Regulation Of Melanin Synthesis Research Articles

Low-concentration imiquimod treatment promotes enhanced skin barrier functions through epidermal melanization reaction regulation.

The primary function of the skin is to form a mechanical, permeability, antimicrobial, and ultraviolet radiation barrier, which is essential for maintaining physiological homeostasis. Our previous studies demonstrated that cutaneous pigmentation could promote skin barrier function in addition to providing anti-ultraviolet irradiation defense. The present study aimed to develop a new regimen that enhances skin barrier function by regulating skin pigmentation using low-concentration imiquimod. Results showed that topical application of low-concentration imiquimod effectively induced skin hyperpigmentation in the dorsal skin and external ear of mice without inducing inflammatory cell infiltration. An in vitro study also revealed that low-concentration imiquimod did not induce any cytotoxic effects on melanoma cells but triggered excessive melanin synthesis. In coculture systems, low-concentration imiquimod was noted to increase tyrosinase activity in a broader cellular context, revealing the potential role of neighboring cells in melanin production. The next-generation sequencing result indicated that PKCη and Dnm3 might regulate melanin synthesis and release during imiquimod treatment. Overall, our study presents new insights into the regulation of melanin production by low-concentration imiquimod, both in a mice model and cultured cells. Furthermore, our study highlights the potential benefits of imiquimod in promoting melanin synthesis without causing skin disruptions or inducing inflammation, validating its potential to serve as a method for enhancing skin barrier functions by regulating the epidermal melanization reaction.

CAMP-Mediated CREM-MITF-TYR Axis Regulates Melanin Synthesis in Pacific Oysters.

Colorful shells in bivalves are mostly caused by the presence of biological pigments, among which melanin is a key component in the formation of shell colours. Cyclic adenosine monophosphate (cAMP) is an important messenger in the regulation of pigmentation in some species. However, the role of cAMP in bivalve melanogenesis has not yet been reported. In this study, we performed in vitro and in vivo experiments to determine the role of cAMP in regulating melanogenesis in Pacific oysters. Besides, the function of cAMP-responsive element modulator (CREM) and the interactions between CREM and melanogenic genes were investigated. Our results showed that a high level of cAMP promotes the expression of melanogenic genes in Pacific oysters. CREM controls the expression of the MITF gene under cAMP regulation. In addition, CREM can regulate melanogenic gene expression, tyrosine metabolism, and melanin synthesis. These results indicate that cAMP plays an important role in the regulation of melanogenesis in Pacific oysters. CREM is a key transcription factor in the oyster melanin synthesis pathway, which plays a crucial role in oyster melanin synthesis through a cAMP-mediated CREM-MITF-TYR axis.

Comparative Transcriptome Analysis of the Skin and the Peritoneal Wall Layer of Triplophysa stenura Distributed in High Elevations.

A total of 81,868 All-Unigenes were sequenced and assembled by the transcriptome in the dorsal skin, the lateral skin, and the peritoneal wall layer of Triplophysa stenura with a total assembly length of 123,827,585 bp, and 68,750 unigenes were annotated to seven functional databases. A total of 588 DEGs were screened between the dorsal and lateral skin, 17,097 DEGs were screened between the dorsal skin and the peritoneal wall layer, and 16,598 DEGs were screened between the lateral skin and the peritoneal wall layer. Most of DEGs in three tissues were annotated to GO terms related to cellular structures, binding, cellular processes, and catalytic activity. They were also annotated to KEGG pathways such as the MAPK signaling pathway, PI3K-Akt signaling pathway, Wnt signaling pathway, melanogenesis, tyrosine metabolism, and cell cycle. A total of twenty-three DEGs were found to be enriched in the melanin synthesis pathway by a local Blast comparison, of which nine DEGs were significantly upregulated in the peritoneal wall layer and six DEGs were significantly upregulated in the dorsal and lateral skin. The results suggest that these genes may be associated with the molecular mechanism of melanin synthesis in T. stenura, and the differential regulation of genes may be related to the differences in UVR intensity and tissue sites of melanin synthesis. Further investigation is needed on how these genes specifically regulate melanin synthesis.

Prognostic significance of melanogenesis pathway and its association with the ultrastructural characterisation of melanosomes in uveal melanoma

BackgroundPigmentation could be a relevant prognostic factor in uveal melanoma (UM) development. Microphthalmia-associated transcription factor (MITF) regulates melanin synthesis by activating tyrosinase-related protein 2 (TYRP2) and silver protein (SILV) that...

