Melanogenesis In Epidermal Melanocytes Research Articles

The mucin protein MUCL1 regulates melanogenesis and melanoma genes in a manner dependent on threonine content.

SummaryBackgroundThe regulation of melanogenesis has been investigated as a long‐held aim for pharmaceutical manipulations with denotations for malignancy of melanoma. Mucins have a protective function in epithelial organs; however, in the most outer organ, the skin, the role of mucins has not been studied enough.ObjectivesOur initial hypothesis developed from the identification of correlations between pigmentation and expressions of skin mucins, particularly those existing in skin tissue. We aimed to investigate the action of mucins in human melanocytic cells.Materials and methodsThe expression of mucin proteins in human skin was investigated using microarray data from the Human Protein Atlas consortium (HPA) and the Genotype‐Tissue Expression consortium (GTEx) database. Mucin expression was measured at RNA and protein levels in melanoma cells. The findings were further validated and confirmed by analysis of independent experiments.ResultsWe found that the several mucin proteins showed expression in human skin cells and among these, mucin‐like protein 1 (MUCL1) showed the highest expression and also clear negative correlation with melanogenesis in epidermal melanocytes. We confirmed the correlations between melanogenesis and MUCL1 by revealing negative correlations in melanocytes with different melanin production, resulting from increased composition of threonine, mucin‐conforming amino acid, and increased autophagy‐related forkhead‐box O signalling. Furthermore, threonine itself affects melanogenesis and metastatic activity in melanoma cells.ConclusionsWe identified a significant association between MUCL1 and threonine with melanogenesis and metastasis‐related genes in melanoma cells. Our results define a novel mechanism of mucin regulation, suggesting diagnostic and preventive roles of MUCL1 in cutaneous melanoma.

Major approaches of molecular and physiopathological mechanisms for hormonal treatment of melasma: a systematic review

Introduction: Epidemiological data showed that melasma occurs in 14.5% -56% of pregnant women and in 11.3% -46% of individuals who take oral contraceptives in different countries. In this respect, by inducing the synthesis of melanogenic enzymes, such as tyrosinase and proteins related to tyrosinase 1 and 2, estrogens stimulate melanogenesis in human melanocytes. The increase in progesterone levels that occurs during pregnancy and the increase in estrogen production that occurs from the eighth to the thirtieth week of pregnancy reflects the progression of hyperpigmentation. Objective: The main predictors, pathophysiological mechanisms, and experimental and clinical results of melasma were addressed through a systematic literature review, discussing the main outcomes of clinical studies. Methods: The present study followed a systematic review model. After literary search criteria using MeSH Terms, a total of 98 clinical studies were compared and submitted to eligibility analysis and, after that, 70 studies were selected, following the rules of PRISMA. The search strategy was carried out in the databases PubMed, Embase, Ovid and Cochrane Library, Web Of Science, ScienceDirect Journals (Elsevier), Scopus (Elsevier), OneFile. Results: Sex hormones, such as estrogens, especially 17-β-estradiol (E2) and progesterone, are factors involved in the regulation of pigmentation. Levels of estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were found to be higher in the serum of women with melasma. Estrogen and progesterone receptors are expressed differently in melasma skin than in perilesional or non-lesional skin. Few authors have analyzed the effects of progesterone on pigmentation, and no data has been reported with concentrations of progesterone found in non-pregnant men and women. An increase in keratinocyte proliferation was observed with baseline progesterone concentrations. It is well known that keratinocytes secrete exosomes and factors that regulate melanogenesis, differentiation, and proliferation of melanocytes. Progesterone is involved in the pathogenesis of melasma, stimulating melanogenesis in epidermal melanocytes. Conclusion: The prevention of melasma can occur by progesterone components in oral contraceptives since progesterone can reduce melanocyte proliferation without significant effects on tyrosine activity. Estrogen can increase melanogenesis in the melanocyte monolayer and induce the production of melanogenic factors by keratinocytes. Estrogen can support hyperpigmentation, increasing the number of blood vessels and, thus, stimulating the secretion of endothelin-1.

Inhibitory effect of a novel combination of Salvia hispanica (chia) seed and Punica granatum (pomegranate) fruit extracts on melanin production

In recent years, dietary fatty acids have been extensively evaluated for nutritional as well as cosmetic benefits. Among the dietary fats, the omega-3 (ω3) and omega-6 (ω6) forms of polyunsaturated fatty acids (PUFAs) have been found to exhibit many biological functions in the skin such as prevention of transepidermal water loss, maintenance of the stratum corneum epidermal barrier, and disruption of melanogenesis in epidermal melanocytes. In this study, we examined the effect of chia seed extract, high in ω3 (linolenic acid) and ω6 (linoleic acid) PUFAs, for its capacity to affect melanogenesis. Chia seed extract was shown to inhibit melanin biosynthesis in Melan-a cells; however, linoleic and α-linolenic acids alone did not effectively reduce melanin content. Further investigation demonstrated that chia seed extract in combination with pomegranate fruit extract had a synergistic effect on the inhibition of melanin biosynthesis with no corresponding effect on tyrosinase activity. Investigation of the possible mechanism of action revealed that chia seed extract downregulated expression of melanogenesis-related genes (Tyr, Tyrp1, and Mc1r), alone and in combination with pomegranate fruit extract, suggesting that the inhibition of melanin biosynthesis by a novel combination of chia seed and pomegranate fruit extracts is possibly due to the downregulation of gene expression of key melanogenic enzymes.

