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Melanin Synthesis (melanin + synthesis)
Selected AbstractsDown-Regulation of Melanin Synthesis by a Biphenyl Derivative and Its MechanismPIGMENT CELL & MELANOMA RESEARCH, Issue 5 2003Kyoko Nakamura Down-regulation of melanin synthesis is required for recovery of pigmentary disorders and it is known that direct inhibitors of tyrosinase, the key enzyme in melanin synthesis, such as hydroquinone with a phenol structure, suppress melanin synthesis. We screened several phenolic derivatives using B16 melanoma cells and found that a biphenyl derivative, 2,2,-dihydroxy-5,5,-dipropyl-biphenyl (DDB), down-regulated melanin synthesis effectively. Although DDB has a phenol structure, it did not inhibit tyrosinase in vitro, thus we examined its mechanism in detail. Western blotting revealed that the amount of tyrosinase was decreased by DDB, and pulse-chase labeling and immunoprecipitation analysis showed a decrease of mature tyrosinase and acceleration of tyrosinase degradation in its presence. These results suggest that DDB down-regulates melanin synthesis by inhibiting the maturation of tyrosinase, leading to acceleration of tyrosinase degradation. [source] Inhibitory effects of Hoelen extract on melanogenesis in B16/F1 melanoma cellsPHYTOTHERAPY RESEARCH, Issue 9 2010Mun Seog Chang Abstract Melanin synthesis is regulated by melanogenic proteins, such as tyrosinase, tyrosinase-related protein 1 (TRP-1) and TRP-2. The effects of Hoelen extract on melanogenesis were investigated in B16Fl murine melanoma cells. Specifically, tyrosinase activity, cell viability and melanin content were assayed, and western blotting and RT-PCR for tyrosinase, TRP-1 and TRP-2 conducted. The results show that Hoelen significantly inhibited melanin synthesis through inhibition of TRP-2 expression, while it did not affect tyrosinase activity or its expression. Taken together, RT-PCR results showed that the depigmentation effect of Hoelen may be due to inhibition of TRP-2 gene transcription. These results suggest that Hoelen may be a useful inhibitor for the attenuation of melanogenesis and hyperpigmentation in skin cells. Copyright © 2010 John Wiley & Sons, Ltd. [source] Long-term suppression of tyrosinase by terrein via tyrosinase degradation and its decreased expressionEXPERIMENTAL DERMATOLOGY, Issue 6 2009Seo-Hyoung Park Abstract:, Previously, we reported that a fungal metabolite, terrein, decreases melanin synthesis via downregulation of microphthalmia-associated transcription factor (MITF). In the present study, we further investigated the long-term hypopigmenting action of terrein in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment with terrein at a concentration of 50 ,m strongly decreased melanogenesis in a time-dependent manner. Interestingly, the decreased tyrosinase protein levels lasted for at least 7 days, even though the MITF protein levels were restored after 3 days of treatment. In accordance with the results of Western blot analyses, the tyrosinase mRNA levels were found to be continuously decreased for at least 7 days, even though recovery of the MITF mRNA levels began after 3 days of terrein treatment. Therefore, we evaluated tyrosinase downregulation to determine if it is caused by proteasomal degradation. We found that the reduction in tyrosinase levels that was induced by terrein was clearly recovered by MG-132, a proteasome inhibitor. Moreover, ubiquitination of tyrosinase increased following treatment with terrein in the presence of MG-132. Taken together, these results suggest that terrein decreases melanogenesis through ubiquitin-dependent proteasomal degradation as well as via decreased expression of its mRNA. [source] Antimelanogenesis effect of Tunisian herb Thymelaea hirsuta extract on B16 murine melanoma cellsEXPERIMENTAL DERMATOLOGY, Issue 12 2007Mitsuko Kawano Abstract:, Skin pigmentation is the result of melanogenesis that occurs in melanocytes and/or melanoma cells. Although melanogenesis is necessary for the prevention of DNA damage and cancer caused by UV irradiation, excessive accumulation of melanin can also cause melanoma. Thus, we focused on the antimelanogenesis effect of an extract from Thymelaea hirsuta, a Tunisian herb. Murine melanoma B16 cells were treated with T. hirsuta extract, and then cell viability and synthesized melanin content were measured. We found that the T. hirsuta extract decreased the synthesized melanin content in B16 cells without cytotoxicity. Tyrosinase is a key enzyme of melanogenesis and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation is known to be related to melanogenesis inhibition. To clarify its mechanism, we also determined ERK1/2 phosphorylation and tyrosinase expression level. ERK1/2 was immediately phosphorylated in cells just after treatment with the extract. The tyrosinase expression was inhibited after 24 h of stimulation with the extract. The T. hirsuta extract was fractionated, and we found that one fraction considerably decreased the melanin synthesis in B16 cells and that this fraction contains daphnanes as the main component. This indicates