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There are growing numbers of significant skin disorders, including skin pigmentation. It states that skin color is determined by the amount of melanin produced by the body. The two main categories of skin pigmentation are hyperpigmentation, in which pigment seems to overflow, and hypopigmentation, in which pigment appears to decrease. However, many skin conditions share characteristics, making it difficult for dermatologists to correctly early diagnose their patients. Consequently, the accurate detection of skin disorders and the diagnosis of dermatoscopy pictures can be greatly aided by machine learning and deep learning approaches. The most effective deep learning technique for picture identification was investigated to diagnose hyperpigmented skin diseases. YOLO, DenseNet201, GoogLeNet, InceptionResNetV2, and MobileNet were among the pretrained models used to classify four most common hyperpigmented skin disorders. Using assessment metrics like accuracy and AUC (Area Under Curve), it was determined which deep learning method would work best for creating a clinical diagnostic system. The study analyzed the accuracy rates of five pretrained models, including GoogleNet, MobileNet, DenseNet201, InceptionResNetV2, and YOLO, after 50 iterations. Using metrics such as accuracy and Area Under the Curve (AUC), the study evaluated the models' performance on a small dataset split into 80% for training and 20% for testing. Training accuracy rates were 93.8%, 100%, 100%, 98.77%, and 97.43%, respectively, while test accuracy rates were 87.18%, 79.49%, 87.18%, 89.74%, and 97.56%. DenseNet201 showed strong performance, particularly for cafe-au-lait spots (CS), melasma (ML), and nevi (MN), but struggled with congenital nevus (CN). Despite DenseNet201′s strong traditional CNN capabilities and generalization, YOLO emerged as the top model due to its stable accuracy and AUC values, as confirmed by confusion matrices. While these models show promise as diagnostic tools for dermatologists, further research, including expanding the dataset and exploring hybrid models, is needed to enhance their clinical accuracy and effectiveness. [ABSTRACT FROM AUTHOR]

4- n -butylresorcinol (4-nBR) is a valuable ingredient to lighten skin and reduce pigmentation, contributing to an even skin tone and a more youthful appearance. However, its poor solubility, low stability, and strong irritation to the skin limit its application. In this study, 4-nBR was prepared into 4- n -butylresorcinol nanoemulsion (4-nBR-NE) for the first time, enhancing the solubility and stability of 4-nBR while greatly reducing its skin irritation. The relationship between the viscosity of nanoemulsion and the formulation process, as well as the impact of surfactant ratio on the formability of 4-nBR-NE were further studied. This led to the successful development of a nanoemulsion with adjustable viscosity (AV-NE) and with a low surfactant content. The particle size of 4-nBR-NE was 13.34 ± 0.16 nm with a PDI of 0.0853 ± 0.0191, indicating a uniform particle size distribution. The encapsulation rate of 4-nBR-NE was determined to be 80.05 ± 0.75 % via UV–Vis spectrophotometry. In addition, 4-nBR-NE demonstrated excellent stability over several months, with negligible changes in particle size. Cellular and transdermal evaluations confirmed that the preparation of 4-nBR-NE effectively reduced the original irritation cause by 4-nBR on cells and skin. Then, 4-nBR-NE was incorporated into an essence. This advancement enhances the applicability of 4-nBR in treating pigmentation disorders such as melasma and freckles, thereby increasing its applicability in pharmaceutical and cosmetic industries. [Display omitted] • 4-nBR has excellent to treat hyperpigmentation, its low solubility, skin irritation and poor stability severely limit its applications. • The use of nanoemulsion formulations could significantly improve the solubility and stability of 4-nBR. • As a carrier, nanoemulsion can reduce skin irritation and improve the percutaneous absorption efficiency of 4-nBR. • A nanoemulsion with adjustable viscosity and nanoemulsion with low surfactant content has been successfully developed. [ABSTRACT FROM AUTHOR]

Objectify: Skin pigmentation disorders are one of the most frequent sequelae after burn injury. While these conditions often improve over time, some are permanent and cause severe psychological disorders (especially on the face). Given the frequency of these disorders and their benign nature, the scientific community has great difficulty postponing these patient follow-ups. Publications on their management are rare, and there is no consensus on the gold standard treatment for skin dyschromia. Herein, we performed a literature review including the various treatments currently proposed to manage these hyperpigmentations.Methods: All reported articles up to February 2021 were reviewed on Pubmed. Studies on the treatment of hyperpigmented scars were included if they were secondary to burn injuries. Excluded articles evaluated transient treatments, such as makeup, and articles on inflammatory hyperpigmentation without etiological details or not secondary to burns.Results: 201 articles were identified, and 13 studies were included. Topical creams used in inflammatory hyperpigmented lesions such as hydroquinone and first-line retinoids are controversial due to their inconstant efficacy. Various types of laser and pulsed light treatments have shown their effectiveness but can also aggravate pigmentation.Conclusion: Dyschromia after burn remains a therapeutic challenge. Hyperpigmentations after burn should be treated on a case-by-case basis, using data from the literature, clinical experience and measuring the risk/benefit ratio. [ABSTRACT FROM AUTHOR]

Melanogenesis is a multistep process in which melanocytes produce melanin pigments within melanosomes. However, the roles played by the biological factors and pathways in this process are not yet fully understood. To investigate the role of ATP-binding cassette subfamily B member 6 (ABCB6) in the regulation of melanogenesis in vitro. Real-time PCR and western blotting were used to assess the knockdown efficiency of ABCB6 in MNT-1 and PIG1 stable cell lines. Cleavage by NaOH was used to determine melanin content, while the number of melanosomes was examined for each stage by transmission electron microscopy. Immunofluorescence microscopy was used to evaluate endogenous protein location. Differentially expressed genes were detected using RNA sequencing, and gene expression was assessed by quantitative real-time PCR. KEGG mapping was used for pathway enrichment analysis. Co-immunoprecipitation was used for protein-protein interactions analysis. We found that ABCB6 inhibition could impair melanocyte maturation and melanin production in human melanoma (MNT-1) and immortalized human melanocyte (PIG1) cell lines. Moreover, ABCB6 knockdown inhibited the protein expression of melanocyte inducing microphthalmia-associated transcription factor (MITF) and its three downstream melanogenic enzymes (TYR, TYRP1 and TYRP2). Mechanistically, we revealed that ABCB6 could interact with and modulate glycogen synthase kinase 3 beta (GSK3-β) to exert its biological effect on melanogenesis. Our findings suggest that ABCB6 is a key regulator of melanogenesis via the GSK3-β/β-catenin signaling pathway. However, further in-depth studies are essential to uncover the relationship between ABCB6 and pigmentation disorders. • ABCB6 is a key protein in the maturation process of melanosomes in MNT-1 and PIG1 cells. • ABCB6 regulates melanin synthesis and the expression of melanin-related proteins. • ABCB6 modulates melanogenesis through the GSK3-β/β-catenin signaling axis. [ABSTRACT FROM AUTHOR]

• Injection of human NCSTN mutations encoding null alleles leads to zebrafish hypopigmentation. • Alterations in melanophore number, size, migration, and distribution are observed. • Phenotype can be rescued by co-injection of zebrafish ncstn and human NCSTN mRNA. • Hypopigmentation is also reversed by co-injection of human NCSTN missense mutation p.P211R. • The zebrafish ncstn gene and the human NCSTN gene may have acquired evolutionarily distinct roles. Mutations in the genes that encode the human γ-secretase subunits Presenilin-1, Presenilin Enhancer Protein 2, and Nicastrin (NCSTN) are associated with familial hidradenitis suppurativa (HS); and, regarding Presenilin Enhancer Protein 2, also with comorbidity for the hereditary pigmentation disorder Dowling-Degos disease. Here, the consequences of targeted inactivation of ncstn, the zebrafish homologue of human NCSTN, were studied. After morpholino (MO)-mediated ncstn -knockdown, the possibilities of phenotype rescue through co-injection of ncstn -MO with wildtype zebrafish ncstn or human NCSTN mRNA were investigated. Further, the effects of the co-injection of a human missense, nonsense, splice-site, and frameshift mutation were studied. MO-mediated ncstn -knockdown resulted in a significant reduction in melanophore morphology, size and number; and alterations in their patterns of migration and distribution. This phenotype was rescued by co-injection of zebrafish ncstn RNA, human NCSTN RNA, or a construct encoding the human NCSTN missense mutation p.P211R. Human NCSTN mutations encoding null alleles confer loss-of-function regarding pigmentation homeostasis in zebrafisch. In contrast, the human missense mutation p.P211R was less harmful, asserting sufficient residual ncstn activity to maintain pigmentation in zebrafish. Since fish lack the anatomical structures affected by HS, our data suggest that the zebrafish ncstn gene and the human NCSTN gene have probably acquired different functions during evolution. In fish, one major role of ncstn is the maintenance of pigmentation homeostasis. In contrast, one of the roles of NCSTN in humans is the prevention of inflammatory processes in the adnexal structures of the skin, as seen in familial HS. [ABSTRACT FROM AUTHOR]

