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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. [ABSTRACT FROM AUTHOR]

Yuehong Ma, Hongqin Chang Department of Dermatology, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of ChinaCorrespondence: Hongqin Chang, Department of Dermatology, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, No. 588 Gehu Middle Road, Wujin District, Changzhou, Jiangsu, 213000, People’s Republic of China, Email 13685261123@163.comBackground: Vitiligo is an autoimmune disease characterized by loss of skin pigmentation and currently has no effective treatment. This study aimed to investigate the function of SIRT7, being an important desuccinylase mediating multiple disease progression, and its mechanism in vitiligo progression.Methods: Normal human melanocytes (NHM) PIG1 and vitiligo human melanocytes (VHM) PIG3V were utilized in this research. The role of sirtuin 7 (SIRT7) and Ezrin (EZR) on melanin synthesis was investigated by detecting tyrosinase activity, melanin content, α-MSH levels, and the protein levels of melanin-related markers. The function of EZR was identified via rescue experiments, while the underlying mechanism was investigated via bioinformatic analysis, co-immunoprecipitation (co-IP), immunoprecipitation (IP), and Western blot techniques.Results: Results showed that only SIRT7 was highly expressed in vitiligo human melanocytes, where knockingdown SIRT7 translated into increased melanin synthesis in melanocytes. Mechanistically, SIRT7 knockdown promoted the succinylation of EZR at the Lys (K)60 site. Moreover, overexpressing EZR induced higher melanin synthesis in melanocytes, while its knocking down exerted the opposite effect by inhibiting SIRT7 knockdown-induced melanin synthesis.Conclusion: SIRT7 inhibited melanin synthesis in melanocytes by suppressing the succinylation of EZR. These findings are envisaged to provide a novel theoretical basis for vitiligo treatment.Keywords: SIRT7, EZR, succinylation, vitiligo, melanin synthesis

Melanin naturally exists in organisms and is synthetized by tyrosinase (TYR); however, its over-production may lead to aberrant pigmentation and skin conditions. Loquat (Eriobotrya japonica (Thunb.) Lindl.) flowers contain a variety of bioactive compounds, while studies on their suppressive capabilities against melanin synthesis are limited. Loquat flower isolate product (LFP) was obtained by ethanol extraction and resin purification, and its inhibitory efficiency against TYR activity was investigated by enzyme kinetics and multiple spectroscopy analyses. In addition, the impact of LFP on melanin synthesis-related proteins' expression in mouse melanoma B16 cells was analyzed using Western blotting. HPLC-MS/MS analysis indicated that LFP was composed of 137 compounds, of which 12 compounds, including flavonoids (quercetin, isorhamnoin, p-coumaric acid, etc.) and cinnamic acid and its derivatives, as well as benzene and its derivatives, might have TYR inhibitory activities. LFP inhibited TYR activity in a concentration-dependent manner with its IC50 value being 2.8 mg/mL. The inhibition was an anti-competitive one through altering the enzyme's conformation rather than chelating copper ions at the active center. LFP reduced the expression of TYR, tyrosinase-related protein (TRP) 1, and TRP2 in melanoma B16 cells, hence inhibiting the synthesis of melanin. The research suggested that LFP had the potential to reduce the risks of hyperpigmentation caused by tyrosinase and provided a foundation for the utilization of loquat flower as a natural resource in the development of beauty and aging-related functional products. [ABSTRACT FROM AUTHOR]

Skin hyperpigmentation is mainly caused by excessive synthesis of melanin; however, there is still no safe and effective therapy for its removal. Here, we found that the dermal freezer was able to improve UVB‐induced hyperpigmentation of guinea pigs without causing obvious epidermal damage. We also mimic freezing stimulation at the cellular level by rapid freezing and observed that freezing treatments <2.5 min could not decrease cell viability or induce cell apoptosis in B16F10 and Melan‐A cells. Critically, melanin content and tyrosinase activity in two cells were greatly reduced after freezing treatments. The dramatic decrease in tyrosinase activity was associated with the downregulation of MITF, TYR, TRP‐1 and TRP‐2 protein expression in response to freezing treatments for two cells. Furthermore, our results first demonstrated that freezing treatments significantly reduced the levels of p‐GSK3β and β‐catenin and the nuclear accumulation of β‐catenin in B16F10 and Melan‐A cells. Together, these data suggest that fast freezing treatments can inhibit melanogenesis‐related gene expression in melanocytes by regulating the Wnt/β‐catenin signalling pathway. The inhibition of melanin production eventually contributed to the improvement in skin hyperpigmentation induced by UVB. Therefore, fast freezing treatments may be a new alternative of skin whitening in the clinic in the future. [ABSTRACT FROM AUTHOR]

This study investigates the effectiveness of Kaempferol, a compound extracted from broccoli (Brassica oleracea var. italica), as a catalyst in controlling melanin production through its interaction with the tyrosinase protein. Utilizing a variety of computational tools, including Pymol, Pyrex, Protein Plus, and Lepinski Rule software, the study explores Kaempferol's binding affinity with tyrosinase and its molecular properties. The findings reveal Kaempferol's notable binding scores with tyrosinase and its structural stability as indicated by RMSD analysis. Furthermore, Protein Plus software confirms the interaction between Kaempferol and tyrosinase protein. Lipinski's analysis of Kaempferol shows it meets key pharmacokinetic properties like molecular weight, hydrogen bond formation potential, and reactivity. These insights establish a preliminary understanding of Kaempferol's role as a catalyst in melanin synthesis regulation, suggesting its potential application in treating skin pigment disorders. [ABSTRACT FROM AUTHOR]

Shell color is one of the shell traits of molluscs, which has been regarded as an economic trait in some bivalves. Pacific oysters (Crassostrea gigas) are important aquaculture shellfish worldwide. In the past decade, several shell color strains of C. gigas were developed through selective breeding, which provides valuable materials for research on the inheritance pattern and regulation mechanisms of shell color. The inheritance patterns of different shell colors in C. gigas have been identified in certain research; however, the regulation mechanism of oyster pigmentation and shell color formation remains unclear. In this study, we performed transcriptomic and physiological analyses using black and white shell oysters to investigate the molecular mechanism of melanin synthesis in C. gigas. Several pigmentation-related pathways, such as cytochrome P450, melanogenesis, tyrosine metabolism, and the cAMP signaling pathway were found. The majority of differentially expressed genes and some signaling molecules from these pathways exhibited a higher level in the black shell oysters than in the white, especially after l-tyrosine feeding, suggesting that those differences may cause a variation of tyrosine metabolism and melanin synthesis. In addition, the in vitro assay using primary cells from mantle tissue showed that l-tyrosine incubation increased cAMP level, gene and protein expression, and melanin content. This study reveals the difference in tyrosine metabolism and melanin synthesis in black and white shell oysters and provides evidence for the potential regulatory mechanism of shell color in oysters. [ABSTRACT FROM AUTHOR]

Abstract Rice blast is a serious threat to the safe production of grain crops such as rice and wheat. Sporulation, appressorium formation, and invasive growth of Magnaporthe oryzae are the key stages of the development and spread of rice blast epidemics. M. oryzae is a hemibiotrophic fungus that undergoes changes in available carbon sources during the infection cycle. Lipid is a major storage for M. oryzae spores and a major carbon source used in glycerol synthesis and turgor pressure generation in appressoria. The formation of a dense cell wall melanin layer is necessary for an appressorium to produce turgor and to be pathogenic. The plant cell wall is an important carbon source during the infection stage of M. oryzae. Transcription factors regulate gene expression in fungi and are key intermediates between the reception of external environmental signals and the control of development and pathogenicity in M. oryzae. The disease cycle of M. oryzae is controlled by some key transcription factors, such as sporulation by Cos1 and Hox2, appressorium formation by Sfl1, Hox7, and Vrf1, invasive growth by Mst12 and Mig1, and resistance to host basal immunity by Ap1 and Atf1. This review focuses on describing the key transcription factors of M. oryzae that regulate sporulation, appressorium formation, invasive growth, lipid metabolism, carbohydrate metabolism, melanin synthesis, oxidative response, and host basal immunity, as well as the working mechanism of the transcription factors.

