Melanocortin 1 Receptor Research Articles

33323 Dersimelagon, a melanocortin-1 receptor agonist, maintains efficacy regardless of seasons in subjects with erythropoietic protoporphyria: Results from a post hoc analysis of phase 2 clinical trial data

Background: Dersimelagon, a novel synthetic, orally administered, selective melanocortin-1 receptor agonist, has demonstrated the potential to increase pain-free light exposure in subjects with the rare genetic phototoxicities erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). This post hoc analysis aimed to evaluate the efficacy of dersimelagon across seasons and geographic regions.

34420 Perspective of patients with erythropoietic protoporphyria treated with dersimelagon, a selective melanocortin-1 receptor agonist: Results of the ENDEAVOR study exit questionnaire

Background: Erythropoietic protoporphyria (EPP) imposes a significant burden on the quality of life (QoL) of patients. Dersimelagon, a novel synthetic, orally administered, selective melanocortin-1 receptor agonist, has demonstrated statistically and clinically significant improvement from baseline in average daily time to first prodromal symptoms in a phase 2 clinical trial. Methods: ENDEAVOR was a multicenter, phase 2, randomized double-blind, placebo-controlled study with a 16-week treatment and 6-week follow-up period. Here we report the results of a post hoc analysis assessing the clinical benefit of dersimelagon treatment and patient perspective of QoL using an online exit questionnaire composed of 28 close-ended questions completed after week 22 visit or post study completion. Participants rated their perceived change since the start of the study. Results: Of 102 participants, 75 (placebo, n = 24; dersimelagon, 100 mg, n = 28, 300 mg n = 23) completed the questionnaire. More recipients of dersimelagon (100 mg, 57.6%; 300 mg 31.4%) rated their EPP as “very much better” than placebo group participants (5.9%). They were also “much more often” (100 mg, 69.7%; 300 mg 48.6%) able to be outside at the end of the study than patients in the placebo group (8.8%). More participants who received dersimelagon (100 mg, 72.7%; 300 mg 62.9%) reported being “very satisfied” with the study drug vs placebo recipients (14.7%). Conclusions: A greater proportion of patients who received dersimelagon reported improvements in their EPP and associated disease impacts than placebo group participants. The findings from the exit questionnaire support the results from the primary analysis and the potential use of dersimelagon for treatment of patients with EPP.

Genes affecting coat colour and the resulting variation in horses (Equus caballus) – A Review

Horse colour is important. People chose horses for their colour pattern diversity, according to archaeological investigations and biological evidence. Horses were generally dark coloured before domestication, according to molecular testing. After domestication, the genes for white patterns and dilutions appeared. The appearance of their horses, as well as their competence and willingness to work, must have been important to early people. In many cases, the genes that impact coat colour patterns in one species also influence coat colour patterns in another. In horses, humans, cattle, dogs, and other species, the MC1R gene encodes the alleles for red and black of the Extension locus. White spotting is caused by mutations in the KIT gene in horses (tobiano, roan, sabino, dominant white), mice, and humans. Because of its similarity to a white hair gene seen in humans with Hirschprung's illness, the gene for overo in horses was discovered. The genes that impact coat colour patterns in one species generally play a similar role in another, according to molecular studies. It came as no surprise. Earlier geneticists claimed that coat colours in horses were caused by the action of genes similar to those observed in other species based solely on phenotype. This is a crucial lesson for genetic studies: we can apply what we have learned from other species to our own. All in all, the study of coat colour variations in the horse is a study of the horse's nature.

Implication of Melanocortin Receptor Genes in the Familial Comorbidity of Type 2 Diabetes and Depression.