• Rhamnazin inhibits the intracellular actin-based transport of melanosomes. • Polyubiquitinated melanophilin (MLPH) accumulates after rhamnazin treatment. • Rhamnazin interacts with each component (RAB27A, MLPH, and MYO5A) of the melanosome transport-associated tripartite complex. • Rhamnazin blocks melanosome transport through the proteasomal degradation of MLPH. Melanosomes are intracellularly transported from the perinuclear region to the cell periphery and then to neighboring keratinocytes. We recently reported that the flavonoid rhamnazin suppresses melanosomal transport within pigment cells, yet the action mechanism remained unclear. Our aim was to elucidate how rhamnazin influences the intracellular transport of melanosomes. A melanosome distribution assay and immunostaining were performed using B16F10 mouse melanoma cells and normal human epidermal melanocytes, respectively. Expression levels of melanosome transport-related proteins, including melanophilin (MLPH), RAB27A, and myosin VA (MYO5A), were analyzed by immunoblotting. Ubiquitinated MLPH was detected using a commercial ubiquitin detection kit. To investigate the interaction between rhamnazin and MLPH, we prepared rhamnazin conjugated with magnetic FG beads. Immunoblotting analysis revealed that rhamnazin specifically reduces the expression of MLPH but not RAB27A or MYO5A proteins. The ubiquitin detection assay, which made use of a proteasome inhibitor, showed that MLPH accumulated as a polyubiquitinated protein after treatment with rhamnazin. We speculated that the affinity of rhamnazin for the components of the melanosome transport-related tripartite complex may alter the stability of the formation of the tripartite assembly. By using affinity-based techniques with B16F10 whole cell lysates or recombinant MLPH and RAB27A proteins, we revealed the interaction of rhamnazin with the components of the tripartite complex. We found that rhamnazin inhibits intracellular transport of melanosomes through proteasomal degradation of MLPH. Our results suggest that topical application of rhamnazin may provide a new approach for treating skin pigmentation disorders. [ABSTRACT FROM AUTHOR]

A basic requirement for artificial intelligence (AI)–based image analysis systems, which are to be integrated into clinical practice, is a high robustness. Minor changes in how those images are acquired, for example, during routine skin cancer screening, should not change the diagnosis of such assistance systems. To quantify to what extent minor image perturbations affect the convolutional neural network (CNN)–mediated skin lesion classification and to evaluate three possible solutions for this problem (additional data augmentation, test-time augmentation, anti-aliasing). We trained three commonly used CNN architectures to differentiate between dermoscopic melanoma and nevus images. Subsequently, their performance and susceptibility to minor changes ('brittleness') was tested on two distinct test sets with multiple images per lesion. For the first set, image changes, such as rotations or zooms, were generated artificially. The second set contained natural changes that stemmed from multiple photographs taken of the same lesions. All architectures exhibited brittleness on the artificial and natural test set. The three reviewed methods were able to decrease brittleness to varying degrees while still maintaining performance. The observed improvement was greater for the artificial than for the natural test set, where enhancements were minor. Minor image changes, relatively inconspicuous for humans, can have an effect on the robustness of CNNs differentiating skin lesions. By the methods tested here, this effect can be reduced, but not fully eliminated. Thus, further research to sustain the performance of AI classifiers is needed to facilitate the translation of such systems into the clinic. • Convolutional neural networks (CNNs) show potential in skin cancer diagnoses. • Minor dermoscopic image changes suffice to influence the CNNs' diagnosis. • CNNs' susceptibility to such changes can be reduced but not eliminated. • Practitioners need to be aware and attempt to minimise this phenomenon. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the association between skin disorders and depression in children and adolescents in Germany.Methods: This retrospective case-control study was based on data from the Disease Analyzer database (IQVIA). The present study included children and adolescents diagnosed for the first time with depression in 185 pediatric practices between January 2017 and December 2019 (index date) and matched controls without depression. Chronic skin conditions documented within 12 months prior to the index date (i.e. date of first depression diagnosis) were included in the analyses if their prevalence was at least 0.5% in the study population. Associations between nine different skin disorders and depression (dependent variable) were analyzed in a conditional logistic regression model.Results: This study included 7,061 cases with depression and 7,061 matched controls without depression (mean age 11.3 (SD: 3.8) years; 53.4% female). Three disorders were significantly associated with depression: atopic dermatitis/eczema (OR = 1.50, 95% CI = 1.37-1.64), nail disorders (OR = 1.84, 95% CI = 1.20-2.82), and hair loss (OR = 1.84, 95% CI = 1.30-2.60). In sex-stratified regression analyses, atopic dermatitis/eczema (OR = 1.43, 95% CI = 1.26-1.61) and hair loss (OR = 2.04, 95% CI = 1.37-3.03), were significantly associated with depression in females, since only atopic dermatitis/eczema was associated with depression (OR = 1.58, 95% CI = 1.39-1.80) in males. However, strong non-significant association was additionally observed for nail disorders (OR = 2.07, 95% CI = 1.07-4.01), and pigmentation disorders (OR = 1.93, 95% CI = 1.05-3.54) in females.Conclusions: Some skin disorders are positively associated with depression in children and adolescents. Further research is needed for better understanding of the underlying mechanisms and mediating factors. [ABSTRACT FROM AUTHOR]

Terra firma-forme dermatosis is an underreported acquired pigmentation disorder caused by keratinocyte retention that is not mentioned in many textbooks. It is characterized by the onset of asymptomatic hyperpigmented patches or velvety plaques potentially involving any part of the body, including the trunk, extremities, and the skin folds such as neck, axilla, inguinal region, and umbilical folds. It affects both sexes equally and all age groups, although it seems more prevalent in children with a mean age of 10.4 years. The prompt regression after rubbing with an alcohol-soaked gauze is diagnostic and curative. The cause of this affection remains unknown, although less rigorous hygiene or an atopic background is contributory. [ABSTRACT FROM AUTHOR]

Previous studies have shown that all kinin system is constitutively expressed in the normal and inflamed skin, with a potential role in both physiological and pathological processes. However, the understanding regarding the involvement of the kinin system in skin pigmentation and pigmentation disorders remains incomplete. In this context, the present study was designed to determine the role of kinins in the Monobenzone (MBZ)-induced vitiligo-like model. Our findings showed that MBZ induces higher local skin depigmentation in kinin receptors knockout mice (KOB1R, KOB2R and KOB1B2R) than in wild type (WT). Remarkably, lower levels of melanin content and reduced ROS generation were detected in KOB1R and KOB2R mice treated with MBZ. In addition, both KOB1R and KOB2R show increased dermal cell infiltrate in vitiligo-like skin, when compared to WT-MBZ. Additionally, lack of B1R was associated with greater skin accumulation of IL-4, IL-6, and IL-17 by MBZ, while KOB1B2R presented lower levels of TNF and IL-1. Of note, the absence of both kinin B1 and B2 receptors demonstrates a protective effect by preventing the increase in polymorphonuclear and mononuclear cell infiltrations, as well as inflammatory cytokine levels induced by MBZ. In addition, in vitro assays confirm that B1R and B2R agonists increase intracellular melanin synthesis, while bradykinin significantly enhanced extracellular melanin levels and proliferation of B16F10 cells. Our findings highlight that the lack of kinin receptors caused more severe depigmentation in the skin, as well as genetic deletion of both B1/B2 receptors seems to be linked with changes in levels of constitutive melanin levels, suggesting the involvement of kinin system in crucial skin pigmentation pathways. [Display omitted] • Kinin receptors play a role in the regulation of skin pigmentation is described. • Absence of both B1 and B2 kinin receptors reduces total melanin content in skin. • Kinin receptors modulate inflammatory responses in vitiligo lesions, controlling infiltration of inflammatory cells and levels of cytokines. • In melanocytes, both kinin receptors have a potential impact on melanin synthesis, and B2 receptors have a correlation with proliferation. [ABSTRACT FROM AUTHOR]

Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main driver for diversity of skin pigmentation. Dark melanin acts to protect against the deleterious effects of ultraviolet (UV) radiation, including photo-aging and skin cancer formation. In turn, UV radiation activates skin melanocytes to induce further pigmentation (i.e. , "tanning pathway"). The well-characterized MSH/MC1R-cAMP-MITF pathway regulates UV-induced melanization. Pharmacologic activation of this pathway ("sunless tanning") represents a potential strategy for skin cancer prevention, particularly in those with light skin or the "red hair" phenotype who tan poorly after UV exposure due to MC1R inactivating polymorphisms. Skin hyperpigmentation can also occur as a result of inflammatory processes and dermatological disorders such as melasma. While primarily of cosmetic concern, these conditions can dramatically impact quality of life of affected patients. Several topical agents are utilized to treat skin pigmentation disorders. Here, we review melanogenesis induced by UV exposure and the agents that target this pathway. Unlabelled Image [ABSTRACT FROM AUTHOR]

Vitiligo (VL) is a chronic autoimmune pigmentation disorder characterized by destruction of melanocytes. The condition is associated with several other autoimmune diseases, but autoimmune thyroid diseases, especially Hashimoto's thyroiditis (HT), is the most prevalent organ-specific autoimmune disease with a co-morbidity up to 34%. Among the many hypotheses that have been proposed for the pathogenesis of both diseases, autoimmunity and oxidative stress-mediated toxicity in melanocytes or thyrocytes, respectively, have been the most widely accepted - with autoimmunity being the presumed consequence of oxidative stress-mediated toxicity. However, the predominant etiologic basis for impairment of redox balance has rarely been studied. The two autoimmune diseases are not only linked by a concordance of clinical presentations and an autoimmune/oxidative stress-mediated toxicity pathogenesis but also by an apparent biochemical commonality. The target molecules produced in the thyroid and skin, i.e., thyroxine and melanin, respectively, are derived from the same primordial parent molecule, tyrosine. On the basis of these similarities between Hashimoto's thyroiditis and vitiligo, specifically with respect to the activation of oxidative stress, we propose a novel hypothesis accounting for the destruction of melanocytes or thyrocytes in VL and AT. We suggest a new therapeutic regimen of quinone derivatives to combat ROS-induced autoimmunity resulting from this common biochemical etiologic error. [ABSTRACT FROM AUTHOR]

KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT. This is the case for the lung, heart, nervous system, gastrointestinal tract, pancreas, kidney, liver, and bone. For this reason, the tyrosine kinase inhibitors that were originally developed for the treatment of hemato-oncological diseases are being currently investigated for the treatment of non-oncological disorders such as asthma, rheumatoid arthritis, and alzheimer's disease, among others. The beneficial effects of some of these tyrosine kinase inhibitors have been proven to depend on KIT inhibition. This review will focus on KIT expression and regulation in healthy and pathologic conditions other than cancer. Moreover, advances in the development of anti-KIT therapies, including tyrosine kinase inhibitors, and their application will be discussed. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play crucial roles in skin pigmentation in animals. Rainbow trout (Oncorhynchus mykiss) is a key economic fish species worldwide, and skin color directly affects its economic value. However, the functions of miRNAs in rainbow trout skin pigmentation remain largely unknown. Herein, we overexpressed and silenced miR-495 in vitro and in vivo to investigate its functions. The analysis of spatial and temporal expression patterns suggested that miR-495 is a potential regulator during the process of skin pigmentation. In vitro, mc1r was validated as a direct target for miR-495 by dual-luciferase reporter assay, and overexpression of miR-495 significantly inhibited mc1r expression; in contrast, mc1r and its downstream gene mitf levels were markedly upregulated by decreased miR-495. In vivo, overexpressed miR-495 by injecting agomiR-495 led to a substantial decrease in the expression of mc1r and mitf in dorsal skin and liver, while the opposite results were obtained after miR-495 silencing by antagomiR-495. These findings suggested that miR-495 can target mc1r to regulate rainbow trout skin pigmentation, which provide a potential basis for using miRNAs as target drugs to treat pigmentation disorders and melanoma. [ABSTRACT FROM AUTHOR]

Acquired brachial cutaneous dyschromatosis (ABCD) is a relatively newly described, acquired disorder of pigmentation characterized by geographic-shaped, gray-brown, hyperpigmented patches and interspersed with hypopigmented macules, involving the dorsal aspects of the forearms in postmenopausal women. There is a suggested relationship with hypertension and antihypertensive medication intake, specifically angiotensin-converting enzyme inhibitors, or a cumulative effect of sun damage, as possible triggers. ABCD is benign, asymptomatic, and more of an esthetic concern. Topical depigmenting agents, chemical peels, and laser therapy may be helpful. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Baicalin or berberine were encapsulated in ultradeformable vesicles. • Antioxidant and photoprotective effects of ultradeformable vesicles were confirmed. • Ultradeformable vesicles had a great potential as stimulant of pigmentation. • Promising formulations for the treatment of vitiligo symptoms were developed. Abstract 0.5–1% of the world's population is affected by vitiligo, a disease characterized by a gradual depigmentation of the skin. Baicalin and berberine are natural compounds with beneficial activities, such as antioxidant, anti-inflammatory and proliferative effects. These polyphenols could be useful for the treatment of vitiligo symptoms, and their efficacy can be improved by loading in suitable carriers. The aim of this work was to formulate and characterize baicalin or berberine loaded ultradeformable vesicles, and demonstrate their potential as adjuvants in the treatment of vitiligo. The vesicles were produced using a previously reported simple, scalable method. Their morphology, size distribution, surface charge and entrapment efficiency were assessed. The ability of the vesicles to promote the permeation of the polyphenols was evaluated. The antioxidant and photoprotective effects were investigated in vitro using keratinocytes and fibroblasts. Further, the stimulation of melanin production and tyrosinase activity in melanocytes after treatment with the vesicles were assessed. Ultradeformable vesicles were small in size, homogeneously dispersed, and negatively charged. They were able to incorporate high amounts of baicalin and berberine, and promote their skin permeation. In fact, the polyphenols concentration in the epidermis was higher than 10%, which could be indicative of the formation of a depot in the epidermis. The vesicles showed remarkable antioxidant and photoprotective capabilities, presumably correlated with the stimulation of melanin production and tyrosinase activity. In conclusion, baicalin or berberine ultradeformable vesicles, and particularly their combination, may represent promising nanosystem-based adjuvants for the treatment of vitiligo symptoms. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 'Vinhão' has black-bluish skin color, highly appreciated for wine production. • First insights into the genetics behind the color feature of the cv. 'Vinhão'. • MYBA genes play a major role on the berry skin color of the cv. 'Vinhão'. • Berry color locus of cv. 'Vinhão' carries the most ancestral haplotype (Hap C-N). • The involvement of key anthocyanin genes was revealed, mainly from veraison onwards. Abstract 'Vinhão' is an autochthonous Portuguese cultivar with an intense black-bluish skin color, highly appreciated due to this feature. This study aimed to give the first insights into the genetic background that may be responsible for the skin color properties of cv. 'Vinhão'. For this purpose, the allelic composition of MYBA1 and MYBA2 genes was investigated, along with quantification of the expression levels of structural and regulatory genes involved in the anthocyanin biosynthetic pathway via qRT-PCR. The molecular characterization of MYBA1 and MYBA2 loci revealed that cv. 'Vinhão' is homozygous for the functional allele in both genes, corresponding to the most ancestral haplotype, which is consistent with the high colored phenotype that characterizes this cultivar. There were no differences in the DNA sequence of the MYBA1 promoter region between cv. 'Vinhão' and the grapevine reference genome Pinot Noir. The expression patterns of genes playing key functional roles in anthocyanin biosynthesis was analyzed in four developmental stages. The dynamics occurring throughout grape berry development revealed the involvement of these genes in the progression of key development events, mainly from veraison to mature berries. These findings provide the first molecular characterization focused on the skin color feature of cv. 'Vinhão' to improve our understanding of the genetics behind its intense skin pigmentation. [ABSTRACT FROM AUTHOR]