Understanding key genetic make-up of different coat colour in Bayinbuluke sheep through a comparative transcriptome profiling analysis

Coat color is a distinctive feature of mammals, especially in distinguishing animal breeds, and the diversity of animal coat color provides an important model phenotype for exploring gene roles and studying gene mutations. Selective breeding programs can be used to enhance or modify certain physical traits in Bayinbuluke sheep, including their coat color. To elaborately understand the differential expression of coat tissue of Bayinbuluke sheep with respect to coat colour and genetic make ups, the molecular mechanism of the difference in coat color phenotype of the sheep's head and neck was explored through RT-PCR assay based transcriptomic analysis. In this study, sixteen samples of coat tissues of 8 individuals Bayinbuluke sheep with different hair colors were collected for transcriptome sequencing analysis, and the differential expression genes of MEwhite module in BL vs BR group and WGCNA were analyzed by gene ontology and Kyoto Gene Encyclopedia enrichment, and the results were significantly enriched in G protein-coupled receptor, transmembrane signaling receptor activity, tyrosine metabolism, melanin production and other metabolic pathways. The identified DCT, ASIP, GPR143, PMEL, TYRP1 and MC1R genes Bayinbuluke sheep coat have all been linked with important roles in the regulation of melanin synthesis as immune stability. Therefore, understanding the genetic and molecular basis of these pathways can help in developing novel approaches in sheep coat colour as well as improved sheep immunity.

1260 Roles of ubiquitin specific peptidase in the regulation of melanin synthesis and mitochondrial oxidative stress

1260 Roles of ubiquitin specific peptidase in the regulation of melanin synthesis and mitochondrial oxidative stress

Proprotein Convertase Furin Regulates Melanogenesis via the Notch Signaling Pathway.

Furin is a calcium-dependent serine protease found in almost all mammals. It plays an important role in embryogenesis, tissue homeostasis, tumors pathogenesis, viral infectious diseases, and neurodegenerative diseases. However, whether furin directly regulates melanin synthesis and transport has rarely been evaluated yet. The present study aimed to investigate furin potential function and mechanisms in melanogenesis. Short hairpin RNAs targeting furin gene (sh-furin RNAs) were used to inhibit furin gene expression in human melanoma cell line MNT-1 cells. Then, intracellular melanin content was measured using a sodium hydroxide method. Extracellular melanin content was measured determining cell culture medium absorbance at 450 nm. Levodopa (L-DOPA) oxidation rate was measured to assess the tyrosinase activity. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were performed to measure melanogenesis-related genes and Notch pathway-related genes expression levels. Human primary melanocytes (MCs) were extracted from foreskin tissues and were stimulated with a furin inhibitor. Then, the extracellular and intracellular melanin content, tyrosinase activity and molecules related to melanogenesis and the Notch pathway expression were measured in MCs with or without a furin inhibitor. Additionally, morpholino technology was used to inhibit furin in zebrafish. Zebrafish pigmentary phenotypes in the control group and furin inhibition group were observed with a stereo microscope. Then, MCs number in the tail and head of the zebrafish were counted using Image J software (version 1.53t, National Institute of Health, Bethesda, MD, USA). Meanwhile, melanin content, tyrosinase activity, and molecules related to melanogenesis and the Notch pathway expression levels were measured. Subsequently, valproic acid (VPA), a Notch pathway agonist, was used in MNT-1 melanoma cells treated with or without sh-furin lentiviral vectors for rescue experiments. Furin inhibition enhanced intracellular and extracellular melanin content, and cellular tyrosinase activity in MNT-1 cells and MCs. Additionally, furin inhibition increased melanin synthesis-associated and transport-associated proteins expression levels while inhibiting Notch pathway-relevant proteins. After using VPA to activate the Notch pathway in MNT-1 cells transfected with a sh-furin RNA, the biological effects resulting from furin knockdown were reversed. In addition, the results of in vivo experiments using morpholino to knock down furin gene in zebrafish further confirmed that furin knockdown regulated melanogenesis and impaired the Notch pathway. This study clarified that furin affected the synthesis and transport of melanin via Notch pathway. Notch pathway may be a potential therapeutic target for pigmented skin diseases.