The melanocortin receptors are G-protein-coupled receptors, which are essential components of the hypothalamic–pituitary–adrenal axis, and they mediate the actions of melanocortins (melanocyte-stimulating hormones: α-MSH, β-MSH, and γ-MSH) as well as the adrenocorticotropin hormone (ACTH) in skin pigmentation, adrenal steroidogenesis, and stress response. Three melanocortin receptor genes (MC1R, MC2R, and MC5R) contribute to the risk of major depressive disorder (MDD), and one melanocortin receptor gene (MC4R) contributes to the risk of type 2 diabetes (T2D). MDD increases T2D risk in drug-naïve patients; thus, MDD and T2D commonly coexist. The five melanocortin receptor genes might confer risk for both disorders. However, they have never been investigated jointly to evaluate their potential contributing roles in the MDD-T2D comorbidity, specifically within families. In 212 Italian families with T2D and MDD, we tested 11 single nucleotide polymorphisms (SNPs) in the MC1R gene, 9 SNPs in MC2R, 3 SNPs in MC3R, 4 SNPs in MC4R, and 2 SNPs in MC5R. The testing used 2-point parametric linkage and linkage disequilibrium (LD) (i.e., association) analysis with four models (dominant with complete penetrance (D1), dominant with incomplete penetrance (D2), recessive with complete penetrance (R1), and recessive with incomplete penetrance (R2)). We detected significant (p ≤ 0.05) linkage and/or LD (i.e., association) to/with MDD for one SNP in MC2R (rs111734014) and one SNP in MC5R (rs2236700), and to/with T2D for three SNPs in MC1R (rs1805007 and rs201192930, and rs2228479), one SNP in MC2R (rs104894660), two SNPs in MC3R (rs3746619 and rs3827103), and one SNP in MC4R genes (Chr18-60372302). The linkage/LD/association was significant across different linkage patterns and different modes of inheritance. All reported variants are novel in MDD and T2D. This is the first study to report risk variants in MC1R, MC2R, and MC3R genes in T2D. MC2R and MC5R genes are replicated in MDD, with one novel variant each. Within our dataset, only the MC2R gene appears to confer risk for both MDD and T2D, albeit with different risk variants. To further clarity the role of the melanocortin receptor genes in MDD-T2D, these findings should be sought among other ethnicities as well.

Editing MC1R in human melanoma cells by CRISPR/Cas9 and functional analysis.

MC1R (melanocortin 1 receptor) encodes the melanocortin-1 receptor, which can activate intracellular cAMP synthesis under the stimulation of the α-melanocyte stimulating hormone (α-MSH) ligand. Increased cAMP then activates the protein kinase A (PKA) pathway, resulting in the up-regulation of the expression of the microphthalmia-associated transcription factor (MITF) which is a critical regulatory factor of melanin synthesis, and tyrosinase (TYR), the rate-limiting enzyme of melanin synthesis tyrosinase (TYR), and ultimately affects production of eumelanin and pheomelanin, and the coat color phenotype of mammalian species. Previous reports have indicated that the mutation A243T in the transmembrane domain 6 (TM6) of MC1R protein might disrupt the function of MC1R, contributing to the red phenotype in Duroc pig. However, functional analysis of the A243T mutation in MC1R has not yet been carried out. In this study, we attempted to used single-stranded oligo-deoxyribonucleotides (ssODN) as donor templates to introduce the c.727G>A (A243T) mutation into MC1R in human melanoma cell line SK-MEL-2 by CRISPR/Cas9 to analyze its effects on MC1R functions. We found the occurrence of ssODN recombination reached to 10%. Unfortunately, Sanger sequencing MC1R in six single-cell clones revealed that none carried the c.727G>A mutation, but all carried undesired mutations surrounding the target site. Cells transfected with CRISPR/Cas9 plasmids and ssODN presented significantly attenuated cAMP activation, and down-regulated MITF and TYR expression, indicating that the editing MC1R could affect the melanin synthesis function in cells. This study provides a basis for further investigation the mechanism of MC1R mutation on animal coat color.

Pharmacological Modulation of Melanocortin 1 Receptor Signaling by Mrap Proteins in Xenopus tropicalis.