Purpose To describe the phenotypic spectrum of a large cohort of albino patients, to investigate the relationship between the ocular abnormalities and the visual acuity (VA), and to define diagnostic criteria for the white population. We also estimated the prevalence of albinism in The Netherlands. Design Retrospective cohort study. Participants We investigated the phenotype of 522 patients with albinism from the databases of Bartiméus (452 patients), Leiden University Medical Center (44 patients), and the Academic Medical Center Amsterdam (26 patients). Methods We collected clinical, genetic, and electrophysiologic data of patients with albinism. We used grading schemes for iris translucency, fundus hypopigmentation, and foveal hypoplasia. Main Outcome Measures Visual acuity, nystagmus, iris translucency, fundus pigmentation, foveal hypoplasia, and misrouting. Results Nystagmus was absent in 7.7% (40/521), iris translucency could not be detected in 8.9% (44/492), 3.8% (19/496) had completely normal fundus pigmentation, 0.7% (3/455) had no foveal hypoplasia, and misrouting was not established in 16.1% (49/304). The VA varied from −0.1 to 1.3 logarithm of the minimum of angle of resolution (logMAR). The foveal hypoplasia grading correlated best with the VA (r = 0.69, P < 0.001), whereas iris translucency, fundus pigmentation, and misrouting did not predict the VA significantly. We estimated a prevalence of albinism in The Netherlands of at least 1:12 000. Conclusions None of the characteristics of albinism were consistently present in our cohort. To be able to distinguish albinism from other conditions with similar ocular features, especially in northern and western European countries, we propose major and minor clinical criteria. Major criteria would be (1) foveal hypoplasia grade 2 or more, (2) misrouting, and (3) ocular hypopigmentation, either iris translucency or fundus hypopigmentation grade 2 or more. Minor criteria would be (1) nystagmus, (2) hypopigmentation of skin and hair, (3) grade 1 fundus hypopigmentation, and (4) foveal hypoplasia grade 1. We propose that 3 major criteria or 2 major and 2 minor criteria are necessary for the diagnosis. In the presence of a molecular diagnosis, 1 major criterion or 2 minor criteria will be sufficient. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4 , 9 , and 10 , bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 3-Hydroxycoumarin loaded within vesicles inhibits recombinant human tyrosinase. • 3-Hydroxycoumarin loaded vesicles can be formulated as liquids or gels. • Liquid or gel formulations deliver 3-hydroxycoumarin to the deeper skin layers. Abstract Tyrosinase is one of the key enzymes in mammalian melanin biosynthesis. Decreasing tyrosinase activity has been targeted for the prevention of conditions related to the hyperpigmentation of the skin, such as melasma and age spots. This paper is devoted to the engineering of vesicle formulations loaded with 3-hydroxycoumarin for topical pharmaceutical applications. At first, it was demonstrated the strong inhibiting ability of 3-hydroxycoumarin against recombinant human tyrosinase. Then, such a drug was effectively encapsulated within liquid or gel-like vesicle formulations, both based on monoolein and lauroylcholine chloride. In vitro skin penetration and permeation studies proved these formulations efficiently overcome the barrier represented by the stratum corneum, delivering 3-hydroxycoumarin to the deeper skin layers. The effect of applying for different times the liquid and the gel formulation was also evaluated. Results revealed that application of the gel formulation for 2 h favored the drug accumulation into the skin with low transdermal delivery, thus indicating this combination of administration time and formulation as ideal to locally inhibit tyrosinase activity with minimal systemic absorption. Moreover, when incubated with B16F10 melanoma cells, the liquid vesicle formulations did not show cytotoxic activity. [ABSTRACT FROM AUTHOR]

Background Piebaldism is a pigmentary disorder characterized by a white forelock and depigmented patches. Although the loss-of-function mutations in the KIT gene underlie the disease, the intracellular dynamics of the mutant KIT are largely unknown. We herein report a Japanese family with piebaldism in which the affected members showed a mild phenotype. Objective The objective of this study is to investigate the functions and intracellular dynamics of the mutant KIT protein. Methods We performed genetic analyses of the KIT gene using peripheral blood cells. We analyzed the intracellular localization of the mutant KIT protein in HEK293T cells transfected with wild-type (Wt) and/or mutant KIT genes. Immunoprecipitation analyses, immunoblotting and immunofluorescence studies were performed using antibodies against KIT and downstream signaling proteins. Glycosidase digestion analysis was performed to clarify the intracellular localization of KIT protein. Results A genetic analysis revealed a novel heterozygous mutation c.645_650delTGTGTC which results in the in-frame deletion of Val 216 and Ser 217 in the extracellular domain of KIT . Immunoprecipitation analyses confirmed that the wild and mutant KIT formed a heterodimer after treatment with stem cell factor (SCF); however, the phosphorylation of the downstream signaling factors was decreased. In an immunofluorescence study, the mutant KIT accumulated predominantly in the endoplasmic reticulum (ER) and was sparsely expressed on the cell surface. A glycosidase digestion study revealed that the mutant KIT is predominantly localized in the ER. Conclusion These data reveal an aberrant function and intracellular localization of mutant KIT protein in piebaldism. [ABSTRACT FROM AUTHOR]

The sea cucumber Apostichopus japonicus (Selenka), which has nutritive and medical properties, is considered the most valuable commercial marine species in many parts of Asia. Of the different color morphs, the albino sea cucumber is rare and has great appeal to consumers. Identification of factors contributing to albinism in the sea cucumber is therefore likely to provide a scientific basis for improving the cultivability of this morph. In this study, illumina sequencing was performed on three pigmentation stages of the albino sea cucumber: the early pigmentation stage (Wa), the mid pigmentation stage (Wb) and the late pigmentation stage (Wc). In total, 120,365 unigenes were generated with an N50 length of 3360 bp and 60,224 unigenes were annotated from seven functional databases (NR, NT, GO, COG, KEGG, Swissprot and Interpro). In addition, 39,285 SSRs were detected, distributed on 26,156 unigenes. Compared with sea cucumbers during the early pigmentation stage, 842 genes were identified as differentially expressed in the body wall of albino sea cucumbers during the mid-pigmentation stage, including 331 upregulated and 511 downregulated genes. Additionally, compared with sea cucumbers in the mid-pigmentation stage, 247 genes were identified as differentially expressed in the body wall of albino sea cucumbers during the late-pigmentation stage, including 67 upregulated and 180 downregulated genes. GO and KEGG analyses revealed possible differentially expressed genes, including “melanogenesis”, “Ras-signaling pathway”, “cAMP signaling pathway” and “epithelium development” involved in albinism formation in albino sea cucumbers. In conclusion, these studies identified many candidate albinism-related and pigmentation-related genes and signaling pathways. In addition, a comparative analysis was conducted of the differentially expressed genes from albino sea cucumber body walls in different pigmentation stages. The results should be highly useful in further elucidating the mechanisms underlying albinism in sea cucumbers. [ABSTRACT FROM AUTHOR]

Objective: Primary mucosal malignant melanoma of the head and neck (HN-PMMM) is an aggressive and uncommon neoplasm. Herein, we present a series of 33 patients and the results of treatment, and aimed to determine prognostic factors in HN-PMMM.Methods: Patients who were diagnosed as having HN-PMMM in our reference hospital, between 2005 and 2014 were evaluated. Thirty-three of these patients who had follow-up data were included. Surgical margin status was extracted from the original pathology reports. Archived materials were retrieved for the histopathologic findings: ulceration, necrosis, lymphovascular invasion, perineural invasion, pigmentation, and presence of an in situ component. Mitotic activity was evaluated using phosphohistone H3 (PHH3) immunohistochemical staining.Results: We found an association of PHH3 mitotic activity with overall survival in a univariate analysis and to our knowledge, this is the first report among the available case series of HN-PMMM to evaluate mitotic activity using immunohistochemical staining. We also investigated the relationship between multicentricity and locoregional recurrence, which the authors believe is also a first.Conclusion: PHH3 mitotic activity can be used a prognostic factor for head and neck mucosal malignant melanoma. [ABSTRACT FROM AUTHOR]