Rice blast is a serious threat to the safe production of grain crops such as rice and wheat. Sporulation, appressorium formation, and invasive growth of Magnaporthe oryzae are the key stages of the development and spread of rice blast epidemics. M. oryzae is a hemibiotrophic fungus that undergoes changes in available carbon sources during the infection cycle. Lipid is a major storage for M. oryzae spores and a major carbon source used in glycerol synthesis and turgor pressure generation in appressoria. The formation of a dense cell wall melanin layer is necessary for an appressorium to produce turgor and to be pathogenic. The plant cell wall is an important carbon source during the infection stage of M. oryzae. Transcription factors regulate gene expression in fungi and are key intermediates between the reception of external environmental signals and the control of development and pathogenicity in M. oryzae. The disease cycle of M. oryzae is controlled by some key transcription factors, such as sporulation by Cos1 and Hox2, appressorium formation by Sfl1, Hox7, and Vrf1, invasive growth by Mst12 and Mig1, and resistance to host basal immunity by Ap1 and Atf1. This review focuses on describing the key transcription factors of M. oryzae that regulate sporulation, appressorium formation, invasive growth, lipid metabolism, carbohydrate metabolism, melanin synthesis, oxidative response, and host basal immunity, as well as the working mechanism of the transcription factors. [ABSTRACT FROM AUTHOR]

Simple Summary: Strong ultraviolet radiation is an extreme environmental characteristic of the Tibetan Plateau. Melanin is the most important light-protective substance that allows fish to resist ultraviolet radiation. In order to explore the melanin protection mechanism of fish in the Tibetan Plateau against strong ultraviolet radiation, Triplophysa stenura distributed in high elevation areas was selected as the research object. Transcriptome differences were compared between skin and peritoneal wall layers with different melanin contents to explore the regulatory genes related to melanin synthesis. This provides basic data for analyzing the molecular mechanism of melanin protection in plateau fish against strong ultraviolet radiation. The results indicate that a total of twenty-three DEGs are enriched in the melanin synthesis pathway by a local Blast comparison, of which nine DEGs are significantly upregulated in the peritoneal wall layer and six DEGs are 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 the UVR intensity and tissue sites of melanin synthesis. Further investigation is needed to determine how these genes specifically regulate melanin synthesis. 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. [ABSTRACT FROM AUTHOR]

Melanocytes, which originate from the neuroectoderm, are specialized cells responsible for producing pigments and possessing a dendritic morphology. These cells migrate to the epidermis and follicles, contributing to skin and hair pigmentation during embryonic development. The remarkable self-renewal capacity of melanocytes enables them to effectively restore hair and skin pigmentation. The synthesis of melanin to safeguard the skin against damage caused by ultraviolet radiation, as well as the enigmatic immune function of melanocytes, demonstrate their indispensable contributions to maintaining cutaneous homeostasis. The regulation of cutaneous pigmentation involves an intricate network influenced by intrinsic cellular signals within melanocytes and extracellular cues. Therefore, this paper provides a comprehensive review of the role of melanocytes in skin biology. This in-depth analysis could open novel avenues for research aimed at the prevention and treatment of skin disorders. [ABSTRACT FROM AUTHOR]

Melanin naturally exists in organisms and is synthetized by tyrosinase (TYR); however, its over-production may lead to aberrant pigmentation and skin conditions. Loquat (Eriobotrya japonica (Thunb.) Lindl.) flowers contain a variety of bioactive compounds, while studies on their suppressive capabilities against melanin synthesis are limited. Loquat flower isolate product (LFP) was obtained by ethanol extraction and resin purification, and its inhibitory efficiency against TYR activity was investigated by enzyme kinetics and multiple spectroscopy analyses. In addition, the impact of LFP on melanin synthesis-related proteins’ expression in mouse melanoma B16 cells was analyzed using Western blotting. HPLC-MS/MS analysis indicated that LFP was composed of 137 compounds, of which 12 compounds, including flavonoids (quercetin, isorhamnoin, p-coumaric acid, etc.) and cinnamic acid and its derivatives, as well as benzene and its derivatives, might have TYR inhibitory activities. LFP inhibited TYR activity in a concentration-dependent manner with its IC50 value being 2.8 mg/mL. The inhibition was an anti-competitive one through altering the enzyme’s conformation rather than chelating copper ions at the active center. LFP reduced the expression of TYR, tyrosinase-related protein (TRP) 1, and TRP2 in melanoma B16 cells, hence inhibiting the synthesis of melanin. The research suggested that LFP had the potential to reduce the risks of hyperpigmentation caused by tyrosinase and provided a foundation for the utilization of loquat flower as a natural resource in the development of beauty and aging-related functional products.

(1) Background: It was found that the melanin of black-bone chicken has various effects such as scavenging DPPH free radicals and anti-oxidation, and the synthesis of melanin is affected by various factors including hormones. In addition, several studies have found that melatonin affects the melanoma cell synthesis of melanin, which has not been reported in chicken primary melanocytes; so, relevant studies were conducted. (2) Methods: In this study, chicken primary melanocytes were isolated and characterized, and then melanocytes were treated with different concentrations of melatonin to investigate the effects of melatonin on melanin synthesis in chicken melanocytes in terms of melanin synthesis-related genes, melanin content, and tyrosinase activity, and combined with RNA seq to detect the change in gene expression level of chicken melanocytes after melatonin treatment. (3) Results: We isolated and characterized primary melanocytes, and indirect immunofluorescence assay results showed positive melanocyte marker genes. RT-qPCR results showed that melatonin decreased the expression of melanin synthesis-related genes. In addition, melatonin reduced the melanin content and decreased the tyrosinase activity of melanocytes in the treated group. A total of 1703 differentially expressed genes were screened by RNA-seq, and in addition, in the KEGG results, the signaling pathway associated with melanin synthesis, and the mTOR signaling pathway were enriched. (4) Conclusions: Melatonin could decrease the synthesis of melanin in chicken primary melanocytes. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine (5-HT)) is a biogenic monoamine with pleiotropic functions. It exerts its roles by binding to specific 5-HT receptors (5HTRs) classified into different families and subtypes. Homologs of 5HTRs are widely present in invertebrates, but their expression and pharmacological characterization have been scarcely investigated. In particular, 5-HT has been localized in many tunicate species but only a few studies have investigated its physiological functions. Tunicates, including ascidians, are the sister group of vertebrates, and data about the role of 5-HTRs in these organisms are thus important for understanding 5-HT evolution among animals. In the present study, we identified and described 5HTRs in the ascidian Ciona intestinalis. During development, they showed broad expression patterns that appeared consistent with those reported in other species. Then, we investigated 5-HT roles in ascidian embryogenesis exposing C. intestinalis embryos to WAY-100635, an antagonist of the 5HT1A receptor, and explored the affected pathways in neural development and melanogenesis. Our results contribute to unraveling the multifaceted functions of 5-HT, revealing its involvement in sensory cell differentiation in ascidians. [ABSTRACT FROM AUTHOR]