The melanocortin system consists of five G protein–coupled receptors (MC1R-MC5R), the bidirectional endogenous ligands (MSH and Agouti families), and accessory proteins (MRAP1 and MRAP2). Accumulative studies of vertebrate species find high expression level of melanocortin 1 receptor (MC1R) in the dermal melanocyte and elucidate the essential roles in the skin and fur pigmentation, morphological background adaptation, and stress response. The diploid amphibian Xenopus tropicalis (xt) has been utilized as a fantastic animal model for embryonic development and studies of physiological cryptic colouring and environmental adaptiveness. However, the interaction of xtMc1r signaling with xtMrap proteins has not been assessed yet. In this study, we carried out in silico evolutionary analysis of protein alignment and genetic phylogenetic and genomic synteny of mc1r among various vertebrates. Ubiquitous expression of mrap1 and mrap2 and the co-expression with mc1r transcripts in the skin were clearly observed. Co-immunoprecipitation (ip) and fluorescent complementary approach validated the direct functional interaction of xtMc1r with xtMrap1 or xtMrap2 proteins on the plasma membrane. Pharmacological assay showed the improvement of the constitutive activity and alpha melanocyte-stimulating hormone (α-MSH) stimulated plateau without dramatic alteration of the cell surface translocation of xtMc1r in the presence of xtMrap proteins. Overall, the pharmacological modulation of xtMc1r by dual xtMrap2 proteins elucidated the potential role of this protein complex in the regulation of proper dermal function in amphibian species.

Melanocortin‐1 receptor influence in equine opioid sensitivity

SummaryIndividual variation in opioid sensitivity can have a profound impact on the safety and efficacy of equine veterinary treatments, with the ability to adequately manage equine pain in a clinical setting currently limited. This review aims to explore the overlap between biological mechanisms associated with opioid metabolism and those mechanisms associated with coat colour in horses as has been documented in humans, with particular focus on the melanocortin‐1 receptor (MC1R) gene. In the future, the use of the MC1R coat colour genotype could help to indicate variable opioid sensitivities thereby greatly improving the use of opioids in clinical settings. The MC1R gene has a well‐established role in melanogenesis and pigment switching, but involvement in the pain‐modulating periaqueductal grey (PAG) descending pathway and in immune responses, both of which contain opioid receptors, has also been suggested in humans. However, this relationship between opioid metabolism and the connection to the three known MC1R variants (EE, Ee and Eea) in horses is yet to be explored.

Density-dependent selection and the maintenance of colour polymorphism in barn owls.

The capacity of natural selection to generate adaptive changes is (according to the fundamental theorem of natural selection) proportional to the additive genetic variance in fitness. In spite of its importance for development of new adaptations to a changing environment, processes affecting the magnitude of the genetic variance in fitness-related traits are poorly understood. Here, we show that the red-white colour polymorphism in female barn owls is subject to density-dependent selection at the phenotypic and genotypic level. The diallelic melanocortin-1 receptor gene explained a large amount of the phenotypic variance in reddish coloration in the females ([Formula: see text]). Red individuals (RR genotype) were selected for at low densities, while white individuals (WW genotype) were favoured at high densities and were less sensitive to changes in density. We show that this density-dependent selection favours white individuals and predicts fixation of the white allele in this population at longer time scales without immigration or other selective forces. Still, fluctuating population density will cause selection to fluctuate and periodically favour red individuals. These results suggest how balancing selection caused by fluctuations in population density can be a general mechanism affecting the level of additive genetic variance in natural populations.

Role of Phytochemicals in Skin Photoprotection via Regulation of Nrf2

Ethnopharmacological studies have become increasingly valuable in the development of botanical products and their bioactive phytochemicals as novel and effective preventive and therapeutic strategies for various diseases including skin photoaging and photodamage-related skin problems including abnormal pigmentation and inflammation. Exploring the roles of phytochemicals in mitigating ultraviolet radiation (UVR)-induced skin damage is thus of importance to offer insights into medicinal and ethnopharmacological potential for development of novel and effective photoprotective agents. UVR plays a role in the skin premature aging (or photoaging) or impaired skin integrity and function through triggering various biological responses of skin cells including apoptosis, oxidative stress, DNA damage and inflammation. In addition, melanin produced by epidermal melanocytes play a protective role against UVR-induced skin damage and therefore hyperpigmentation mediated by UV irradiation could reflect a sign of defensive response of the skin to stress. However, alteration in melanin synthesis may be implicated in skin damage, particularly in individuals with fair skin. Oxidative stress induced by UVR contributes to the process of skin aging and inflammation through the activation of related signaling pathways such as the mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1), the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), the nuclear factor kappa B (NF-κB) and the signal transducer and activator of transcription (STAT) in epidermal keratinocytes and dermal fibroblasts. ROS formation induced by UVR also plays a role in regulation of melanogenesis in melanocytes via modulating MAPK, PI3K/Akt and the melanocortin 1 receptor (MC1R)-microphthalmia-associated transcription factor (MITF) signaling cascades. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidant defenses can affect the major signaling pathways involved in regulation of photoaging, inflammation associated with skin barrier dysfunction and melanogenesis. This review thus highlights the roles of phytochemicals potentially acting as Nrf2 inducers in improving photoaging, inflammation and hyperpigmentation via regulation of cellular homeostasis involved in skin integrity and function. Taken together, understanding the role of phytochemicals targeting Nrf2 in photoprotection could provide an insight into potential development of natural products as a promising strategy to delay skin photoaging and improve skin conditions.