What Should Be Considered in Treatment of Melasma

Melasma is a common acquired hyperpigmentary skin disorder characterized by light to dark brown macules and patches occurring in the sun-exposed areas of the face. Melasma lesional skin is characterized by epidermal hyperpigmentation through increased melanogenesis in epidermal melanocytes. Some patients have dermal melanin but its amount is not significant and its distribution is very heterogeneous in the whole melasma lesional skin. Melasma is not homogeneous disease and there are personal characteristics of patients with melasma. The pathogenesis of melasma is not fully understood, but several hypotheses have been suggested. Increased vascularity in melasma lesions has suggested the role of increased number of enlarged vessels in the development of melasma. Endogeneous and exogeneous stimuli such as sex hormones and ultraviolet irradiation respectively may stimulate the microenvironment leading to the release of various mediators that cause activation of melanocytes and/or these stimuli may directly activate the melanocytes. Melasma patients may have specialized melanocytes with an intrinsic sensitivity to these stimuli.

Association of COX2 functional polymorphisms and the risk of vitiligo in Chinese populations

Background Cyclooxygenase-2 (COX2) plays an important role in the production of prostaglandin E2 (PGE2), which is made by epidermal keratinocytes in response to ultraviolet radiation (UVR). PGE2 is important for the proliferation and melanogenesis of epidermal melanocytes, the loss of which leads to vitiligo. COX2-1195A > G, -765G > C, and -8473T > C polymorphisms may influence the mRNA levels of COX2 and affect the production of PGE2 subsequently. Therefore, we supposed that these polymorphisms may be associated with vitiligo. Objective The aim of the study was to elucidate the association between three functional COX2 polymorphisms and the risk of vitiligo. Methods This was a hospital-based, case–control study of 755 vitiligo patients and 774 vitiligo-free controls who were frequency matched by age and sex. We genotyped COX2-1195A > G, -765G > C , and -8473T > C polymorphisms by using PCR-restriction fragment length polymorphism (RFLP) method and assessed their respective associations with the risk of vitiligo in Han Chinese populations. Results We found a statistically significant increased risk of vitiligo to be associated with the COX2-1195 G variant allele ( p = 0.004). Significantly higher vitiligo risks were found among subgroups with these characteristics: age >20 years, male, active, nonsegmental vitiligo, and onset age >20 years. In addition, the interaction between COX2-1195 and COX2- 8473 was statistically significant ( p = 0.004). Conclusion For the first time, we provide evidence that functional polymorphisms in the COX2 gene may influence the risk of vitiligo in Han Chinese populations, suggesting new clues that help to clarify the pathogenesis of vitiligo. Larger studies are needed to verify these findings.

Effect of pituitary and ovarian hormones on human melanocytes in vitro.

Normal human melanocytes in culture became enlarged and dendritic after a 2-day incubation with either the pituitary (beta-MSH, a potent analog of alpha-MSH, ACTH, FSH and LH) or the ovarian (estradiol, estriol and progesterone) hormones. Under the same experimental conditions, pituitary hormones also increased both the tyrosinase activity and tyrosinase-related protein-1 (TRP-1) while ovarian hormones increased TRP-1 but not tyrosinase activity. The results suggest that pituitary and ovarian hormones possibly induce hyperpigmentation of the skin by stimulating the melanogenesis in epidermal melanocytes, and that estradiol and progesterone may be involved in the pathogenesis of melasma (chloasma) usually developing between early adulthood and menopause in which a high concentration of serum ovarian hormones was maintained.

Ultraviolet radiation-induced melanogenesis in human melanocytes. Effects of modulating protein kinase C.

The mechanism by which ultraviolet radiation induces melanogenesis in epidermal melanocytes is unknown. Previous observations that in cultured human melanocytes 1-oleoyl-2-acetylglycerol augmented both basal and ultraviolet radiation-induced melanogenesis, suggested that the responses were mediated via protein kinase C. However, paradoxically the phorbol ester TPA was without effect. Therefore, the present study has examined the involvement of protein kinase C in melanogenesis. Analysis of the isozyme profile of human melanocytes revealed the presence of protein kinase C alpha, beta I, epsilon and zeta but not the isozyme eta. Following exposure to 500 nM TPA for 24 hours, isozymes alpha, beta I and epsilon were downregulated, but zeta was unaffected. Similar isozyme profiles were observed in S91 and SKMEL3 melanoma cells. The melanogenic responses to 1-oleoyl-2-acetylglycerol and ultraviolet radiation were unaffected by inhibition of protein kinase C with Ro31-8220, or ablation by downregulation with 500 nM TPA, in human melanocytes and melanoma cells. 1-Oleoyl-2-acetylglycerol had no effect on protein kinase C activity in human melanocytes, as measured by rapid phosphorylation of the 80 kDa protein myristoylated alanine-rich C kinase substrate (MARCKS). Ultraviolet radiation induced a small increase in MARCKS protein phosphorylation but this effect was inhibited by pretreatment for 24 hours with 500 nM TPA, which had no effect on ultraviolet-induced melanogenesis. Overall, these findings indicate that 1-oleoyl-2-acetylglycerol and ultraviolet radiation activate melanogenesis via protein kinase C-independent pathways.