that our findings might be attributable to daphnanes. [source] ,-MSH and cAMP signalling in normal human melanocytesEXPERIMENTAL DERMATOLOGY, Issue 9 2004R. Buscŕ Melanocytes are neural crest-derived skin cells specialized in the synthesis of melanin pigments responsible, in human, for skin and hair colour. The pro-opiomelanocortin peptide, ,-MSH is a strong melanogenic agent secreted by keratinocytes following UV radiation. ,-MSH through the binding to the MC1R and activation of the cyclic AMP pathway plays a pivotal role in melanocyte differentiation and in the regulation of skin pigmentation. During the last few years, we have elucidated the molecular events linking the cAMP pathway to melanogenesis upregulation. This cascade involves the activation of protein kinase A and CREB transcription factor, leading to the upregulation of the expression of microphthalmia-associated transcription factor (MITF). MITF binds and activates the melanogenic gene promoters thereby increasing their expression, which results in an increased melanin synthesis. Beyond this simplified scheme, other intracellular signalling pathways are regulated by cAMP and participate to the regulation of melanocyte differentiation. Indeed, cAMP inhibits the phosphatidyl inositol 3-kinase pathway, leading to the inhibition of AKT and to the activation of GSK3,. This kinase phosphorylates MITF and allows its binding to the target sequence. Such pathways are involved in the upregulation of melanogenesis. ,-MSH and cAMP signalling also regulate melanocyte dendricity, and melanosome transport through the inhibition of the Rho GTPase cascade that function downstream the PI3 kinase. It should be also mentioned that cAMP activates the ERK pathway through a melanocyte-specific pathway involving Ras and B-Raf. The activation of ERK and RSK1 leads to the phosphorylation of MITF and target MITF to the proteasome degradation pathway. Interestingly, several proteins involved in melanocyte differentiation by ,-MSH (MC1R, PI3K, B-Raf and MITF) have also been implicated in the development of melanoma, suggesting that the cAMP pathway could influence melanocyte transformation. [source] Fungal tyrosinases: new prospects in molecular characteristics, bioengineering and biotechnological applicationsJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2006S. Halaouli Abstract Tyrosinases are type-3 copper proteins involved in the initial step of melanin synthesis. These enzymes catalyse both the o -hydroxylation of monophenols and the subsequent oxidation of the resulting o -diphenols into reactive o -quinones, which evolve spontaneously to produce intermediates, which associate in dark brown pigments. In fungi, tyrosinases are generally associated with the formation and stability of spores, in defence and virulence mechanisms, and in browning and pigmentation. First characterized from the edible mushroom Agaricus bisporus because of undesirable enzymatic browning problems during postharvest storage, tyrosinases were found, more recently, in several other fungi with relevant insights into molecular and genetic characteristics and into reaction mechanisms, highlighting their very promising properties for biotechnological applications. The limit of these applications remains in the fact that native fungal tyrosinases are generally intracellular and produced in low quantity. This review compiles the recent data on biochemical and molecular properties of fungal tyrosinases, underlining their importance in the biotechnological use of these enzymes. Next, their most promising applications in food, pharmaceutical and environmental fields are presented and the bioengineering approaches used for the development of tyrosinase-overproducing fungal strains are discussed. [source] Mitigating Photosensitivity of Erythropoietic Protoporphyria Patients by an Agonistic Analog of ,-Melanocyte Stimulating Hormone,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 6 2009Juergen H. Harms Erythropoietic protoporphyria (EPP) is a rare hereditary disorder characterized by dermal accumulation of the photosensitizer protoporphyrin IX. Following sunlight exposure, the resulting photosensitivity is manifested first as pain, later as erythema, edema and dermal lesions. Afamelanotide (Nle4 -d-Phe7 -,-MSH), a synthetic analog of ,-melanocyte stimulating hormone and agonist of the melanocortin-1-receptor, promotes melanin synthesis, increasing skin pigmentation. This study examines the efficacy of afamelanotide in preventing symptoms in patients with EPP. A sustained-release subcutaneous implant of 20 mg afamelanotide was administered twice, with a 60-day interval to five EPP patients. Therapeutic efficacy was assessed by a photoprovocation test using standardized white light irradiation, melanin density (MD) determination and daily recording of sunlight exposure and symptoms. From Day 30 to Day 120 tolerance to photoprovocation significantly increased compared with baseline (P = 0.007) and skin MD was significantly higher than that recorded at baseline (P = 0.004). Except for two low-grade pain episodes, patients recorded no phototoxic events