Functional divergence of the pigmentation gene melanocortin-1 receptor (MC1R) in six endemic Macaca species on Sulawesi Island

Coat color is often highly variable within and between animal taxa. Among hundreds of pigmentation-related genes, melanocortin-1 receptor (MC1R) plays key roles in regulating the synthesis of the dark eumelanin and the red–yellow pheomelanin. The six species of macaques that inhabit Sulawesi Island diverged rapidly from their common ancestor, M. nemestrina. Unlike most macaques, Sulawesi macaques commonly have a dark coat color, with divergence in shade and color pattern. To clarify the genetic and evolutionary basis for coat color in Sulawesi macaques, we investigated the MC1R sequences and functional properties, including basal cAMP production and α-MSH-induced activity in vitro. We found fixed non-synonymous substitutions in MC1R in each species. Furthermore, we found that six species-specific variants corresponded with variation in agonist-induced and basal activity of MC1R. Inconsistent with the dark coat color, four substitutions independently caused decreases in the basal activity of MC1R in M. hecki, M. nigra, M. tonkeana, and M. ochreata. Selective analysis suggested MC1R of M. nigra and M. nigrescens underwent purifying selection. Overall, our results suggest that fixed differences in MC1R resulted in different functional characteristics and might contribute to divergence in color among the six Sulawesi macaque species.

Selection signatures in melanocortin-1 receptor gene of turkeys (Meleagris gallopavo) raised in hot humid tropics.

Feather colours are used by avian species for defense, adaptation and signaling. Melanocortin-1 receptor (MC1R) gene is one of the genes responsible for feather colour. This study identified selection signatures in MC1R gene of Nigerian indigenous turkeys (NIT) using British United turkeys (BUT) as control breed to investigate the evolutionary processes that have shaped NIT with various feather colours. Complete MC1R gene of 146 NIT (76 males and 70 females) and 32 BUT (18 males and 14 females) were sequenced. Transition/transversion and codon usage biases were predicted using MEGA v6 software. The selective force acting on the gene was predicted using HyPhy software. The FST values were estimated using Arlequin v3.5. The highest transition/transversion bias was predicted for white BUT (1.00) while the lowest was predicted for black NIT (0.50). Negative dN-dS values, indicative of purifying selection, were observed in MC1R gene of all the turkeys. The highest pairwise FST was observed between the MC1R gene of white BUT and black NIT while the least was observed between lavender NIT and white NIT. No recombination event was observed in black NIT and white BUT. The relative synonymous codon usage was the same among different colours for some codons. Presence of purifying selection in MC1R gene of all the turkeys with different feather colours confirms that the gene plays role in many biological processes such as feather colouration, behaviour, pain perception, immunity, growth and adaptation. The results also suggested that the genetic mechanisms generating different feather colours in turkeys are conserved.

Retention and Evaluation of Precision and Generic Prevention Materials for Melanoma: A Qualitative Study Comparing Young Adults and Adults.

It is important to evaluate information within groups defined by periods of the life trajectory, e.g., AYA and adults, to best inform preferences, knowledge, and motivation for behavior change. By assessing retention, evidence-based interventions can be designed to better support public health messaging and encourage positive health behaviors.