Insights into the treatment strategies for hypopigmentation disorders by natural herbs: current updates and future prospects

Skin pigmentation is a natural phenomenon that plays an important part in the appearance and biology of all animals, including humans. The process of melanogenesis, which results in the formation of the pigment melanin within melanocytes, determines skin colour. This process is controlled by both inherent and external factors. Tyrosinase catalyzes an essential step in melanogenesis; dysfunction of tyrosinase leads to reduce melanin synthesis which results in severe clinical and aesthetic problem of hypopigmentation disorders. Therefore, the key method in the management of aberrant skin pigmentation for both cosmetic and therapeutic purposes is the regulation of melanin synthesis. In order to regulate and control skin hypopigmentation, this review article discusses the treatment strategies from plant extracts and their active principles with stimulating effects on melanin synthesis and tyrosinase activity, as well as to elucidate scientifically validated plant extracts in order to naturally increase melanin synthesis and treat hypopigmentary disorders.

Mechanism Underlying Light Intensity-Induced Melanin Synthesis of Auricularia heimuer Revealed by Transcriptome Analysis.

Auricularia heimuer is a traditional edible and medicinal mushroom, which is widely used in biochemical research and is regarded as a good dietary supplement. The color of the ear-like fruiting body is an important indicator of its commercial quality. However, the mechanism by which light intensity influences the melanin synthesis of A. heimuer remains unclear. Here, we show that fruiting body color is significantly affected by light intensity. Transcriptional profiles of the fruiting bodies of A. heimuer grown in different light intensities were further analyzed. More differentially expressed genes (DEGs) were identified with a greater light intensity difference. A total of 1388 DEGs were identified from six comparisons, including 503 up-regulated genes and 885 down-regulated genes. The up-regulated genes were mainly associated with light sensing via photoreceptors, signal transduction via the mitogen-activated protein kinase (MAPK) signaling pathway, and melanin synthesis via the tyrosine metabolic pathway. Therefore, the genes involved in these processes may participate in regulating melanin synthesis under high light intensity. This insight into the transcriptional regulation of A. heimuer to light intensity should help to further comprehensively elucidate the underlying mechanism of light-induced melanin synthesis.

The potential impact of melanosomal pH and metabolism on melanoma.

Melanin is synthesized in melanocytes and is transferred into keratinocytes to block the effects of ultraviolet (UV) radiation and is important for preventing skin cancers including melanoma. However, it is known that after melanomagenesis and melanoma invasion or metastases, melanin synthesis still occurs. Since melanoma cells are no longer involved in the sun tanning process, it is unclear why melanocytes would maintain melanin synthesis after melanomagenesis has occurred. Aside from blocking UV-induced DNA mutation, melanin may provide other metabolic functions that could benefit melanoma. In addition, studies have suggested that there may be a selective advantage to melanin synthesis in melanoma; however, mechanisms regulating melanin synthesis outside the epidermis or hair follicle is unknown. We will discuss how melanosomal pH controls melanin synthesis in melanocytes and how melanosomal pH control of melanin synthesis might function in melanoma. We will also discuss potential reasons why melanin synthesis might be beneficial for melanoma cellular metabolism and provide a rationale for why melanin synthesis is not limited to benign melanocytes.

Requirement of Zebrafish Adcy3a and Adcy5 in Melanosome Dispersion and Melanocyte Stripe Formation.

cAMP-PKA signaling plays a pivotal role in melanin synthesis and melanosome transport by responding to the binding of the α-melanocyte-stimulating hormone (α-MSH) to melanocortin-1 receptor (MC1R). Adenylate cyclases (ADCYs) are the enzymes responsible for the synthesis of cAMP from ATP, which comprises nine transmembrane isoforms (ADCYs 1-9) and one soluble adenylate cyclase (ADCY 10) in mammals. However, little is known about which and how ADCY isoforms regulate melanocyte generation, melanin biosynthesis, and melanosome transport in vivo. In this study, we have generated a series of single and double mutants of Adcy isoforms in zebrafish. Among them, adcy3a-/- and adcy5-/- double mutants cause defects in melanosome dispersion but do not impair melanoblast differentiation and melanocyte regeneration during the embryonic or larval stages. Activation of PKA, the main effector of cAMP signaling, significantly ameliorates the defects in melanosome dispersion in adcy3a-/- and adcy5-/- double mutants. Mechanistically, Adcy3a and Adcy5 regulate melanosome dispersion by activating kinesin-1 while inhibiting cytoplasmic dynein-1. In adult zebrafish, Adcy3a and Adcy5 participate in the regulation of the expression of microphthalmia transcription factor (Mitfa) and melanin synthesis enzymes Tyr, Dct, and Trp1b. The deletion of Adcy3a and Adcy5 inhibits melanin production and reduces pigmented melanocyte numbers, causing a defect in establishing adult melanocyte stripes. Hence, our studies demonstrate that Adcy3a and Adcy5 play essential but redundant functions in mediating α-MSH-MC1R/cAMP-PKA signaling for regulating melanin synthesis and melanosome dispersion.