Melanosis and quality changes of pre-cooked Pacific white shrimp treated with epigallocatechin gallate (EGCG) with the aid of ultrasound were monitored during refrigerated storage at 4 °C for 10 days. Shrimps subjected to pre-cooking (70 °C, 30 s), followed by soaking in 0.25% (w/v) EGCG solution with sonication (ultrasound: frequency of 20 kHz, intensity power of 750 W) showed lower melanosis score than those treated with EGCG prior to pre-cooking. Longer sonication time (10–15 min) enhanced the efficacy of melanosis inhibition in treated shrimp ( P < 0.05). Microbiological analyses revealed that pre-cooked shrimps treated with EGCG solution using ultrasound showed lower total viable count, psychrophilic bacteria, Pseudomonas spp., H 2 S-producing bacteria and Enterobacteriaceae counts than the control and those treated with EGCG or ultrasound alone, throughout 10 days of storage. Lower total volatile base (TVB) content was detected in shrimps treated with EGCG and ultrasound, and these shrimps also showed higher scores for color and overall likeness with coincidentally lower melanosis score than others ( P < 0.05) at the end of storage. Therefore, soaking of pre-cooked shrimps in EGCG solution with the aid of ultrasound for sufficient time could be a promising method to prevent melanosis and deterioration in pre-cooked Pacific white shrimp during the extended refrigerated storage. [ABSTRACT FROM AUTHOR]

Two new caffeic acid ester derivatives, caffeic acid-4-(2-hydroxyethyl) morpholine ester (Z-1) and caffeic acid-4-(3-hydroxypropyl) morpholine ester (Z-2), were synthesized, and their structures were characterized by LC–MS, IR, and 1 H NMR. The activation effects of the two compounds on tyrosinase activity were evaluated. Compounds Z-1 and Z-2 showed potent activation effects, and their EC 50 values were determined to be 0.075 and 0.0375 mmol/L, respectively. Moreover, the activation mechanism was determined to be of noncompetitive activation type. Interactions of the two compounds with tyrosinase were further analyzed by fluorescence quenching and molecular simulation assays. The results indicated that the effects on the tyrosinase activity were relative to the length of the carbon chain of the compounds. In addition, human M14 melanoma cells showed increased intracellular tyrosinase activity after treatment with the two compounds for 24 h. The expressions of TYR, TRP-1, TRP-2, and α-MSH proteins were upregulated in a dose-dependent manner during a 24-h treatment. These results suggested that compounds Z-1 and Z-2 might represent a novel approach for an effective therapy for diseases associate with tyrosinase dysfunction, such as vitiligo and hair graying. [ABSTRACT FROM AUTHOR]

Dermal fibroblasts are traditionally recognized as synthesizing, remodeling and depositing collagen and extracellular matrix, the structural framework for tissues, helping to bring thickness and firmness to the skin. However, the role of fibroblasts on skin pigmentation arouses concern recently. More is known about the interactions between epidermal melanocytes and keratinocytes. This review highlights the importance of fibroblast-derived melanogenic paracrine mediators in the regulation of melanocyte activities. Fibroblasts act on melanocytes directly and indirectly through neighboring cells by secreting a large number of cytokines (SCF), proteins (DKK1, sFRP, Sema7a, CCN, FAP-α) and growth factors (KGF, HGF, bFGF, NT-3, NRG-1, TGF-β) which bind to receptors and modulate intracellular signaling cascades (MAPK/ERK, cAMP/PKA, Wnt/β-catenin, PI3K/Akt) related to melanocyte functions. These factors influence the growth, the pigmentation of melanocytes via the expression of melanin-producing enzymes and melanosome transfer, as well as their dendricity, mobility and adhesive properties. Thus, fibroblasts are implicated in both skin physiological and pathological pigmentation. In order to investigate their contribution, various in vitro models have been developed, based on cellular senescence. UV exposure, a major factor implicated in pigmentary disorders, may affect the secretory crosstalk between dermal and epithelial cells. Therefore, identification of the interactions between fibroblasts and melanocytes could provide novel insights not only for the development of melanogenic agents in the clinical and cosmetic fields, but also for a better understanding of the melanocyte biology and melanogenesis regulation. [ABSTRACT FROM AUTHOR]

We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities. [ABSTRACT FROM AUTHOR]

Hyperpigmentation is one of the most common skin disorder that affects both men and women of all ethnic groups, caused by several factors, such as UV exposure and skin inflammation. Topical whitening agents were found to be the best and the least aggressive therapy for treating hyperpigmentation compared to instrumental approaches. However, topical treatment faces several obstacles due to the low stability of the whitening agents. Therefore, the encapsulation of these agents was found to be crucial as it enhances their physicochemical stability and increases their concentration at the targeted site via an improved skin permeation, penetration or distribution. In this article, we review the literature aimed to enhance the stability and the targeting of skin whitening agents through their encapsulation in various nano and micro-particulate systems. [ABSTRACT FROM AUTHOR]

Background Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1–WS4) where WS4 or Shah–Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10 , EDN3 / EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4. Method A two-generation pedigree with three affected members and considerable phenotypic heterogeneity was recruited. The proband was a 15-year-old boy, with severe to profound sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eyes and Hirschprung disease. The other two also presented characteristics of WS2 and complained of chronic constipation with normal anorectal reflex. Sequencing of all exons and exon-intron boundaries of SOX10 , EDN3 / EDNRB revealed a heterozygous variant c.422T > C in exon 3 of SOX10 confirmed by a series of evidence to be pathogenic. It resulted in p.L141P at the protein level. Leucin 141 is located in Nuclear Export signal, HMG box of the protein. Conclusion This study is the first report of a WS4 family in the Iranian population. The mutation is associated with distinctive phenotypic profile (association of anosmia and chronic constipation with SOX10 mutations) and could further improve diagnosis and counseling of WS in the Iranian population and can contribute to phenotype-directed genetic analysis. [ABSTRACT FROM AUTHOR]

Mutations in retinitis pigmentosa 2 (RP2) account for 10-20% of X-linked retinitis pigmentosa (RP) cases. The encoded RP2 protein is implicated in ciliary trafficking of myristoylated and prenylated proteins in photoreceptor cells. To date >70 mutations in RP2 have been identified. How these mutations disrupt the function of RP2 is not fully understood. Here we report a novel in-frame 12-bp deletion (c.357-368del, p.Pro120-Gly123del) in zebrafish rp2. The mutant zebrafish shows reduced rod phototransduction proteins and progressive retinal degeneration. Interestingly, the protein level of mutant Rp2 is almost undetectable, whereas itsmRNAlevel is near normal, indicating a possible post-translational effect of the mutation. Consistent with this hypothesis, the equivalent 12-bp deletion in human RP2 markedly impairs RP2 protein stability and reduces its protein level. Furthermore, we found that a majority of the RP2 pathogenic mutations (including missense, singleresidue deletion, and C-terminal truncation mutations) severely destabilize the RP2 protein. The destabilized RP2 mutant proteins are degraded via the proteasome pathway, resulting in dramatically decreased protein levels. The remaining non-destabilizing mutations T87I, R118H/R118G/R118L/R118C, E138G, and R211H/R211L are suggested to impair the interaction between RP2 and its protein partners (such as ARL3) or with as yet unknown partners. By utilizing a combination of in silico, in vitro, and in vivo approaches, our work comprehensively indicates that loss of RP2 protein structural stability is the predominating pathogenic consequence for most RP2 mutations. Our study also reveals a role of the C-terminal domain of RP2 in maintaining the overall protein stability. [ABSTRACT FROM AUTHOR]