Endocrine disrupting effects of 4-tert-butylphenol (4-t-BP) are well described in literature. However, the evidence regarding developmental toxic effect of 4-t-BP is still vague. The present study used zebrafish as a model organism to investigate the toxic effect of 4-t-BP. The results showed that 4-t-BP exposure at 3, 6, and 12 μM induced developmental toxicity in zebrafish, such as reduced embryo hatchability and abnormality morphological. Flow cytometry analysis showed that 4-t-BP also induced intracellular ROS production. 4-t-BP induced changes in the expression of genes related to cardiac development and melanin synthesis, resulting in cardiotoxicity and hypopigmentation. 4-t-BP also caused oxidative stress, and initiated apoptosis through p53-bcl-2/bax-capase3 pathway. Integrative biomarker response analysis showed time- and dose-dependent effects of 4-t-BP on oxidative damage and developmental toxicity in zebrafish embryos. Overall, this study contributed to a comprehensive evaluation of the toxicity of 4-t-BP, and the findings provided new evidence for early warning of residues in aquatic environments. [ABSTRACT FROM AUTHOR]

Simple Summary: Silkworms have remarkable protein synthesis ability, which is favored by biomaterials and biomedicine researchers. The silk gland is the most concerned target tissue of sericulture. Many studies have focused on introducing exogenous functional fibrin genes into the silkworm genome, and have obtained biomedical proteins with good biological activity and multifunctional silk fibers with special properties using the silk gland bioreactor. However, the silk gland of transgenic silkworms often suffers from low vitality, stunting and other problems, and the reasons are still unknown; the biosafety of transgenic silkworms is also unknown. Therefore, we studied the effect of the recombinant Ser3 ectopic gene expressed in the posterior silk gland on hemolymph melanization and metabolism in silkworms. The results showed that although the mutant had normal vitality in normal environments, hemolymph metabolism and immunity were significantly affected. Therefore, the results have positive significance to promote the safe assessment and development of genetically modified organisms. The transgenesis of silkworms is an important way to innovate genetic resources and silk function. However, the silk-gland (SG) of transgenic silkworms, which is the most concerned target tissue of sericulture, often suffers from low vitality, stunting and other problems, and the reasons are still unknown. This study trans engineered recombinant Ser3, a middle silk gland (MSG) specific expression gene, in the posterior silk gland (PSG) of the silkworm, and studied hemolymph immune melanization response changes in mutant pure line SER (Ser3+/+). The results showed that although the mutant had normal vitality, the melanin content and phenoloxidase (PO) activity in hemolymph related to humoral immunity were significantly reduced, and caused significantly slower blood melanization and weaker sterilization ability. The mechanism investigation showed that the mRNA levels and enzymatic activities of phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and dopamine decarboxylase (DDC) in the melanin synthesis pathway in mutant hemolymph, as well as the transcription levels of the PPAE, SP21 and serpins genes in the serine protease cascade were significantly affected. Moreover, the total antioxidant capacity, superoxide anion inhibition capacity and catalase (CAT) level related to the redox metabolic capacity of hemolymph were significantly increased, while the activities of superoxide dismutase (SOD) and glutathione reductase (GR), as well as the levels of hydrogen peroxide (H2O2) and glutathione (GSH), were significantly decreased. In conclusion, the anabolism of melanin in the hemolymph of PSG transgenic silkworm SER was inhibited, while the basic response level of oxidative stress was increased, and the hemolymph immune melanization response was decreased. The results will significantly improve the safe assessment and development of genetically modified organisms. [ABSTRACT FROM AUTHOR]

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.

Nostoc verrucosum, an edible microalgal species, forms colonies in streams. Here, we investigated the antimelanogenic and anti-oxidative effects of N. verrucosum extracts. We collected N. verrucosum from Toyama Prefecture, Japan, and successfully cultured it in indoor cultivation systems. Aqueous, methanol, and hexane extracts of N. verrucosum were prepared for various experiments. To elucidate the antimelanogenic effects of N. verrucosum, we performed tyrosinase assay, melanin content assay, western blotting, and real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Anti-oxidative effects were evaluated using the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assay. The methanol and hexane extracts significantly inhibited melanin synthesis in B16F1 melanoma cells. Western blotting showed that 12.5 and 25.0 µg/mL N. verrucosum hexane extract suppressed tyrosinase activity. The qRT-PCR analysis revealed that N. verrucosum hexane extract inhibited α-melanocyte stimulating hormone-enhanced tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, and melanocortin 1 receptor (MC1R) mRNA expression. On the contrary, N. verrucosum hexane extract did not alter microphthalmia-associated transcription factor (Mitf) transcription. The ABTS assay showed that all extracts had radical scavenging activities, and the IC50 values of the aqueous and methanol extracts were 294.6 and 172.8 µg/mL, respectively. Our findings demonstrate that N. verrucosum is a suitable candidate for the development of antimelanogenic agents, cosmetics, or functional food ingredients. [ABSTRACT FROM AUTHOR]

Cyclobutane pyrimidine dimers (CPDs) are ultraviolet radiation (UV)-induced carcinogenic DNA photoproducts that lead to UV signature mutations in melanoma. Previously, we discovered that, in addition to their incident formation (iCPDs), UV exposure induces melanin chemiexcitation (MeCh), where UV generates peroxynitrite (ONOO−), which oxidizes melanin into melanin-carbonyls (MCs) in their excited triplet state. Chronic MeCh and energy transfer by MCs to DNA generates CPDs for several hours after UV exposure ends (dark CPD, dCPDs). We hypothesized that MeCh and the resulting dCPDs can be inhibited using MeCh inhibitors, and MC and ONOO− scavengers. Here, we investigated the efficacy of Acetyl Zingerone (AZ), a plant-based phenolic alkanone, and its chemical analogs in inhibiting iCPDs and dCPDs in skin fibroblasts, keratinocytes, and isogenic pigmented and albino melanocytes. While AZ and its methoxy analog, 3-(4-Methoxy-benzyl)-Pentane-2,4-dione (MBPD) completely inhibited the dCPDs, MBPD also inhibited ~50% of iCPDs. This suggests the inhibition of ~80% of total CPDs at any time point post UV exposure by MBPD, which is markedly significant. MBPD downregulated melanin synthesis, which is indispensable for dCPD generation, but this did not occur with AZ. Meanwhile, AZ and MBPD both upregulated the expression of nucleotide excision repair (NER) pathways genes including Xpa, Xpc, and Mitf. AZ and its analogs were non-toxic to the skin cells and did not act as photosensitizers. We propose that AZ and MBPD represent "next-generation skin care additives" that are safe and effective for use not only in sunscreens but also in other specialized clinical applications owing to their extremely high efficacy in blocking both iCPDs and dCPDs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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Melanocytes are highly specialized dendritic cells that synthesize and store melanin in subcellular organelles called melanosomes, before transfer to keratinocytes. Melanin is a complex pigment that provides colour and photoprotection to the skin, hair and eyes. The process of synthesis of melanin is called melanogenesis and is regulated by various mechanisms and factors such as genetic, environmental and endocrine factors. The knowledge of the pigmentation process is important to understand hypopigmentation disorders such as vitiligo and also to design adequate treatments. In the present work, we review the signalling pathways involved in vitiligo. Finally, current therapies and treatments including topical, oral and phototherapies are discussed and described, emphasizing future therapies based on different pigmentation mechanisms.