Expression of Coat Colour Gene, MC1R in Cattle

Background: Scanty reports are available in the literature about the coat colour inheritance and its related genes in cattle. Therefore, an experiment was conducted to know the expression of coat colour gene, MC1R in cattle. Methods: DNA was extracted from 85 whole blood samples of Red Chittagong cattle (RCC), Non-descriptive deshi and their crossbred of which 75 positive samples were sequenced by Sanger sequencer. Sequence alignment, pair and multi-alignment comparison of the MC1R gene of different genotype and a phylogenic tree constructed by MEGA6 software. Result: RCC has a dominant R gene for red colour. Point mutation was observed at 954 bp and substitution (395G→A) was found in the MC1R gene of RCC genotype. The evolutionary history of branching pattern showed the relatedness of MC1R nucleotide sequences of cattle and this gene have been regulating coat colour inheritance of cattle.

Novel 64Cu-Labeled NOTA-Conjugated Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptides with Enhanced Tumor to Kidney Uptake Ratios.

The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of 64Cu-NOTA-PEG2Nle-CycMSHhex {64Cu-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and 64Cu-NOTA-AocNle-CycMSHhex {64Cu-NOTA-8-aminooctanoic acid-Nle-CycMSHhex} on melanoma-bearing mice. NOTA-PEG2Nle-CycMSHhex and NOTA-AocNle-CycMSHhex were synthesized and purified by HPLC. The melanocortin-1 (MC1) receptor binding affinities of the peptides were examined on B16/F10 melanoma cells. The biodistributions of 64Cu-NOTA-PEG2Nle-CycMSHhex and 64Cu-NOTA-AocNle-CycMSHhex were determined on B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of 64Cu-NOTA-PEG2Nle-CycMSHhex was further examined on B16/F10 melanoma-bearing C57 mice because of its higher melanoma uptake than 64Cu-NOTA-AocNle-CycMSHhex. The IC50 values of NOTA-PEG2Nle-CycMSHhex and NOTA-AocNle-CycMSHhex were 1.24 ± 0.07 and 2.75 ± 0.48 nM on B10/F10 melanoma cells. 64Cu-NOTA-PEG2Nle-CycMSHhex and 64Cu-NOTA-AocNle-CycMSHhex were readily prepared with more than 90% radiolabeling yields and showed MC1R-specific binding on B16/F10 cells. 64Cu-NOTA-PEG2Nle-CycMSHhex exhibited higher tumor uptake than 64Cu-NOTA-AocNle-CycMSHhex at 0.5, 2, 4, and 24 h post-injection. The tumor uptake of 64Cu-NOTA-PEG2Nle-CycMSHhex was 16.23 ± 0.42, 19.59 ± 1.48, 12.83 ± 1.69, and 8.78 ± 2.29% ID/g at 0.5, 2, 4, and 24 h post-injection, respectively. Normal organ uptake of 64Cu-NOTA-PEG2Nle-CycMSHhex was lower than 2% ID/g at 2 h post-injection except for kidney uptake. The renal uptake of 64Cu-NOTA-PEG2Nle-CycMSHhex was 3.66 ± 0.52, 3.27 ± 0.52, and 1.47 ± 0.56 ID/g at 2, 4, and 24 h post-injection, respectively. 64Cu-NOTA-PEG2Nle-CycMSHhex showed high tumor to normal organ uptake ratios after 2 h post-injection. The B16/F10 melanoma lesions could be clearly visualized by positron emission tomography (PET) using 64Cu-NOTA-PEG2Nle-CycMSHhex as an imaging probe at 2 h post-injection. High tumor uptake and low kidney uptake of 64Cu-NOTA-PEG2Nle-CycMSHhex underscored its potential as an MC1R-targeted theranostic peptide for melanoma imaging and therapy.

Novel Al18F-NOTA-Conjugated Lactam-Cyclized α-Melanocyte-Stimulating Hormone Peptides with Enhanced Melanoma Uptake.