We occasionally discovered a mouse with spontaneous retinitis pigmentosa (RP) from Kunming (KM) mouse breeding colony, with no obvious waveforms in ERG recordings. The aim of this study is to cross the spontaneously hereditary retinal degeneration mice (temporarily designated as KM/rd mice) derived from KM mice with C57BL/6J mice to establish a congenic inbred strain (temporarily designated as the B6/rd mice), and study the ocular phenotype and genotype of the mice. Fundus photography, tissue morphology, electroretinography (ERG), qRT-PCR, western blot and DNA sequence analysis were performed to observe the ocular phenotype and genotype of KM/rd and B6/rd mice. The fundus photography showed progressive retinal vascular degeneration and depigmentation in KM/rd and B6/rd mice. Compared to wild-type mice, the histological analysis revealed that the outer nuclear layer of the mutated mice was significantly reduced at 14 days post born (P14), and almost disappeared by P21. No obvious waveforms were detected at P14 and P21 in the ERG from KM/rd and B6/rd mice. qRT-PCR results showed that the expression quantities of mRNA of pde6b gene in KM/rd and B6/rd mice were significantly lower compared with those of wild-type controls at P21. Western blot results confirmed an abnormal protein expression of pde6b gene in KM/rd and B6/rd mice with no protein products, while there was an obvious protein expression in wild-type mice. The nonsense mutation in exon 7 (a mutation that changes the codon 347 from TAC to TAA) in the pde6b gene of KM/rd and B6/rd mice was identified by genomic DNA sequence analysis. All these findings revealed that the ocular phenotype and genotype of KM/rd and B6/rd mice were similar to those of rd1 mice, which indicates that KM/rd and B6/rd mice can be used as an RP mouse model. [ABSTRACT FROM AUTHOR]

The traditional use of Prunus species against skin diseases and especially for skin lightning cosmeceutical purposes is widespread in many cultures. Prunus mahaleb L. is a well known food plant and used in the baking industry for flavoring. The fruit kernels (endocarp) are used in India for hyperpigmentation. To investigate the chemical composition with the antimelanogenesis effect of P. mahaleb seed and kernel extracts and isolated compounds. Isolation studies performed from the methanol extracts obtained from kernels and structures were determined using NMR and MS analysis. Antimelanogenesis effect was determined by mushroom tyrosinase assay, cellular tyrosinase assay and melanin content assay using B16F10 murine melanoma cells. Five cinnamic acid derivatives were isolated and their structures (2- O - β -glucopyranosyloxy-4-methoxy-hydrocinnamic acid (1) , cis -melilotoside (2) , dihydromelilotoside (3) , trans –melilotoside (4) , 2- O - β -glucosyloxy-4-methoxy trans -cinnamic acid (5)) were elucidated using advanced spectroscopic methods. Mushroom tyrosinase enzyme inhibition of extracts, fractions and pure compounds obtained from P. mahaleb kernels were investigated and structure-activity relationship revealed. According to a detailed, comprehensive and validated LC–MS/MS technique analysis, vanilic acid (41.407 mg/g), protocatechuic acid (8.992 mg/g) and ferulic acid (4.962 mg/g) in the kernel ethylacetate fraction; quinic acid (14.183 mg/g), fumaric acid (8.349 mg/g) and aconitic acid (5.574 mg/g) were found as major phenolic compounds in the water fraction. The correlation of trace element copper content in extracts and fractions with mushroom enzyme activity was determined. By examining the enzyme kinetics of the compounds with effective cinnamic acid derivatives, inhibition types and enzyme binding constants K i were calculated. Compounds 1,3 and 5 exhibited high noncompetitive tyrosinase inhibitory activity against L-tyrosine substrates, with IC 50 values of 0.22, 0.31 and 0.37 mM respectively. In addition compounds 1, 3 and 5 showed dose-dependent inhibitory effects on intracellular tyrosinase and melanin levels in α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 melanoma cells. Potent tyrosinase inhibitory compounds and extracts of P. mahaleb kernels suggest that it could be a new, non-toxic and inexpensive resource for the cosmeceutical industry and in skin diseases associated with hyperpigmentation. [Display omitted] [ABSTRACT FROM AUTHOR]

Expression of T17M rhodopsin (T17M) in rods activates the Unfolded Protein Response (UPR) and leads to the development of autosomal dominant retinitis pigmentosa (adRP). The rod death occurs in adRP retinas prior to cone photoreceptor death, so the mechanism by which cone photoreceptors die remains unclear. Therefore, the goal of the study was to verify whether UPR in rods induces TNFa-mediated signaling to the cones and to determine whether the TNFa deficit could prevent adRP cone cell death. Primary rod photoreceptors and cone-derived 661W cells transfected with siRNA against TNFa were treated with tunicamycin to mimic activation of UPR in T17M retinas expressing normal and reduced TNFa levels. The 661W cells were then exposed to recombinant TNFa to evaluate cell viability. In vivo , the role of TNFa was assessed in T17M TNFa +/− mice by electroretinography, optical coherence tomography, histology, immunohistochemistry, and a cytokine enzyme-linked immunosorbent assay. Rods overexpressed and secreted TNFa in response to UPR activation. The recombinant TNFa treatment lowered the number of viable cones, inducing cell death through elevation of pro-inflammatory cytokines and caspase-3/7 activity. The TNFa deficiency significantly protected adRP retinas. The photopic ERG amplitudes and the number of surviving cones dramatically increased in T17M TNFa +/− mice. This neuroprotection was associated with a reduced level of pro-inflammatory cytokines. Our results indicate that rod photoreceptors, following UPR activation during adRP progression, secrete TNFa and signal a self-destructive program to the cones, resulting in their cell death. TNFa therefore holds promise as a therapeutic target for treatment of adRP. [ABSTRACT FROM AUTHOR]

Pterin derivatives are involved in various biological functions, including enzymatic processes that take place in human skin. Unconjugated oxidized pterins are efficient photosensitizers under UV-A irradiation and accumulate in the skin of patients suffering from vitiligo, a chronic depigmentation disorder. These compounds are able to photoinduce the oxidation of the peptide α-melanocyte-stimulating hormone (α-MSH), which stimulates the production and release of melanin by melanocytes in skin and hair. In the present work we have used two peptides in which the amino acid sequence of α-MSH was mutated to specifically investigate the reactivity of tryptophan (Trp) and tyrosine residues (Tyr). The parent compound of oxidized pterins (Ptr) was used as a model photosensitizer in aqueous solution at pH 5.5 and was exposed to UV-A radiation, a wavelength range where the peptides do not absorb. Trp residue yields N-formylkynurenine and hydroxytryptophan as oxidized products, whereas the Tyr undergoes dimerization and incorporation of oxygen atoms. In both cases, the first step of the mechanism involves an electron transfer from the amino acid to the photosensitizer triplet excited state, Ptr is not consumed and hydrogen peroxide (H 2 O 2 ) is released. The role of singlet oxygen produced by energy transfer from 3 Ptr ⁎ to dissolved O 2 was negligible or minor. Other amino acid residues, such as histidine, might be also affected. [ABSTRACT FROM AUTHOR]

Background Vitiligo is a common acquired depigmentation skin disease characterized by loss or dysfunction of melanocytes within the skin lesion, but its pathologenesis is far from lucid. The gene expression profiling of segmental vitiligo (SV) and generalized vitiligo (GV) need further investigation. Objective To better understanding the common and distinct factors, especially in the view of gene expression profile, which were involved in the diseases development and maintenance of segmental vitiligo (SV) and generalized vitiligo (GV). Methods Peripheral bloods were collected from SV, GV and healthy individual (HI), followed by leukocytes separation and total RNA extraction. The high-throughput whole genome expression microarrays were used to assay the gene expression profiles between HI, SV and GV. Bioinformatics tools were employed to annotated the biological function of differently expressed genes. Quantitative PCR assay was used to validate the gene expression of array. Results Compared to HI, 239 over-expressed genes and 175 down-expressed genes detected in SV, 688 over-expressed genes and 560 down-expressed genes were found in GV, following the criteria of log2 (fold change) ≥ 0.585 and P value < 0.05. In these differently expressed genes, 60 over-expressed genes and 60 down-expressed genes had similar tendency in SV and GV. Compared to SV, 223 genes were up regulated and 129 genes were down regulated in GV. In the SV with HI as control, the differently expressed genes were mainly involved in the adaptive immune response, cytokine-cytokine receptor interaction, chemokine signaling, focal adhesion and sphingolipid metabolism. The differently expressed genes between GV and HI were mainly involved in the innate immune, autophagy, apoptosis, melanocyte biology, ubiquitin mediated proteolysis and tyrosine metabolism, which was different from SV. While the differently expressed genes between SV and GV were mainly involved in the metabolism pathway of purine, pyrimidine, glycolysis and sphingolipid. Conclusions Above results suggested that they not only shared part bio-process and signal pathway, but more important, they utilized different biological mechanism in their pathogenesis and maintenance. Our results provide a comprehensive view on the gene expression profiling change between SV and GV especially in the side of leukocytes, and may facilitate the future study on their molecular mechanism and theraputic targets. [ABSTRACT FROM AUTHOR]