past Day 4 of treatment. Tolerance to natural sunlight was up to 24 times longer than prior to therapy. The findings demonstrate beneficial effects of afamelanotide in patients with EPP. Due to the limited number of patients enrolled and the design being an open-label study, confirmation by a large-scale trial is required. [source] Inhibitory effects of Hoelen extract on melanogenesis in B16/F1 melanoma cellsPHYTOTHERAPY RESEARCH, Issue 9 2010Mun Seog Chang Abstract Melanin synthesis is regulated by melanogenic proteins, such as tyrosinase, tyrosinase-related protein 1 (TRP-1) and TRP-2. The effects of Hoelen extract on melanogenesis were investigated in B16Fl murine melanoma cells. Specifically, tyrosinase activity, cell viability and melanin content were assayed, and western blotting and RT-PCR for tyrosinase, TRP-1 and TRP-2 conducted. The results show that Hoelen significantly inhibited melanin synthesis through inhibition of TRP-2 expression, while it did not affect tyrosinase activity or its expression. Taken together, RT-PCR results showed that the depigmentation effect of Hoelen may be due to inhibition of TRP-2 gene transcription. These results suggest that Hoelen may be a useful inhibitor for the attenuation of melanogenesis and hyperpigmentation in skin cells. Copyright © 2010 John Wiley & Sons, Ltd. [source] Fifteen-year quest for microphthalmia-associated transcription factor target genesPIGMENT CELL & MELANOMA RESEARCH, Issue 1 2010Yann Cheli Summary Microphthalmia-associated transcription factor (MITF) was initially shown to play a key role in melanocyte differentiation through the direct transcriptional control of TYROSINASE, TYRP1 and DCT genes, encoding the three enzymes involved in melanin synthesis or melanogenesis. Sixteen years after the first description of MITF, more than 40 direct MITF target genes have been described. They play a key role in melanocyte, osteoclast and mast cell specific functions. Furthermore, several MITF target genes, e.g. BCL2, CDK2, CDKN1A, CDKN2A, MET and HIF1A, link MITF to general cellular processes such as growth or survival. In this review, we provide an overview of the MITF-regulated genes. We pay special attention to the MITF target genes in melanocytes and raise questions about target specificity. [source] Oculocutaneous albinism type 4: six novel mutations in the membrane-associated transporter protein gene and their phenotypesPIGMENT CELL & MELANOMA RESEARCH, Issue 5 2006Katsuhiko Inagaki Summary Oculocutaneous albinism type 4 (OCA4) is an autosomal recessive hypopigmentary disorder caused by mutations in the Membrane-Associated Transporter Protein gene (SLC45A2). The SLC45A2 protein is a 530-amino-acid polypeptide that contains 12 putative transmembrane domains, and appears to be a transporter that mediates melanin synthesis. Eighteen pathological mutations have been reported so far. In this study, six novel mutations, p.Y49C (c.146A > G), p.G89R (c.265G > A), p.C229Y (c.686G > A), p.T437A (c.1309A > G), p.T440A (c.1318A > G) and p.G473D (c.1418G > A) were found in eight Japanese patients with various clinical phenotypes. The phenotypes of OCA4 were as various as the other types of OCA and probably depended on the mutation sites in the SLC45A2 gene. [source] Down-Regulation of Melanin Synthesis by a Biphenyl Derivative and Its MechanismPIGMENT CELL & MELANOMA RESEARCH, Issue 5 2003Kyoko Nakamura Down-regulation of melanin synthesis is required for recovery of pigmentary disorders and it is known that direct inhibitors of tyrosinase, the key enzyme in melanin synthesis, such as hydroquinone with a phenol structure, suppress melanin synthesis. We screened several phenolic derivatives using B16 melanoma cells and found that a biphenyl derivative, 2,2,-dihydroxy-5,5,-dipropyl-biphenyl (DDB), down-regulated melanin synthesis effectively. Although DDB has a phenol structure, it did not inhibit tyrosinase in vitro, thus we examined its mechanism in detail. Western blotting revealed that the amount of tyrosinase was decreased by DDB, and pulse-chase labeling and immunoprecipitation analysis showed a decrease of mature tyrosinase and acceleration of tyrosinase degradation in its presence. These results suggest that DDB down-regulates melanin synthesis by inhibiting the maturation of tyrosinase, leading to acceleration of tyrosinase degradation. [source] Variation of the melanocortin 1 receptor gene in the macaquesAMERICAN JOURNAL OF PRIMATOLOGY, Issue 8 2008Kazuhiro Nakayama Abstract Melanocortin 1 receptor (MC1R), a G-coupled seven-transmembrane receptor protein, plays a key role in the regulation of melanin synthesis in mammals. Sequence variation of the MC1R gene (MC1R) has been associated with pigmentation phenotypes in humans and in several animal species. The macaques (genus Macaca) are known to show a marked inter-specific variation in coat color although the causative genetic variation remains unclear. We investigated nucleotide sequences of the MC1R in 67 individuals of 18 macaque species with different coat color phenotypes including black and agouti. Twenty-eight amino acid replacements were identified in the macaques, but none of these amino acid replacements could explain the black coat color of Macaca silenus and the Sulawesi macaque species. Our molecular evolutionary analysis has revealed that nonsynonymous substitution/synonymous substitution (dN/dS) ratio of the MC1R has not been uniform in the macaque groups and, moreover, their coat color and dN/dS ratio were not related. These results suggest that the MC1R is unlikely to be responsible for the coat color variation of the macaques and functions of MC1R other than pigmentation might be associated with the different selective pressures on the MC1R in macaques. Am. J. Primatol. 