Two isocoumarins (6-methoxymellein and 6-hydroxymellein), one pyrrole compound (minaline), one lactone derivative (butyrolactone II), five phenolic acids (phenylacetic, veratric (3,4-dimethoxybenzoic), 4-hydroxyphenylacetic, 4-hydroxybenzoic and protocatechuic acid), and two phenolic acid methyl esters ((2-hydroxyphenyl) acetic acid methyl ester and methyl 4-hydroxyphenylacetate), along with 1,3-bis(4-hydroxyphenyl) propan-2-one were isolated from the fungal strain Aspergillus terreus XJA8. The fungal strain was isolated from the root of the medicinal plant Vernonia anthelmintica for first time. All isolated secondary metabolites were evaluated for their antimicrobial activity and melanin synthesis in murine B16 cells. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune‐related disease with a complex aetiology that involves innate immunity. Toll‐like receptors (TLRs) are important parts of innate immunity and are related to a variety of autoimmune diseases, including vitiligo, through an unknown mechanism. In this study, we found that the TLR4 gene expression was increased in blood samples of patients with advanced stage vitiligo, and then, we evaluated the effect of TLR4 ligand lipopolysaccharide (LPS) on melanin synthesis in a vitiligo melanocyte cell line PIG3V and along with its mechanism. LPS suppressed melanin synthesis, downregulated the expression of melanin synthesis‐related proteins and activated autophagy in vitiligo melanocytes. Inhibiting autophagy with 3‐methyladenine or chloroquine blocked these effects. This suggests that LPS inhibits skin pigmentation by modulating autophagy, thus providing novel insights into the pathogenesis of vitiligo. [ABSTRACT FROM AUTHOR]

Melanocytes are highly specialized dendritic cells that synthesize and store melanin in subcellular organelles called melanosomes, before transfer to keratinocytes. Melanin is a complex pigment that provides colour and photoprotection to the skin, hair and eyes. The process of synthesis of melanin is called melanogenesis and is regulated by various mechanisms and factors such as genetic, environmental and endocrine factors. The knowledge of the pigmentation process is important to understand hypopigmentation disorders such as vitiligo and also to design adequate treatments. In the present work, we review the signalling pathways involved in vitiligo. Finally, current therapies and treatments including topical, oral and phototherapies are discussed and described, emphasizing future therapies based on different pigmentation mechanisms. [ABSTRACT FROM AUTHOR]

Clove, a dried flower buds of Syzygium aromaticum, is used in traditional medicine, for culinary purposes, and in essential oil production. In our preliminary screening of crude drugs used in Japanese Kampo formulas, a methanol (MeOH) extract of clove buds was found to exhibit a melanin induction. To date, the effects of clove buds or their constituents on the activation of melanogenesis remain unclear. Thus, this study aimed to isolate active compounds from the MeOH extract of clove buds associated with melanin synthesis in melanoma cells and to investigate the molecular mechanism involved. The MeOH extract of clove buds increased melanin content in murine B16-F1 melanoma cells. To identify the active compounds responsible for melanin induction, the MeOH extract was suspended in water and successively partitioned using hexane, ethyl acetate (EtOAc), and n-butanol (n-BuOH). Comparative analysis revealed that the EtOAc fraction induced melanin synthesis. Bioassay-guided separation of the EtOAc fraction isolated three compounds including eugenol. The analysis of structure-activity relationships of eugenol and structurally related compounds indicated that eugenol was the most potent melanin inducer among the 11 compounds, and that a hydroxyl group at C-1 and a methoxy group at C-2 may contribute to melanin induction. Eugenol induced melanin synthesis in human HMV-II melanoma cells as well as in B16-F1 cells. Further analysis indicated that eugenol may invoke intracellular tyrosinase activity and expression of tyrosinase, tyrosinaserelated protein (TRP)-1, TRP-2, and microphthalmia-associated transcription factor (MITF). These results suggest that eugenol enhances melanin synthesis by upregulating the expression of MITF and subsequent expression of melanogenic enzymes, and that it may be a potent therapeutic agent for hypopigmentation. [ABSTRACT FROM AUTHOR]

Secreted frizzled-related protein 5 (SFRP5) plays a pivotal role in regulating the development of many tissues and organs, however, as an inhibitor of Wnt signaling, the role of SFRP5 in vitiligo remains unknown. Hence, we speculated that SFRP5 might be associated with melanogenesis in melanocytes by regulating Wnt signaling in vitiligo. In this study, we found that SFRP5 was overexpressed in the skin lesions of patients with vitiligo. Compared with that in normal epidermal melanocytes (PIG1), the expression of SFRP5 was increased in vitiligo melanocytes (PIG3V). To investigate the effect of SFRP5 on melanin synthesis, PIG1 cells were infected with recombinant SFRP5 adenovirus (AdSFRP5), and PIG3V cells were infected with recombinant siSFRP5 adenovirus (AdsiSFRP5). The results showed that SFRP5 overexpression inhibited melanin synthesis in PIG1 cells through downregulation of microphthalmia-associated transcription factor (MITF) and its target proteins via suppression of the Wnt/β-catenin signaling pathway. Accordingly, SFRP5 silencing increased melanin synthesis and activated the Wnt signaling pathway in PIG3V cells. Moreover, SFRP5 overexpression also downregulated the transcriptional activity of T cell factor/lymphoid enhancer factor (TCF/LEF) in PIG1 cells. Furthermore, this inhibitory effect of SFRP5 on melanin synthesis was reversed by treatment with the β-catenin agonist, SKL2001. The inhibitory action of SFRP5 in pigmentation was further confirmed in vivo using a nude mouse model. Hence, our results indicate that SFRP5 can inhibit melanogenesis in melanocytes. Additionally, our findings showed that SFRP5 plays a vital role in the development of vitiligo, and thus may serve as a potential therapeutic target for vitiligo.

Simple Summary: Alternative splicing (AS) is one of the hallmarks of human cancer. One of the most common mechanisms of vemurafenib resistance in malignant melanoma is AS of BRAF, occurring in 15–30% of patients. The aim of our study was to investigate the transcriptome and AS D04landscape in the isogenic BRAF V600E cell line pair SK-MEL-239, where the vemurafenib-resistant derivative expresses a truncated BRAF transcript that lacks the RAS-binding domain. Transcriptome analysis showed differential expression of spliceosome components between the two cell lines. AS analysis, by four different tools, DEXSeq, rMATS, ASpli, and LeafCutter, has identified genes enriched for cell motility and melanin synthesis in vemurafenib-resistant cells. Overlapping predictions for all four tools have been experimentally validated. Our study expands the understanding of melanoma drug resistance from a new perspective and supports the need to investigate in detail the aberrant AS landscape in patients with malignant melanoma. Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS in SK-MEL-239 melanoma cells and a BRAF inhibitor (vemurafenib)-resistant derivative that expresses an AS, shortened BRAF V600E transcript. Transcriptome analysis showed differential expression of spliceosome components between the two cell lines. As there is no consensus approach to analysing AS events, we used and compared four common AS softwares based on different principles, DEXSeq, rMATS, ASpli, and LeafCutter. Two of them correctly identified the BRAF V600E AS in the vemurafenib-resistant cells. Only 12 AS events were identified by all four softwares. Testing the AS predictions experimentally showed that these overlapping predictions are highly accurate. Interestingly, they identified AS caused alterations in the expression of melanin synthesis and cell migration genes in the vemurafenib-resistant cells. This analysis shows that combining different AS analysis approaches produces reliable results and meaningful, biologically testable hypotheses. [ABSTRACT FROM AUTHOR]