Purpose To reappraise the autosomal dominant Martinique crinkled retinal pigment epitheliopathy (MCRPE) in light of the knowledge of its associated mutated gene mitogen-activated protein kinase–activated protein kinase 3 ( MAPKAPK3 ), an actor in the p38 mitogen-activated protein kinase pathway. Design Clinical and molecular study. Participants A total of 45 patients from 3 generations belonging to a family originating from Martinique with an autosomal dominant MCRPE were examined. Methods Best-corrected visual acuity, fundus photographs, and spectral-domain optical coherence tomography (SD OCT) of all clinically affected patients and carriers for the causal mutation were reviewed at the initial visit and 4 years later for 10 of them. Histologic retinal lesions of Mapkapk3 −/− mice were compared with those of the human disease. Main Outcome Measures The MCRPE natural history in view of MAPKAPK3 function and Mapkapk3 −/− mouse retinal lesions. Results Eighteen patients had the c.518T>C mutation. One heterozygous woman aged 20 years was asymptomatic with normal fundus and SD OCT (stage 0). All c.518T>C heterozygous patients older than 30 years of age had the characteristic dried-out soil fundus pattern (stages 1 and 2). Complications (stage 3) were observed in 7 cases, including polypoidal choroidal vasculopathy (PCV) and macular fibrosis or atrophy. One patient was homozygous and had a form with severe Bruch's membrane (BM) thickening and macular exudation with a dried-out soil pattern in the peripheral retina. The oldest heterozygous patient, who was legally blind, had peripheral nummular pigmentary changes (stage 4). After 4 years, visual acuity was unchanged in 6 of 10 patients. The dried-out soil elementary lesions radically enlarged in patients with a preferential macular extension and confluence. These findings are in line with the progressive thickening of BM noted with age in the mouse model. During follow-up, there was no occurrence of PCV. Conclusions MCRPE is an autosomal dominant, fully penetrant retinal dystrophy with a preclinical stage, an onset after the age of 30 years, and a preserved visual acuity until occurrence of macular complications. The natural history of MCRPE is in relation to the role of MAPKAPK3 in BM modeling, vascular endothelial growth factor activity, retinal pigment epithelial responses to aging, and oxidative stress. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the in-vivo behavior of topically applied cationic polymeric chitosan nanoparticles (CSNPs) loaded with anti-inflammatory (hydrocortisone, HC) and antimicrobial (hydroxytyrosol, HT) drugs, to elucidate their skin targeting potential for the treatment of atopic dermatitis (AD). Compared to the commercial formulation, the HC-HT loaded CSNPs showed significantly improved drug penetration into the epidermal and dermal layers of albino Wistar rat skin without saturation. Dermal pharmacokinetic of CSNPs with a size of 228.5 ± 7 nm and +39 ± 5 mV charges revealed that they penetrated 2.46-fold deeper than the commercial formulation did, and had greater affinity at the skin target site without spreading to the surrounding tissues, thereby providing substantial safety benefits. In repeated dermal application toxicity studies, the HC-HT CSNPs showed no evidence of toxicity compared to the commercial formulation, which induced skin atrophy and higher liver enzyme levels. In conclusion, the positively charged HC-HT CSNP formulation exhibited promising local delivery and virtually no treatment-related toxicities, suggesting it may be an efficient and viable alternative for commercially available AD treatments. [ABSTRACT FROM AUTHOR]

The skin possesses a photosensitive system comprised of opsins whose function is not fully understood, and clock genes which exert an important regulatory role in skin biology. Here, we evaluated the presence of opsins in normal (Melan-a cells) and malignant (B16–F10 cells) murine melanocytes. Both cell lines express Opn2 , Opn4 – for the first time reported in these cell types – as well as S-opsin . OPN4 protein was found in a small area capping the cell nuclei of B16–F10 cells kept in constant dark (DD); twenty-four hours after the white light pulse (WLP), OPN4 was found in the cell membrane. Despite the fact that B16–F10 cells expressed less Opn2 and Opn4 than Melan-a cells, our data indicate that the malignant melanocytes exhibited increased photoresponsiveness. The clock gene machinery is also severely downregulated in B16–F10 cells as compared to Melan-a cells. Per1 , Per2 , and Bmal1 expression increased in B16–F10 cells in response to WLP. Although no response in clock gene expression to WLP was observed in Melan-a cells, gene correlational data suggest a minor effect of WLP. In contrast to opsins and clock genes, melanogenesis is significantly upregulated in malignant melanocytes in comparison to Melan-a cells. Tyrosinase expression increased after WLP only in B16–F10 cells; however no increase in melanin content after WLP was seen in either cell line. Our findings may prove useful in the treatment and the development of new pharmacological approaches of depigmentation diseases and skin cancer. [ABSTRACT FROM AUTHOR]

Tyrosinase, the key rate-limiting enzyme for melanogenesis, is one of the main targets for skin senescence and some pigmented skin diseases, such as albinism and melanoma. Tyrosinase inhibitors are capable of reducing melanin generation and deposition in the skin through blocking the reaction chain of formation. Thus, it has been used for anti-melanoma and showed the potential to be developed into novel skin whitening and spot removing products. With the trend of back-to-nature, natural tyrosinase inhibitors are receiving more and more attention. Traditional Chinese medicines (TCMs) as the promising source of novel chemotypes and pharmacophores, are huge treasures for the discovery of natural tyrosinase inhibitors characterized with green, safe, and highly efficient. Aim of this review : This review aims to provide a systematic overview of natural tyrosinase inhibitors and a detailed summary of the types of TCMs from which they originate. In addition, this paper also highlights the screening methods developed for exploring tyrosinase inhibitors in recent years, compares the advantages and disadvantages of various methods under the guidance of different screening principles, and predicts their applications in the future. Relevant literature have been obtained using the keywords "tyrosinase inhibitors", "traditional Chinese medicines", "whitening", and "screening" in scientific databases, such as "PubMed", "SciFinder", "Web of Science", "Elsevier", "China Knowledge Resource Integrated databases". Information was also collected from Chinese pharmacopoeia, Chinese herbal classics books, "Google Scholar", "Baidu Scholar", and other literature sources, etc. An overview about the tyrosinase inhibitors derived from TCMs since 2002 has been compiled via the above-mentioned sources. Up to now, 186 components, mainly belonging to flavonoids, lignans, terpenoids, Diels-Alder adducts, simple phenylpropanoids and stilbenes, from 61 kinds of TCMs have been reported to possess tyrosinase inhibitory activity, among which flavonoids are mainly focused on. Furthermore, on the basis of bioactive detection strategies, the screening methods for tyrosinase inhibitors have been classified into bioaffinity-based, intrinsic enzymatic-based, and computer-aided drug design (CADD). Precisely because screening approaches are essential for rapid identification of tyrosinase inhibitors from TCMs, the principles, advantages and disadvantages, and specific applications of each method are presented along with a comparison of applicability. The summary of TCMs-derived inhibitors gives a clue on the discovery of candidates with the property to whiten the skin. Meanwhile, the outlook of developed screening methods provides technical references for the efficient exploration of safer and more effective tyrosinase inhibitors from TCMs. [Display omitted] • A summary and classification of tyrosinase inhibitors currently found in traditional Chinese medicines. • Summarizing the current screening methods for the screening of tyrosinase inhibitors from traditional Chinese medicines. • Providing methodological guidance for future screening of tyrosinase inhibitors from traditional Chinese medicines. [ABSTRACT FROM AUTHOR]