Genome-Wide Association Study for Screening and Identifying Potential Shin Color Loci in Ducks.

Shin color diversity is a widespread phenomenon in birds. In this study, ducks were assessed to identify candidate genes for yellow, black, and spotted tibiae. For this purpose, we performed whole-genome resequencing of an F2 population consisting of 275 ducks crossed between Runzhou crested-white ducks and Cherry Valley ducks. We obtained 12.6 Mb of single nucleotide polymorphism (SNP) data, and the three shin colors were subsequently genotyped. Genome-wide association studies (GWASs) were performed to identify candidate and potential SNPs for the three shin colors. According to the results, 2947 and 3451 significant SNPs were associated with black and yellow shins, respectively, and six potential SNPs were associated with spotted shins. Based on the SNP annotations, the MITF, EDNRB2, POU family members, and the SLC superfamily were the candidate genes regulating pigmentation. In addition, the isoforms of EDNRB2, TYR, TYRP1, and MITF-M were significantly different between the black and yellow tibiae. MITF and EDNRB2 may have synergistic roles in the regulation of melanin synthesis, and their mutations may lead to phenotypic differences in the melanin deposition between individuals. This study provides new insights into the genetic factors that may influence tibia color diversity in birds.

Genome-Wide Analysis Identifies Candidate Genes Encoding Beak Color of Duck.

Beak color diversity is a broadly occurring phenomenon in birds. Here, we used ducks to identify candidate genes for yellow, black, and spotted beaks. For this, an F2 population consisting of 275 ducks was genotyped using whole genome resequencing containing 12.6 M single-nucleotide polymorphisms (SNPs) and three beak colors. Genome-wide association studies (GWAS) was used to identify the candidate and potential SNPs for three beak colors in ducks (yellow, spotted, and black). The results showed that 2753 significant SNPs were associated with black beaks, 7462 with yellow, and 17 potential SNPs with spotted beaks. Based on SNP annotation, MITF, EDNRB2, members of the POU family, and the SLC superfamily were the candidate genes regulating pigmentation. Meanwhile, isoforms MITF-M and EDNRB2 were significantly different between black and yellow beaks. MITF and EDNRB2 likely play a synergistic role in the regulation of melanin synthesis, and their mutations contribute to phenotypic differences in beak melanin deposition among individuals. This study provides new insights into genetic factors that may influence the diversity of beak color.

The Molecular Properties and Roles of Pannier in Harmonia axyridis's Metamorphosis and Melanin Synthesis.

The GATA transcription factor Pannier is identified as the major regulatory gene in color pattern formation in the Asian multi-colored ladybird beetle (Harmonia axyridis). however, the mechanisms of Pannier in regulating melanin synthesis and development in H. axyridis remain elusive. In this study, we identified and characterized Pannier in H. axyridis (HaPnr) and showed it to have two alternative spliced variants named HaPnr-α and HaPnr-β. Analyses of developmental stage expression patterns revealed that HaPnr, HaPnr-α and HaPnr-β were constitutively expressed throughout all developmental stages. To examine the role of HaPnr in H. axyridis development, RNA interference was performed in late larvae (the fourth instar) and early pupae (the first day of pupa stage). The transcript levels of HaPnr were effectively suppressed after the injection of double-stranded RNA of HaPnr (dsHaPnr). The fourth instar larvae injected with dsHaPnr reduced the pupation rates to only 61.50%, compared with 88.5% in the dsGFP-injected group. The un-pupated larvae gradually died after 1 week, and visually unaffected pupae emerged into abnormal adults with malformed hind wings and melanin absent from the cuticle. These abnormal adults gradually died 10 days after eclosion. However, when early pupae were injected with dsHaPnr, the normal eclosion rate was achieved at 88.41% on day 6 after the injection. In addition, these successful eclosion adults also showed an absence of melanin in the cuticle, but they could mate normally and have normal fecundity as compared with the control. We further demonstrated that the suppression of HaPnr-α or HaPnr-β individually did not affect the pupation and eclosion process. The suppression of HaPnr-α expression resulted in elytra melanin decreasing in both the conspicua and the succinea subgroup in H. axyridis. Even though the suppression of HaPnr-β expression only affected the melanin synthesis in the succinea subgroup, it significantly prolonged the time taken for melanin synthesis to occur in the conspicua subgroup in H. axyridis. These results indicate that HaPnr plays an essential role in insect development, especially during their metamorphosis, and also support our hypothesis that HaPnr could regulate melanin synthesis in H. axyridis under the combined action with its two splicing variants, HaPnr-α and HaPnr-β.

