, respectively. The effect of α-MSH on basophil activation was MC-1R mediated (as shown by blockade with a peptide analogue of agouti-signaling protein) and imitated by adrenocorticotropic hormone but not elicited by the tripeptides KPV and KdPT, both of which lack the central pharmacophore of α-MSH. Moreover, α-MSH at physiologic doses significantly suppressed secretion of 3 proallergic cytokines, IL-4, IL-6, and IL-13, in basophils stimulated with anti-IgE, N-formyl-methionyl-leucyl-phenylalanine, or phorbol 12-myristate 13-acetate. Conclusion: Our findings highlight a novel functional activity of α-MSH, which acts as a natural antiallergic basophil-response modifier. These findings might point to novel therapeutic strategies in treating allergic diseases. [Copyright &y& Elsevier]

The article presents a study which investigates the expression patterns of the melanocortin (MC) system and the impacts of α-melanocyte-stimulating hormone (MSH) in the articular chondrocytes of human. It mentions the use of reverse transcription-polymerase chain reaction (RT-PCR) to analyze the chondrocytes and Western blotting to analyze the expression of MC receptors, pro-opiomelanocortin (POMC) and prohormone convertases (PCs). Results show that α-MSH affects chondrocytes.

The article discusses the study which investigates the effects of melanocyte-stimulating hormone on collagen synthesis and fibrosis. The study determines the collagen expression in human dermal fibroblasts through reverse transcription-polymerase chain reaction (PCR) and Western blot analyses. The study provides antifibrogenic therapeutic tool for the treatment of fibrotic disease such as scleroderma of alpha-nuclanocyte-stimulating hormone.

Expression of basic fibroblast growth factor cDNA or dominantly acting oncogenes, e.g., E1A, in immortalized mouse melanocytes leads to autonomous growth in vitro, depigmentation, and in the case of the oncogenes, tumorigenesis. Because downregulation of pigmentation is a common event in human metastatic melanoma cells grown in culture, we determined the molecular basis of depigmentation in a mouse melanocyte model system. We tested the effect of E1A mutants deficient in their ability to neutralize several regulatory proteins and determined changes in melanogenic gene expression. We identified Microphthalmia as the affected, downregulated transcription factor in melanocytes rendered amelanotic by E1A, basic fibroblast growth factor, or the oncogenes ras or neu, and in an amelanotic cell variant of Cloudman S91 mouse melanoma. Against expectations, sequestration of p300, a transcriptional adaptor that mediates responses to cyclic adenosine monophosphate, was not required for the full transforming effects of E1A. Our results suggest that in addition to controlling tyrosinase (albino locus) and tyrosinase-related protein 1 (TRP1/gp75/brown locus), both known to possess the DNA consensus site for binding the Microphthalmia protein, this transcription factor also controls other melanocyte-specific genes such as pink-eyed dilution and Pmel 17 (silver), but not tyrosinase-related protein 2 (slaty locus). Furthermore, these findings show that microphthalmia is downregulated not only by experimentally introduced dominantly acting oncogenes but also by the aberrant expression of basic fibroblast growth factor and by spontaneous tumorigenic transformation. [ABSTRACT FROM AUTHOR]

The family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases consists of phagocytic gp91phox and six-related isoforms. Recent evidence indicates that the NADPH oxidase isoform Nox4 controls vascular, renal and pulmonary injury. We propose that Nox4 is an intrinsic regulator of the activated state of dermal fibroblasts in systemic sclerosis (SSc). Profibrotic cytokines on the one hand and antifibrogenic factors such as α-melanocyte-stimulating hormone on the other hand may target Nox4 as an intracellular nodal point. Via increased or decreased generation of reactive oxygen species and/or hydrogen peroxide, Nox4 could orchestrate collagen synthesis, differentiation of dermal fibroblasts into a profibrotic myofibroblast phenotype and thus dermal fibrosis. Confirmation of this hypothesis will have important consequences in our understanding of the activated state of dermal fibroblasts in SSc. Based on the availability of clinically useful Nox4 inhibitors, novel antifibrotic therapies of SSc can be envisioned. [ABSTRACT FROM AUTHOR]

The melanocortin-1 receptor ( MC1) - being most abundantly expressed in the skin by melanocytes - has a physiological role for melanin pigmentation in many vertebrate species. MC1 has also been implicated in regulation of skin inflammation as this receptor is detectable in the majority of non-melanocytic cell types and its ligand α-melanocyte-stimulating hormone ( α- MSH) exerts immunoregulatory and anti-inflammatory effects. However, in vivo studies on mice with targeted disruption of MC1 have been missing in the context of skin inflammation until recently. Wolnicka-Glubisz et al. now reported that the course of ultraviolet ( UV)-induced inflammation, contact hypersensitivity, neonatal immune tolerance and UV-induced immunosuppression is similar in MC1 signal-deficient (C57BL/6-Mc1r e/e) and wild-type mice. These unexpected findings are supported by own observations in experimentally induced immune-complex-mediated vasculitis: Mc1r e/e mice exhibited a similar extent of the reverse passive cutaneous Arthus reaction compared with wild-type animals. Future studies are thus needed to clarify whether these findings are due to limitations in the chosen mouse model and/or point to additional MC subtypes that may regulate inflammatory and immune responses in the skin. [ABSTRACT FROM AUTHOR]

This article presents a study on the expression of melanocortin 1-receptor (MC1R) in human skin and in primary normal human melanocytes (NHM). Detection and characterization of MC1R isoforms in NHM cultures is discussed. The effects of MC1R isoforms on the melanin biosynthesis pathway are described. Conclusions of the study are given.

Vitiligo pathogenesis is very puzzling, and novel mechanisms possibly involved in the development of this disorder are frequently explored. Recently, some authors proposed an interplay between oxidative stress and immune system at the basis of melanocyte loss. According to the experimental evidence, they suggest that exposition to environmental agents might lead to an association between vitiligo and other autoimmune diseases. Accordingly, it is proposed that increased reactive oxygen species due to environmental agents could induce a modification of both melanocytic structures and other tissue proteins, or might disregulate the immune system, influencing the appearance of vitiligo and autoimmune comorbidities. [ABSTRACT FROM AUTHOR]