The effect of oral supplementation with astaxanthin of different Z-isomer ratios on ultraviolet (UV) light-induced skin damage in guinea pigs was investigated. Astaxanthin with a high Z-isomer content was prepared from the all-E-isomer via thermal isomerization. Intact (all-E)-astaxanthin and the prepared Z-isomer-rich astaxanthin were suspended in soybean oil and fed to guinea pigs for three weeks. The UV-light irradiation was applied to the dorsal skin on the seventh day after the start of the test diet supplementation, and skin parameters, such as elasticity, transepidermal water loss (TEWL), and pigmentation (melanin and erythema values), were evaluated. The accumulation of astaxanthin in the dorsal skin was almost the same after consumption of the all-E-isomer-rich astaxanthin diet (E-AST-D; total Z-isomer ratio = 3.2%) and the Z-isomer-rich astaxanthin diet (Z-AST-D; total Z-isomer ratio = 84.4%); however, the total Z-isomer ratio of astaxanthin in the skin was higher in the case of the Z-AST-D supplementation. Both diets inhibited UV light-induced skin-damaging effects, such as the reduction in elasticity and the increase in TEWL level. Between E-AST-D and Z-AST-D, Z-AST-D showed better skin-protective ability against UV-light exposure than E-AST-D, which might be because of the greater UV-light-shielding ability of astaxanthin Z-isomers than the all-E-isomer. Furthermore, supplementation with Z-AST-D resulted in a greater reduction in skin pigmentation caused by astaxanthin accumulation compared to that of E-AST-D. This study indicates that dietary astaxanthin accumulates in the skin and appears to prevent UV light-induced skin damage, and the Z-isomers are more potent oral sunscreen agents than the all-E-isomer. [ABSTRACT FROM AUTHOR]

Plectropomus leopardus is a valuable marine aquaculture fish, prized by consumers for its high nutritional value and gorgeous appearance. The economic significance of this species is largely influenced by its body color, prompting researchers to become increasingly interested in understanding the mechanisms behind its color formation. However, previous studies have mainly focused on the molecular mechanisms of body color formation during the adult stage of this species. In this study, it was observed that the body color of P. leopardus undergoes four distinct stages during early morphogenesis: transparent (PT), red (PR), red with spots (PRS), and brown with spots (PBS). The L*a*b* values of skin at each stage differ significantly. The number and distribution of erythrophores and melanophores play a crucial role in determining the body colors of P. leopardus. Transcriptome analysis of the skin at these stages revealed multiple differentially expressed genes (DEGs) and signaling pathways related to pigmentation. These pigmentation-related DEGs can be categorized into carotenoid metabolism-related genes (e.g., scarb1, ldlr, plin2, apod, ttc39b , etc), melanin synthesis-related genes (e.g., tyr, tyrp1, dct, pmel, slc7a11 , etc), and genes related to pigment cell development (pnp, ednrb, csf1r1, sox10, bnc2). GO and KEGG enrichment analysis indicated that processes like melanin synthesis (e.g., wnt signal pathway, melanogenesis, tyrosine metabolism, etc.), lipid metabolism (e.g., cholesterol metabolism, linoleic acid metabolism, arachidonic metabolism, fatty acid biosynthesis, etc.), and pigment cell development (e.g., pigment cell differentiation, cell development, etc.) are likely involved in the body color formation in P. leopardus. Finally, we proposed a hypothesis regarding carotenoid metabolism in erythrophores and melanin synthesis in melanophores of P. leopardus skin, drawing from existing research reports and transcriptome data. Overall, this study provides a new perspective on the molecular regulatory mechanisms of body color formation in P. leopardus , laying a theoretical foundation for molecular-assisted breeding of body color traits in this species. • P. leopardus undergoes four distinct body color stages during early morphogenesis. • Genes and pathways related to carotenoid metabolism, melanin synthesis and pigment cell development were identified. • Proposed a hypothesis about carotenoid metabolism in erythrophores and melanogenesis in melanophores of P. leopardus skin. [ABSTRACT FROM AUTHOR]

The visually appealing shell colours and intricate patterns of shellfish not only attract consumers but also enhance their economic value. Understanding the inheritance pattern of shell colour and the molecular mechanism of pigmentation is highly important for enhancing breeding efficiency. This study involved the identification of a tyrosine hydroxylase gene (CgTH) and the investigation of its function in the metabolism of tyrosine and pigmentation in Pacific oysters (Crassostrea gigas). Cg TH contains a conserved Biopterin_H domain that consists of a binding site for iron atoms and a binding site for tetrahydrobiopterin (BH4). Quantitative PCR (qPCR) and immunofluorescence analysis revealed that the expression of Cg TH was higher in the mantle of black shell oysters in comparison to the white strain. The in vitro and in vivo experiments confirmed that Cg TH is involved in tyrosine metabolism through the catalysis of the conversion of L-tyrosine to L-DOPA. In order to examine its functions in melanin synthesis in oysters, 3-Iodo-L-tyrosine (3-IT) treatment, RNA interference (RNAi), and L-DOPA treatment assays were conducted. The results of our study showed that 3-IT effectively inhibited Cg TH activity, leading to a suppression of tyrosine metabolism. Knockdown of Cg TH hindered the cAMP-CREM-MITF axis and decreased pigmentation. On the other hand, L-DOPA stimulated melanin production through cAMP signaling and counteracted the inhibitory effects of 3-IT on the metabolism of tyrosine. These data indicated that there may be a feedback loop involving Cg TH and the cAMP-CREM-MITF axis that regulates tyrosine metabolism and melanogenesis in Pacific oysters. This study enhances our understanding of the molecular mechanism that governs oyster pigmentation and offers a possible molecular indicator for the targeted breeding of particular strains of Pacific oysters. • A Cg TH gene was identified and characterized in Pacific oysters. • Cg TH catalyze L-tyrosine to L-DOPA. • Cg TH knockdown inhibited tyrosine metabolism and reduced melanin synthesis and pigmentation. • A feedback loop involving Cg TH and cAMP-CREM-MITF axis regulates melanin synthesis. [ABSTRACT FROM AUTHOR]

Colorful shells in mollusks are commonly attributable to the presence of biological pigments. In Pacific oysters, the inheritance patterns of several shell colors have been investigated, but little is known about the molecular mechanisms of melanogenesis and pigmentation. cAMP-response element binding proteins (CREB) are important transcription factors in the cAMP-mediated melanogenesis pathway. In this study, we characterized two CREB genes (CREB3L2 and CREB3L3) from Pacific oysters. Both of them contained a conserved DNA-binding and dimerization domain (a basic-leucine zipper domain). CREB3L2 and CREB3L3 were expressed highly in the mantle tissues and exhibited higher expression levels in the black-shell oyster than in the white. Masson-Fontana melanin staining and immunofluorescence analysis showed that the location of CREB3L2 protein was generally consistent with the distribution of melanin in oyster edge mantle. Dual-luciferase reporter assays revealed that CREB3L2 and CREB3L3 could activate the microphthalmia-associated transcription factor (MITF) promoter and this process was regulated by the level of cAMP. Additionally, we found that cAMP regulated melanogenic gene expression through the CREB-MITF-TYR axis. These results implied that CREB3L2 and CREB3L3 play important roles in melanin synthesis and pigmentation in Pacific oysters. [Display omitted] • Two transcription factors (CREB3L2 and CREB3L3) were characterized from Pacific oysters. • CREB3L2 and CREB3L3 regulated MITF expression under cAMP regulation. • A cAMP-CREB-MITF axis regulated melanogenesis in Pacific oysters. [ABSTRACT FROM AUTHOR]