The purpose of this study was to evaluate the effect of linker on tumor targeting and biodistribution of Al18F-NOTA-PEG2Nle-CycMSHhex {Al18F-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-poly(ethylene glycol)-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and Al18F-NOTA-AocNle-CycMSHhex {Al18F-NOTA-8-aminooctanoic acid-Nle-CycMSHhex} on melanoma-bearing mice. NOTA-PEG2Nle-CycMSHhex and NOTA-AocNle-CycMSHhex were synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry. The melanocortin-1 (MC1) receptor binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of Al18F-NOTA-PEG2Nle-CycMSHhex and Al18F-NOTA-AocNle-CycMSHhex was determined on B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of Al18F-NOTA-PEG2Nle-CycMSHhex was further examined on B16/F10 melanoma-bearing C57 mice because of its higher melanoma uptake and lower renal uptake than that of Al18F-NOTA-AocNle-CycMSHhex. The IC50 values of NOTA-PEG2/AocNle-CycMSHhex were 1.24 ± 0.07 and 2.75 ± 0.48 nM on B10/F10 cells. Al18F-NOTA-PEG2Nle-CycMSHhex and Al18F-NOTA-AocNle-CycMSHhex were readily prepared with more than 55% of radiolabeling yields and displayed melanocortin-1 receptor (MC1R)-specific binding on B16/F10 cells. Al18F-NOTA-PEG2Nle-CycMSHhex exhibited higher tumor uptake and lower kidney and liver uptake than Al18F-NOTA-AocNle-CycMSHhex at 1 and 2 h post injection. The tumor and renal uptakes of Al18F-NOTA-PEG2Nle-CycMSHhex were 17.44 ± 0.76 and 2.07 ± 0.43% ID/g at 1 h post injection, respectively. Al18F-NOTA-PEG2Nle-CycMSHhex showed the high tumor to normal organ uptake ratios after 1 h post injection. The B16/F10 melanoma lesions could be clearly visualized by positron emission tomography (PET) using Al18F-NOTA-PEG2Nle-CycMSHhex as an imaging probe at 1 and 2 h post injection. Overall, high tumor uptake, low kidney and liver uptake, and fast urinary clearance of Al18F-NOTA-PEG2Nle-CycMSHhex highlighted its potential as an MC1R-targeted imaging probe for melanoma detection.

Identification of two new recessive MC1R alleles in red-coloured Evolèner cattle and other breeds.

Sequence variations in the melanocortin‐1 receptor (MC1R) gene are associated with melanism in different animal species. Six functionally relevant alleles have been described in cattle to date. In a hypothesis‐free approach we performed a genome‐wide allelic association study with black, red and wild‐coloured cattle of three Alpine cattle breeds (Eringer, Evolèner and Valdostana), revealing a single significant association signal close to the MC1R gene. We searched for candidate causative variants by sequencing the entire coding sequence and identified two novel protein‐changing variants. We propose designating the mutant alleles at MC1R:c.424C>T as ev1 and at MC1R:c.263G>A as ev2 . Both affect conserved amino acid residues in functionally important transmembrane domains (p.Arg142Cys and p.Ser88Asn). Both alleles segregate predominantly in the Swiss Evolèner breed. They occur in other European cattle breeds such as Abondance and Rotes Höhenvieh as well. We observed almost perfect association between the MC1R genotypes and the coat colour phenotype in a cohort of 513 black, red and wild‐coloured cattle. Animals carrying two copies of MC1R loss‐of‐function alleles or that were compound heterozygous for e, ev1 , or ev2 have a red to dark red (chestnut‐like red) coat colour. These findings expand the spectrum of causal MC1R variants causing recessive red in cattle.

Genetic diversity of the melanocortin-1 receptor in an admixed population of Rio de Janeiro: Structural and functional impacts of Cys35Tyr variant.

The melanocortin-1 receptor (MC1R) is one of the key proteins involved in the regulation of melanin production and several polymorphisms have been associated with different phenotypes of skin and hair color in human and nonhuman species. Most of the knowledge is centered on more homogeneous populations and studies involving an admixed group of people should be encouraged due to the great importance of understanding the human color variation. This work evaluates the MC1R diversity and the possible impacts of MC1R variants in an admixed sample population of Rio de Janeiro, Brazil, which is a product of Native American, African, and European miscegenation. Sequencing of complete coding region and part of the 3´UTR of MC1R gene identified 31 variants including one insertion and three novel synonymous substitutions in sample population grouped according to skin, hair and eye pigmentation levels. In nonmetric multidimensional scaling analysis (NMDS), three main clusters were identified, in which the Brazilian dark skin group remained in the African cluster whereas the intermediate and the light skin color phenotype in the European one. None gathered with Asians since their immigration to Brazil was a recent event. In silico analyses demonstrated that Cys35Tyr, Ile155Thr and Pro256Ser, found in our population, have a negative effect on receptor function probably due to changes on the receptor structure. Notably, Cys35Tyr mutation could potentially impair agonist binding. Altogether, this work contributes to the understanding of the genetic background of color variation on an admixed population and gives insights into the damaging effects of MC1R variants.