A 16-year-old boy developed over a 2-month interval a lightly pigmented left upper eyelid lesion measuring 1.5 mm in greatest diameter that, when excised, microscopically was hypercellular and composed almost exclusively of nonpigmented epithelioid cells that created florid, large intraepidermal junctional nests and sheets and nests of subepidermal cells. The diagnosis was a Spitz nevus. HMB-45, MART-1, and microphthalmia-associated transcription factor were all positive and established the melanocytic nature of the benign tumor. The Ki-67 proliferation index (5%) and 2 mitoses/mm 2 were both low; p16 protein was immunohistochemically identified in the nevoid cells. We review the clinical, histopathologic, and other immunohistochemical features of this entity and provide a brief differential diagnosis (including separation from a Spitzoid melanoma). This is only the third eyelid Spitz nevus reported in the literature and is the most fully characterized immunohistochemically. At their present stage of development, contemporary immunohistochemical biomarkers, while providing supplemental information, nonetheless remain less than definitive in terms of reliably distinguishing benign from malignant Spitz lesions. [ABSTRACT FROM AUTHOR]

Background: Incontinentia pigmenti is a rare neurocutaneous disorder that may result in neurological symptoms in addition to its characteristic skin rashes. The pathogenesis of central nervous system disorders in incontinentia pigmenti remains unclear, but it has been suggested that vascular abnormalities and inflammatory processes may play important roles. Notably, there is no established treatment for central nervous system disorders in incontinentia pigmenti. We report a neonate with acute neurological symptoms of incontinentia pigmenti who was effectively treated with corticosteroid therapy. We review the literature and discuss the pathophysiology, diagnosis, and treatment of acute central nervous system disorders in incontinentia pigmenti.Patient Description: A 15-day-old girl with incontinentia pigmenti experienced neurological symptoms such as decreased level of consciousness and a weak sucking reflex. Magnetic resonance imaging revealed multiple cerebral infarctions. We administered corticosteroid therapy, and the symptoms improved immediately and significantly.Conclusion: We suggest that corticosteroid therapy may be an effective treatment during the acute phase of central nervous system dysfunction due to incontinentia pigmenti. It is important to determine the existence of acute phase lesions on magnetic resonance imaging when neurological symptoms occur or worsen. [ABSTRACT FROM AUTHOR]

Genetic skin diseases, or genodermatoses, often have extracutaneous manifestations. Ocular manifestations in particular can have significant clinical implications, like blindness. Other manifestations, such as the corneal opacities that occur in X-linked ichthyosis, are asymptomatic but characteristic of a particular genodermatosis. Ophthalmologic examination can aid in diagnosis when characteristic findings are seen. The genodermatoses with ocular manifestations will be reviewed, but neurocutaneous, syndromes, genetic pigmentary disorders, and genetic metabolic diseases are not included because they are covered elsewhere in this issue. [ABSTRACT FROM AUTHOR]

An automatic pigmented skin lesions tracking system, which is important for early skin cancer detection, is proposed in this work. The input to the system is a pair of skin back images of the same subject captured at different times. The output is the correspondence (matching) between the detected lesions and the identification of newly appearing and disappearing ones. First, a set of anatomical landmarks are detected using a pictorial structure algorithm. The lesions that are located within the polygon defined by the landmarks are identified and their anatomical spatial contexts are encoded by the landmarks. Then, these lesions are matched by labeling an association graph using a tensor-based algorithm. A structured support vector machine is employed to learn all free parameters in the aforementioned steps. An adaptive learning approach (on-the-fly vs offline learning) is applied to set the parameters of the matching objective function using the estimated error of the detected landmarks. The effectiveness of the different steps in our framework is validated on 194 skin back images (97 pairs). [ABSTRACT FROM AUTHOR]

Background The mouse pink-eyed dilution (oculocutaneous albinism II; p/Oca2 p ) locus is known to control tyrosinase activity, melanin content, and melanosome development in melanocytes. Pink-eyed dilution castaneus ( p cas / Oca2 p−cas ) is a novel mutant allele on mouse chromosome 7 that arose spontaneously in Indonesian wild mice, Mus musculus castaneus . Mice homozygous for Oca2 p−cas usually exhibit pink eyes and beige-colored coat on nonagouti C57BL/6 (B6) background. Recently, a novel spontaneous mutation occurred in the progeny between this mutant and B6 mice. The eyes of this novel mutant progressively become black from pink and the coat becomes dark gray from beige with aging. Objective The aim of this study is to clarify whatever differences exist in melanocyte proliferation and differentiation between the ordinary (pink-eyed) and novel (black-eyed) mutant using serum-free primary culture system. Methods The characteristics of melanocyte proliferation and differentiation were investigated by serum-free primary culture system using melanocyte-proliferation medium (MDMD). Results The proliferation of melanoblasts in MDMD did not differ between the two mice. However, when the epidermal cell suspensions were cultured with MDMD supplemented with l -tyrosine (Tyr), the differentiation of black-eyed melanocytes was greatly induced in a concentration-dependent manner compared with pink-eyed melanocytes. Immunocytochemistry demonstrated that the expression of tyrosinase and tyrosinase-related protein-1 (Tyrp1) was greatly induced or stimulated both in pink-eyed and black-eyed melanocytes, whereas the expression of microphthalmia-associated transcription factor (Mitf) was stimulated only in black-eyed melanocytes. Conclusion These results suggest that the age-related coat darkening in black-eyed mutant may be caused by the increased ability of melanocyte differentiation dependent on l -Tyr through the upregulation of tyrosinase, Tyrp1, and Mitf. This mutant mouse may be useful for animal model to clarify the mechanisms of age-related pigmentation in human skin, such as melasma and solar lentigines. [ABSTRACT FROM AUTHOR]

Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions. [ABSTRACT FROM AUTHOR]

The major pigment in eggshells of brownegg laying hens is protoporphyrin IX, but traces of biliverdin and its zinc chelates are also present. The pigment appears to be synthesized in the shell gland. The protoporphyrin IX synthetic pathway is well defined, but precisely where and how it is synthesized in the shell gland of the brown-egg laying hen is still ambiguous. The pigment is deposited onto all shell layers including the shell membranes, but most of it is concentrated in the outermost layer of the calcareous shell and in the cuticle. Recently, the genes that are involved in pigment synthesis have been identified, but the genetic control of synthesis and deposition of brown pigment in the commercial laying hen is not fully understood. The brown coloration of the shell is an important shell quality parameter and has a positive influence on consumer preference. The extent of pigment deposition is influenced by the housing system, hen age, hen strain, diet, stressors, and certain diseases such as infectious bronchitis. In this article, the physiological and biochemical characteristics of the brown pigment in commercial brown-egg layers are reviewed in relation to its various functions in the poultry industry. [ABSTRACT FROM AUTHOR]

Pigmentation often signals status and in general melanin-based pigmentation is indicative of aggression and stress resilience in vertebrates. This is evident in the salmonids Atlantic salmon ( Salmo salar ) and rainbow trout ( Oncorhynchus mykiss ) where more melanin spotted individuals are more stress resilient. However, in the salmonid Arctic charr ( Salvelinus alpinus ) it seems as if it is carotenoid-based pigmentation that signals aggression and stress resilience. In our study, social stress effects on carotenoid-based spots, and behavioural and physiological stress responses were investigated. Socially stressed individuals have more spots, and behavioural stress responses were associated with spots. Some of the results concerning physiological stress responses, such as plasma cortisol levels and monoaminergic activity, are associated with spottiness. Further, the earlier proposed lateralization of spots, with left side connected to stress responsiveness and right side to aggression, is to some extent validated although not conclusively. In conclusion, this study provides further evidence that more stressed charr have more carotenoid spots, and for the first time monoaminergic activity is shown to be connected with carotenoid pigmentation. [ABSTRACT FROM AUTHOR]