Sox transcription factors are vital in numerous fundamental biological processes. In this study, nine Sox gene family members were discovered in the Ruditapes philippinarum genome, classified into the SoxB1, SoxB2, SoxC, SoxD, SoxE, and SoxF groups, marking the first genome-wide identification of this gene family in R. philippinarum. Analyses of phylogeny, exon-intron structures, and domains bolster the support for their categorization and annotation. Furthermore, transcriptomic analyses across various developmental stages revealed that RpSox4, RpSox5, RpSox9, and RpSox11 were significantly expressed in the D-larval stage. Additionally, investigations into transcriptomes of clams with different shell colors indicated that most sox genes exhibited their highest expression levels in orange clams, followed by zebra, white zebra, and white clams, and the results of transcriptomes analysis in different tissues indicated that 8 Sox genes (except RpSox17) were highly expressed in the mantle tissue. Moreover, qPCR was used to detect the expression of Sox gene in R. philippinarum at different developmental periods, different shell colors and different tissues, and the results showed consistency with those of the transcriptomes. This study's findings lay the groundwork for additional exploration into the role of the Sox gene in melanin production in R. philippinarum shells. [Display omitted] • Identification and gene structure of Sox genes was reported in R. philippinarum. • The expression of Sox genes in different shell color and development stages were analyzed. • Sox genes were potentially involved in development and shell color in R. philippinarum. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine (5-HT)) is a biogenic monoamine with pleiotropic functions. It exerts its roles by binding to specific 5-HT receptors (5HTRs) classified into different families and subtypes. Homologs of 5HTRs are widely present in invertebrates, but their expression and pharmacological characterization have been scarcely investigated. In particular, 5-HT has been localized in many tunicate species but only a few studies have investigated its physiological functions. Tunicates, including ascidians, are the sister group of vertebrates, and data about the role of 5-HTRs in these organisms are thus important for understanding 5-HT evolution among animals. In the present study, we identified and described 5HTRs in the ascidian Ciona intestinalis. During development, they showed broad expression patterns that appeared consistent with those reported in other species. Then, we investigated 5-HT roles in ascidian embryogenesis exposing C. intestinalis embryos to WAY-100635, an antagonist of the 5HT1A receptor, and explored the affected pathways in neural development and melanogenesis. Our results contribute to unraveling the multifaceted functions of 5-HT, revealing its involvement in sensory cell differentiation in ascidians.

Simple Summary: Zebrafish (Danio rerio) is an emerging model for studying many diseases, including disorders originating in black pigment cells, melanocytes. In this review of the melanocyte literature, we discuss the current knowledge of melanocyte biology relevant to understanding different forms of albinism and the potential of the zebrafish model system for finding novel mechanisms and treatments. Melanin is the pigment that protects DNA from ultraviolet (UV) damage by absorbing excess energy. Melanin is produced in a process called melanogenesis. When melanogenesis is altered, diseases such as albinism result. Albinism can result in an increased skin cancer risk. Conversely, black pigment cell (melanocyte) development pathways can be misregulated, causing excessive melanocyte growth that leads to melanoma (cancer of melanocytes). Zebrafish is an emerging model organism used to study pigment disorders due to their high fecundity, visible melanin development in melanophores (melanocytes in mammals) from 24 h post-fertilization, and conserved melanogenesis pathways. Here, we reviewed the conserved developmental pathways in zebrafish melanophores and mammalian melanocytes. Additionally, we summarized the progress made in understanding pigment cell disease and evidence supporting the strong potential for using zebrafish to find novel treatment options for albinism. [ABSTRACT FROM AUTHOR]

Sorbus commixta is a tree of the Rosaceae family growing in Asia that has long been used to treat asthma and neuralgia. In a previous report, the chemical isolated from the bark of S. commixta was shown to suppress the production of nitric oxide (NO) and preinflammation by downregulating the NF-кB pathway in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Vitiligo is an acquired immune disease, usually characterized by white spots on the skin; however, its exact cause has not been identified. This study assessed the effects of an ethanol extract of S. commixta twigs (STE) on melanocyte activation, as well as its antiinflammatory and antioxidant properties. STE significantly increased the proliferation and melanin content of B16 melanocytes. Because of the importance of tumor necrosis factor (TNF)-α in inflammatory diseases, including the stimulation of vitiligo, the antiinflammatory effects of STE were tested in TNF-α-stimulated dermal fibroblasts and keratinocytes. STE reduced the levels of expression of IL-6, IL-8 and TNF-α mRNA and proteins. To assess the underlying molecular mechanism, the effects of STE on the mitogen-activated protein kinase (MAPK) signaling process were analyzed in dermal fibroblasts. Results show that STE inactivated extracellular signal-regulated kinase (ERK). In addition, STE exhibited antioxidative properties in assays of DPPH radical scavenging activity. Taken together, these findings suggest that STE has potential therapeutic activity in vitiligo.

Furocoumarins, such as 8-MOP, are the most common medications used to relieve the symptoms of vitiligo clinically. Some furocoumarins also showed excellent performance in an anti-bacterial assay. This paper describes the synthesis of a series of novel Schiff bases (6a-6k), and their promotion in melanogenesis and anti-bacterial properties were studied in vitro.

This study aims to evaluate the effect of protocatechuic acid (PCA) on human hair follicle melanocytes (HFM). Normal primary HFM were isolated and cultured till logarithmic period of second passage, then treated with different concentrations of PCA (0.1–200 μmol L−1) to study the cell proliferation, melanin contents, tyrosinase activity and protein and mRNA expression of melanogenic genes (tyrosinase-related protein 1 (TRP-1), tyrosinase-related protein 2 (TRP-2), and microphthalmia-associated transcription factor (MITF)) in the cultured HFM. In addition, we have also measured the contents of superoxide dismutase (SOD) and glutathione (GSH) in PCA treated HFM. Vitamin C was used as a positive control. The result showed that PCA can decrease the synthesis of melanin and the tyrosinase activity with IC50 = 8.9 μmol L−1 and IC50 = 6.4 μmol L−1, respectively, at the treatment time of 24 hours, without inducing any cytotoxicity in HFM cells. In addition, the mRNA transcription and protein expression levels of TRP-1, TRP-2 and MITF significantly decreased with a dose-dependent manner after 24-hour PCA treated in HFM cells. Furthermore, PCA has significantly increased the SOD and GSH activity in a dose-dependent manner for 24-hour PCA treatment. This study suggested that PCA has an inhibitory effect on the production of melanin through down-regulation of the expression of melanogenesis-related protein and the effect of anti-oxidation, which could be useful for the therapy of melanin overproduction or skin whitening.