Exploring the Role and Mechanism of Adipose Derived Mesenchymal Stem Cells on Reversal of Pigmentation Model Effects.

Interventions for extrinsic aging can be implemented, but these must address photoaging, which is the primary cause of extrinsic aging. Pigmentation due to photoaging depends on the duration and intensity of sun exposure. This study investigated the relationship between adipose-derived mesenchymal stem cells (ASCs) and photoaging pigmentation, and the underlying mechanism of action by establishing a photoaging pigmentation model using various treatments and exposure options in a guinea pigs. The energy dose of each UVB irradiation was 120 mJ/cm2 and the total dose of irradiation was 360 mJ/cm2. After successfully establishing the photoaging model, ASCs (1×106) in an balanced salt solution (0.9 ml), balanced salt solution (0.9 ml), and bFGF (9 μg) mixed with an balanced salt solution (0.9 ml) were injected intradermally in ten guinea pigs. ELISA, macroscopic skin and histological observations, and Masson-Fontana staining were done. At 2 and 4 weeks post-injection, noticeable changes were observed. Guinea pigs receiving ASCs injections displayed significantly lower visible skin scores while the melanin content continued to decrease. Somewhat improved histopathological morphology, including epidermal thinning, dermal thickening, and little inflammatory cell infiltration was observedimmediately after and up to 4 weeks of ASCs injection. Melanocortin 1 receptor (MC1R) and alpha-melanocyte test hormone (alpha-MSH) levels reduced significantly, and basic fibroblast growth factor (bFGF) levels increased significantly immediately after and up to 4 weeks of ASCs injection. The MC1R and alpha-MSH levels reduced significantly immediately after and up to 4 weeks of bFGF injection. Briefly, intradermal ASCs injection can notably eliminate pigmentation in a guinea pig photoaging pigmentation model. This may be related to the fact that bFGF secreted by ASCs lowers MC1R and alpha-MSH levels, blocks the cAMP signalling pathway, and inhibits melanin synthesis. This finding may present new options for treating photoaging pigmentation.Level of Evidence: N/A.

Defining novel causal SNPs and linked phenotypes at melanoma-associated loci.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher’s exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the melanocortin 1 receptor (MC1R) and tyrosinase (TYR) loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.

Expression of Melanocortin-1 Receptor and Serum Melanin in Canities at Young Male students

BACKGROUND: Molecular genetics suggest that hair pigmentation is related to the melanocortin-1 receptor gene. It is a G protein-coupled receptor, which is activated by a number of peptides to stimulate melanogenesis. Melanocortin-1 receptor gene mutation tends to produce functional variability in premature hair graying (PHG) or canities. AIM: Therefore, the objective of this study was to determine melanocortin-1 receptor expression and asses serum melanin in college students canities at Universitas Sumatera Utara. METHODS: This study was a cross-sectional design. We recruited 80 subjects equally divided into normal (control) and premature hair graying groups. The sample included males, aged 25 years who had gray hair and had no history of pigmentary disorders of the skin. Expression of melanocortin-1 receptor was detected with conventional PCR and serum melanin was measured with Elisa using Elisa kit melanin for human. RESULTS: The results showed that the Mean ± SD graying age was 20.28 ± 1.99 years with an age range of 19–24 years and the average age in the control group was 21.25 ± 2.02 years with an age range of 18–24 years. Melanocortin-1 receptor gene expression was shown in the control and PHG groups. Serum melanin levels were decreased significantly (p = 0.0001) in the gray-haired group was 9.27 ± 1.62 μg/dl and the control group was 10.72 ± 1.78 μg/dl. CONCLUSION: Melanocortin-1 receptor gene plays a role in hair graying at young age and there serum melanin levels were low significantly.