Genome-wide association analysis reveal the genetic reasons affect melanin spot accumulation in beak skin of ducks

BackgroundSkin pigmentation is a broadly appearing phenomenon of most animals and humans in nature. Here we used a bird model to investigate why melanin spot deposits on the skin.ResultsOur result showed that growth age and the sunlight might induce melanin deposition in bird beak skin which was determined by genetic factors. GWAS helped us to identify two major loci affecting melanin deposition, located on chromosomes 13 and 25, respectively. The fine mapping works narrowed the candidate regions to 0.98 Mb and 1.0 Mb on chromosomes 13 and 25. The MITF and POU2F3 may be the causative genes and synergistically affect melanin deposition during duck beak skin. Furthermore, our data strongly demonstrated that the pathway of melanin metabolism contributes to melanin deposition on the skin.ConclusionsWe demonstrated that age and sunlight induce melanin deposition in bird beak skin, while heredity is fundamental. The MITF and POU2F3 likely played a synergistic effect on the regulation of melanin synthesis, and their mutations contribute to phenotypic differences in beak melanin deposition among individuals. It is pointed out that melanin deposition in the skin is related to the pathway of melanin metabolism, which provided insights into the molecular regulatory mechanisms and the genetic improvement of the melanin deposition in duck beak.

Melanin Promotes Spore Production in the Rice Blast Fungus Magnaporthe oryzae.

The rice blast pathogen, Magnaporthe oryzae, spreads through spores and invades rice through appressoria. Melanin is necessary for an appressorium to penetrate plant cells, but there are many unknown aspects of its role in fungal conidiation. In this study, we confirmed that melanin promotes spore production in M. oryzae, and that this effect is related to the background melanin content of wild-type strains. In the wild-type 70-15 strain with low melanin content of aerial hyphae, increased melanin synthesis promoted sporulation. In contrast, increased melanin synthesis in the wild-type Guy11 strain, which has higher melanin content, did not promote sporulation. The transcription factor Cnf1 (conidial production negative regulatory factor 1), which negatively regulates melanin synthesis, has opposite effects in conidiophore differentiation of Guy11 and 70-15. Deletion of CNF1 did not abolish the defects of Δcos1 and Δhox2 (where COS1/conidiophore stalk-less 1 or HOX2/homeodomain protein 2 was deleted) in conidiation, while increased the conidiation of Δgcc1 and Δgcf3 (where GCC1/growth, conidiation and cell wall regulatory factor 1, or GCF3/growth and conidiation regulatory factor 3 was deleted). Pig1 (pigment of Magnaporthe 1) regulates the melanin synthesis of hyphae but not of conidiophores, spores, or appressoria. Deletion of the same gene in different wild-type strains can lead to different phenotypes, partly because of differences in melanin content between fungal strains. Overall, this study reveals the functional diversity and complexity of melanin in different M. oryzae strains.

Nutrological control and treatment of melasma in the COVID-19 pandemic: a concise systematic review

Introduction: In the skin disease scenario, hyperpigmentation (melasma) is present in about 14.5%-56% of pregnant women and 11.3%-46% of people taking oral contraceptives worldwide. The coronavirus disease 2019 (COVID-19) pandemic has brought great challenges to the treatment of melasma, as well as doubts about its worsening. Diet and nutrients for topical or oral use play an important role in the control of infectious diseases. Objective: It was to perform a concise systematic review on the occurrence, worsening, and nutrological treatment of melasma in the COVID-19 pandemic. Methods: The present study followed a systematic review model (PRISMA). 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. 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 and Conclusion: Melasma is an acquired hyperpigmentation disorder, and reactive oxygen species play an important role in the regulation of melanin synthesis. In nutrological terms, lycopene is one of the most effective oxygen neutralizers among tomato-derived carotenoids. Furthermore, hydroquinone is a compound that has been used for the treatment of hyperpigmentation by tyrosinase inhibition mechanism and can be found in wheat. Thus, an adequate knowledge of the role of nutritional supplements in dermatological diseases can be a useful tool. Based on this, there is growing interest in oral medications and dietary supplements to improve melasma. Oral medications and dietary supplements evaluated include tranexamic acid, Polypodium leucotomos extract, beta-carotenoid, melatonin, and procyanidin. Also, hydrolyzed collagen is a low molecular weight protein that has been widely used and can prevent melasma. Serum zinc levels can also predict the occurrence of melasma. Finally, there is still no report on skin darkening associated with COVID-19.