Phenylalanine hydroxylase (PAH) is involved in immune defence reactions by providing the starting material, tyrosine, to synthesise catecholamines and melanin. PAH is an important metabolic enzyme of aromatic amino acids and the rate-limiting enzyme in the hydroxylation of amino acid phenylalanine to tyrosine. In the present study, a PAH gene, LvPAH, was cloned and identified from Litopenaeus vannamei. The open reading frame (ORF) of LvPAH was 1383 bp, encoding a protein of 460 amino acids comprised of an ACT domain and a Biopterin_H domain. LvPAH was constitutively expressed in healthy L. vannamei , with the highest expression levels in the eyestalk and the lowest in the hepatopancreas. Both white spot syndrome virus (WSSV) and Vibrio parahaemolyticus infection upregulated LvPAH expression in hemocytes, hepatopancreas and gills of L. vannamei. Inhibition of LvPAH resulted in a significantly lower survival rate of L. vannamei after WSSV infection than the control group, consistent with the observation that WSSV viral load was significantly higher in LvPAH-silenced L. vannamei. After a V. parahaemolyticus challenge, there was no significant difference between the survival rate of LvPAH-silenced and the control L. vannamei. However, the load of V. parahaemolyticus in LvPAH-silenced L. vannamei was significantly higher than the control population for L. vannamei. The effect of LvPAH on L. vannamei from a neuroendocrinological perspective was assessed by measuring l -DOPA, dopamine (DA) and noradrenaline (NE) levels in the hemocytes after the knockdown of LvPAH. The results showed that phenoloxidase (PO), l -DOPA and DA levels in the hemolymph of LvPAH-silenced L. vannamei were significantly decreased starting from 24hpi. In contrast, the NE levels in the hemolymph of shrimp decreased significantly at first and then increased. The results suggest that LvPAH may play an important role in antiviral and bacterial immunity in L. vannamei. • PAH gene was cloned from Litopenaeus vannamei. • LvPAH expression could be induced by WSSV and Vibrio parahaemolyticus infection. • dsRNA-LvPAH injection significantly decreased the survival rates of L. vannamei after WSSV infection. • The loads of WSSV and V. parahaemolyticus in dsRNA-LvPAH injected L. vannamei were significant higher than the control. • The melanisation was regulated by LvPAH silence. [ABSTRACT FROM AUTHOR]

The transgenesis of silkworms is an important way to innovate genetic resources and silk function. However, the silk-gland (SG) of transgenic silkworms, which is the most concerned target tissue of sericulture, often suffers from low vitality, stunting and other problems, and the reasons are still unknown. This study trans engineered recombinant Ser3, a middle silk gland (MSG) specific expression gene, in the posterior silk gland (PSG) of the silkworm, and studied hemolymph immune melanization response changes in mutant pure line SER (Ser3+/+). The results showed that although the mutant had normal vitality, the melanin content and phenoloxidase (PO) activity in hemolymph related to humoral immunity were significantly reduced, and caused significantly slower blood melanization and weaker sterilization ability. The mechanism investigation showed that the mRNA levels and enzymatic activities of phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and dopamine decarboxylase (DDC) in the melanin synthesis pathway in mutant hemolymph, as well as the transcription levels of the PPAE, SP21 and serpins genes in the serine protease cascade were significantly affected. Moreover, the total antioxidant capacity, superoxide anion inhibition capacity and catalase (CAT) level related to the redox metabolic capacity of hemolymph were significantly increased, while the activities of superoxide dismutase (SOD) and glutathione reductase (GR), as well as the levels of hydrogen peroxide (H2O2) and glutathione (GSH), were significantly decreased. In conclusion, the anabolism of melanin in the hemolymph of PSG transgenic silkworm SER was inhibited, while the basic response level of oxidative stress was increased, and the hemolymph immune melanization response was decreased. The results will significantly improve the safe assessment and development of genetically modified organisms.

Nostoc verrucosum, an edible microalgal species, forms colonies in streams. Here, we investigated the antimelanogenic and anti-oxidative effects of N. verrucosum extracts. We collected N. verrucosum from Toyama Prefecture, Japan, and successfully cultured it in indoor cultivation systems. Aqueous, methanol, and hexane extracts of N. verrucosum were prepared for various experiments. To elucidate the antimelanogenic effects of N. verrucosum, we performed tyrosinase assay, melanin content assay, western blotting, and real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Anti-oxidative effects were evaluated using the 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assay. The methanol and hexane extracts significantly inhibited melanin synthesis in B16F1 melanoma cells. Western blotting showed that 12.5 and 25.0 µg/mL N. verrucosum hexane extract suppressed tyrosinase activity. The qRT-PCR analysis revealed that N. verrucosum hexane extract inhibited α-melanocyte stimulating hormone-enhanced tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, and melanocortin 1 receptor (MC1R) mRNA expression. On the contrary, N. verrucosum hexane extract did not alter microphthalmia-associated transcription factor (Mitf) transcription. The ABTS assay showed that all extracts had radical scavenging activities, and the IC50 values of the aqueous and methanol extracts were 294.6 and 172.8 µg/mL, respectively. Our findings demonstrate that N. verrucosum is a suitable candidate for the development of antimelanogenic agents, cosmetics, or functional food ingredients.

Cyclobutane pyrimidine dimers (CPDs) are ultraviolet radiation (UV)-induced carcinogenic DNA photoproducts that lead to UV signature mutations in melanoma. Previously, we discovered that, in addition to their incident formation (iCPDs), UV exposure induces melanin chemiexcitation (MeCh), where UV generates peroxynitrite (ONOO−), which oxidizes melanin into melanin-carbonyls (MCs) in their excited triplet state. Chronic MeCh and energy transfer by MCs to DNA generates CPDs for several hours after UV exposure ends (dark CPD, dCPDs). We hypothesized that MeCh and the resulting dCPDs can be inhibited using MeCh inhibitors, and MC and ONOO− scavengers. Here, we investigated the efficacy of Acetyl Zingerone (AZ), a plant-based phenolic alkanone, and its chemical analogs in inhibiting iCPDs and dCPDs in skin fibroblasts, keratinocytes, and isogenic pigmented and albino melanocytes. While AZ and its methoxy analog, 3-(4-Methoxy-benzyl)-Pentane-2,4-dione (MBPD) completely inhibited the dCPDs, MBPD also inhibited ~50% of iCPDs. This suggests the inhibition of ~80% of total CPDs at any time point post UV exposure by MBPD, which is markedly significant. MBPD downregulated melanin synthesis, which is indispensable for dCPD generation, but this did not occur with AZ. Meanwhile, AZ and MBPD both upregulated the expression of nucleotide excision repair (NER) pathways genes including Xpa, Xpc, and Mitf. AZ and its analogs were non-toxic to the skin cells and did not act as photosensitizers. We propose that AZ and MBPD represent “next-generation skin care additives” that are safe and effective for use not only in sunscreens but also in other specialized clinical applications owing to their extremely high efficacy in blocking both iCPDs and dCPDs.

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.