70:778,785, 2008. © 2008 Wiley-Liss, Inc. [source] Mechanism of tyrosinase inhibition by deoxyArbutin and its second-generation derivativesBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2008S. Chawla Summary Background, Disorders, such as age spots, melasma and hyperpigmentation at sites of actinic damage, emanate from the augmentation of an increased amount of epidermal melanin. Objectives, The ineptness of current therapies in treating these conditions, as well as high cytotoxicity, mutagenicity, poor skin penetration and low stability of skin-depigmenting formulations led us to investigate new compounds that meet the medical requirements for depigmentation agents. We have shown previously that the tyrosinase inhibitor deoxyArbutin (dA) is a more effective and less toxic skin lightener than hydroquinone (HQ). Methods, The efficacy and reversibility of dA and its derivatives on inhibiting tyrosine hydroxylase and DOPAoxidase was assessed using standard assays. Results, dA and its second-generation derivatives inhibit tyrosine hydroxylase and DOPAoxidase activities of tyrosinase dose dependently thereby inhibiting melanin synthesis in intact melanocytes, when used at concentrations that retain 95% cell viability in culture. This depigmenting effect was completely reversible when the compounds were removed. Tyrosinase inhibition was also observed in vitro when tested using human and purified mushroom tyrosinase, establishing that they are direct enzyme inhibitors. Lineweaver,Burk reciprocal plot analysis using mushroom tyrosinase illustrated that dA and its derivatives are more robust competitive inhibitors than HQ, when tyrosine is used as substrate. Conclusions, Thus, dA and its second-generation derivatives, which inhibit melanogenesis at safe concentrations by specifically acting on the tyrosinase enzyme at a post-translational level, are promising agents to ameliorate hyperpigmented lesions or lighten skin. [source] Alterations in the epidermal,dermal melanin axis and factor XIIIa melanophages in senile lentigo and ageing skinBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2006N. Ünver Summary Background, Senile lentigo (SL) is a pigmentation disorder that occurs predominantly on the dorsa of the hands, the forearms and the face; its incidence increases with age. Histological hallmarks of SL lesions are hyperpigmentation of the epidermis and elongation of the epidermal rete ridges. Various factors such as , -melanocyte-stimulating hormone, endothelin-1 or stem cell factor are involved in the onset and maintenance of the increased pigmentation. Alterations of the dermal compartment have not yet been analysed in detail in SL. Objectives, To study the occurrence and distribution of melanin in the dermis from SL and aged skin, biopsies from 12 subjects were morphologically analysed by light and electron microscopy in comparison with unaffected skin. Methods, Punch biopsies of SL and adjacent skin from 12 male or female volunteers aged 52,81 years were prepared for light and electron microscopy and samples were analysed by morphological, morphometric, histochemical and immunohistochemical methods. Results, The epidermis from SL revealed morphological features such as hyperpigmentation of basal keratinocytes and the formation of elongated rete ridges. S100+ melanocytes in the stratum basale were not markedly increased, indicating that the hyperpigmentation is predominantly due to changes in melanin synthesis, distribution or turnover. Quantification of epidermal cells expressing the proliferation marker Ki67 did not show an increase of this parameter in SL, indicating that at least in the established lesion cell proliferation is not enhanced. We further focused on the dermal compartment and observed granulated cells which were more abundant in SL. Electron microscopic and histochemical analysis revealed that the granulation of these cells is based on melanosomes, mostly present in large melanosomal complexes. Immunohistochemistry using antibodies to CD68 and factor XIIIa (FXIIIa) showed these melanophages to be predominantly FXIIIa+ dermal dendrocytes, which were about six times more abundant than CD68+ macrophages. Conclusions, In SL an increased number of melanophages was found compared with unaffected skin from the same subject. These melanophages were identified as FXIIIa+ dermal dendrocytes. Possible functional consequences of the massive melanin uptake by dermal dendrocytes are discussed. [source] | |||||||||||||