Grape Extract Promoted α-MSH-Induced Melanogenesis in B16F10 Melanoma Cells, Which Was Inverse to Resveratrol.

Melanin is a natural pigment produced by cells to prevent damage caused by ultraviolet radiation. Previously, resveratrol was shown to reduce melanin synthesis. As a natural polyphenol with various biological activities, resveratrol occurs in a variety of beverages and plant foods, such as grapes. Therefore, we investigated whether grape extracts containing resveratrol also had the ability to regulate melanin synthesis. In this study, we used mouse B16F10 melanoma cells as a model for melanin synthesis with the melanogenesis-inducing α-melanocyte-stimulating hormone (α-MSH) as a positive control. Our results confirmed previous reports that resveratrol reduces melanin synthesis by reducing the activity of the rate-limiting enzyme tyrosinase. In contrast, the grape extract could not reduce melanin synthesis, and in fact promoted melanogenesis in the presence of α-MSH. The expression of genes related to melanin synthesis, such as tyrosinase, tyrosinase-related protein-1, tyrosinase-related protein-2, and microphthalmia-associated transcription factor, also supports these phenomena, which means that even in the presence of resveratrol, grape extract will strengthen the function of α-MSH in promoting melanin synthesis. Therefore, these results also provide a point of view for research on cosmetics.

Anti-Melanogenic Properties of Velutin and Its Analogs.

Velutin, one of the flavones contained in natural plants, has various beneficial activities, such as skin whitening, as well as anti-inflammatory, anti-allergic, antioxidant, and antimicrobial activities. However, the relationship between the structure of velutin and its anti-melanogenesis activity is not yet investigated. In this study, we obtained 12 velutin derivatives substituted at C5, C7, C3′, and C4′ of the flavone backbone with hydrogen, hydroxyl, and methoxy functionalities by chemical synthesis, to perform SAR analysis of velutin structural analogues. The SAR study revealed that the substitution of functional groups at C5, C7, C3′, and C4′ of the flavone backbone affects biological activities related to melanin synthesis. The coexistence of hydroxyl and methoxy at the C5 and C7 position is essential for inhibiting tyrosinase activity. However, 1,2-diol compounds substituted at C3′ and C4′ of flavone backbone induce apoptosis of melanoma cells. Further, substitution at C3′ and C4′ with methoxy or hydrogen is essential for inhibiting melanogenesis. Thus, this study would be helpful for the development of natural-derived functional materials to regulate melanin synthesis.

Citric acid promoted melanin synthesis in B16F10 mouse melanoma cells, but inhibited it in human epidermal melanocytes and HMV-II melanoma cells via the GSK3β/β-catenin signaling pathway.

Melanin, a pigment synthesized by melanocytes in the skin, resists the damage caused by ultraviolet rays to cells. Citric acid, a well-known food additive, is commonly used as an antioxidant and is an important part of the tricarboxylic acid (TCA) cycle for energy production during cellular metabolism. Here, we aimed to investigate whether the addition of excess citric acid regulates melanin synthesis, and to delineate the underlying mechanism. First, we observed that citric acid exerts opposite redox effects on mouse and human cells. Interestingly, treatment with excess citric acid increased the melanin content in mouse cells but decreased it in human cells. Furthermore, the expression of factors important for melanin synthesis, such as microphthalmia-associated transcription factor (MITF), was also regulated by citric acid treatment—it was promoted in mouse cells and suppressed in human cells. Citric acid also impacted the upstream regulators of MITF, glycogen synthase kinase 3β (GSK3β), and β-catenin. Second, we determined the importance of GSK3β in the citric acid-mediated regulation of melanin synthesis, using a GSK3β inhibitor (BIO). To the best of our knowledge, this is the first study to show that citric acid regulates melanin synthesis via the GSK3β/β-catenin signaling pathway, and that equal amounts of exogenous citric acid exert opposing effects on mouse and human cells.