Sorbus commixta is a tree of the Rosaceae family growing in Asia that has long been used to treat asthma and neuralgia. In a previous report, the chemical isolated from the bark of S. commixta was shown to suppress the production of nitric oxide (NO) and preinflammation by downregulating the NF-B pathway in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Vitiligo is an acquired immune disease, usually characterized by white spots on the skin; however, its exact cause has not been identified. This study assessed the effects of an ethanol extract of S. commixta twigs (STE) on melanocyte activation, as well as its antiinflammatory and antioxidant properties. STE significantly increased the proliferation and melanin content of B16 melanocytes. Because of the importance of tumor necrosis factor (TNF)-a in inflammatory diseases, including the stimulation of vitiligo, the antiinflammatory effects of STE were tested in TNF-a-stimulated dermal fibroblasts and keratinocytes. STE reduced the levels of expression of IL-6, IL-8 and TNF-a mRNA and proteins. To assess the underlying molecular mechanism, the effects of STE on the mitogen-activated protein kinase (MAPK) signaling process were analyzed in dermal fibroblasts. Results show that STE inactivated extracellular signal-regulated kinase (ERK). In addition, STE exhibited antioxidative properties in assays of DPPH radical scavenging activity. Taken together, these findings suggest that STE has potential therapeutic activity in vitiligo. [ABSTRACT FROM AUTHOR]

Although various marine ingredients have been exploited for the development of cosmetic products, no previous study has examined the potential of seaweed extracellular vesicles (EV) in such applications. Our results revealed that EV from Codium fragile and Sargassum fusiforme effectively decreased α-MSH-mediated melanin synthesis in MNT-1 human melanoma cells, associated with downregulation of MITF (microphthalmia-associated transcription factor), tyrosinase and TRP1 (tyrosinase-related proteins 1). The most effective inhibitory concentrations of EV were 250 µg/ml for S. fusiforme and 25 µg/ml for C. fragile, without affecting the viability of MNT-1 cells. Both EV reduced melanin synthesis in the epidermal basal layer of a three-dimensional model of human epidermis. Moreover, the application of the prototype cream containing C. fragile EV (final 5 µg/ml) yielded 1.31% improvement in skin brightness in a clinical trial. Together, these results suggest that EV from C. fragile and S. fusiforme reduce melanin synthesis and may be potential therapeutic and/or supplementary whitening agents. [ABSTRACT FROM AUTHOR]

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Five indole derivatives, 1H-indol-7-ol (1), tryptophol (2), 3-indolepropionic acid (3), tryptophan (4), 3,3-di(1H-indol-3-yl)propane-1,2-diol (5) and two diketopiperazines, cyclo(L-Pro-L-Tyr) (6), cyclo[L-(4-hydroxyprolinyl)-L-leucine (7) along with one dihydrocinnamic acid (8) were isolated from Pantoea ananatis VERA8, that endophytic bacteria derived from Baccharoides anthelmintica roots. This is a first report towards an isolation of endophytic strains (funji or bacteria) from the B. anthelmintica herb. The synergetic properties of the total extract compositions, as well as effects of the pure isolated secondary metabolites evaluated on their melanin synthesis in murine B16 cells towards for vitiligo treatment. [ABSTRACT FROM AUTHOR]

Melanin pigment is a major factor in determining the color of the skin, and its abnormal increase or decrease can cause serious pigmentation disorders. The melanin pigment of the skin is divided into light pheomelanin and dark eumelanin, and a big difference between them is whether they contain sulfur. Melanin synthesis starts from a common reaction in which tyrosine or dihydroxyphenylalanine (DOPA) is oxidized by tyrosinase (TYR) to produce dopaquinone (DQ). DQ is spontaneously converted to leukodopachrome and then oxidized to dopachrome, which enters the eumelanin synthesis pathway. When DQ reacts with cysteine, cysteinyl dopa is generated, which is oxidized to cysteinyl DQ and enters the pheomelanin synthesis pathway. Therefore, thiol compounds can influence the relative synthesis of eumelanin and pheomelanin. In addition, thiol compounds can inhibit enzymatic activity by binding to copper ions at the active site of TYR, and act as an antioxidant scavenging reactive oxygen species and free radicals or as a modulator of redox balance, thereby inhibiting overall melanin synthesis. This review will cover the metabolic aspects of thiol compounds, the role of thiol compounds in melanin synthesis, comparison of the antimelanogenic effects of various thiol compounds, and clinical trials on the skin lightening efficacy of thiol compounds. We hope that this review will help identify the advantages and disadvantages of various thiol compounds as modulators of skin pigmentation and contribute to the development of safer and more effective strategies for the treatment of pigmentation disorders.

Skin-whitening effect is closely linked with the melanogenesis inhibitory activity and free radical scavenging capacity. The purpose of the present study was to evaluate the skin-whitening effect of cumin (Cuminum cyminum L.) extract. The whitening activity was evaluated by cell-free mushroom tyrosinase assay, free radical scavenging assay, cell viability assay, cellular tyrosinase assay and melanin content assay using B16F10 murine melanoma cells. The results showed that cumin extract exhibited concentration-dependent inhibitory effect on both monophenolase and diphenolase activities of mushroom tyrosinase (IC50 values of 1.027mg/mL and 0.977mg/mL, respectively). Kinetic study on diphenolase showed that the cumin extract was a reversible mixed-type inhibitor, and the inhibition constant (KI) was determined to be 0.62mg/mL. In addition, cumin extract significantly suppressed melanin production and cellular tyrosinase activity of B16F10 melanoma cells in a concentration and time dependent manner without cytotoxicity. Moreover, cumin extract exerted strong scavenging capacity on DPPH, hydroxyl and superoxide anion radicals. Taken together, these results strongly suggest that cumin is a potential skin-whitening agent for the cosmetic industry. [ABSTRACT FROM AUTHOR]

Homo sapiens evolved in East Africa and had dark skin, hair, and eyes, in order to protect against deleterious consequences of intensive UV radiation at equatorial latitudes. Intensive skin pigmentation was thought to bear the risk of inefficient vitamin D3 synthesis in the skin. This initiated the hypothesis that within the past 75 000 years, in which humans migrated to higher latitudes in Asia and Europe, the need for vitamin D3 synthesis served as an evolutionary driver for skin lightening. In this review, we summarize the recent archeogenomic reconstruction of population admixture in Europe and demonstrate that skin lightening happened as late as 5000 years ago through immigration of lighter pigmented populations from western Anatolia and the Russian steppe but not primarily via evolutionary pressure for vitamin D3 synthesis. We show that variations in genes encoding for proteins being responsible for the transport, metabolism and signalling of vitamin D provide alternative mechanisms of adaptation to a life in northern latitudes without suffering from consequences of vitamin D deficiency. This includes hypotheses explaining differences in the vitamin D status and response index of European populations. [ABSTRACT FROM AUTHOR]

Background/Aim: Hydrogen sulfide (H2S) has been found to act as a physiological intercellular messenger to regulate cell survival. In this study, we evaluated whether H2S could promote cell proliferation and melanin synthesis in human epidermal melanocytes (HEMs). Methods: Primary HEMs were cocultured with sodium hydrosulfide (NaHS, the most widely used H2S donor) or endogenously overexpressed with cystathionine-γ-lyase (CSE) gene, which is the most predominant H2S-producing enzyme. Then, cell viability, intracellular melanin content, tyrosinase (TYR) activity, and expression of microphthalmia-associated transcription factor (MITF), TYR, together with TYR-related protein 1 (TRP-1) in both transcript and protein levels, were detected. Results: We first confirmed that NaHS (10–100 μm) increased cell viability, intracellular melanin content, and TYR activity in a dose-dependent manner. Then, we found that endogenous H2S production also promoted cell proliferation, intracellular melanin content, and TYR activity. In addition, we observed the mRNA and protein expression of MITF, TYR, and TRP-1 was significantly up-regulated after NaHS treatment and CSE gene transfection. Conclusions: This study demonstrates that H2S promotes cell proliferation and melanin synthesis in HEMs, which indicates pharmacologic regulation of H2S may be potential treatment for skin disorders caused by loss of melanocytes or dysfunction of melanogenesis. [ABSTRACT FROM AUTHOR]