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In previous studies, we analyzed that exosomal microRNA (miRNA) secreted by keratinocytes exposed to Ultraviolet B(UVB) light regulate melanogenesis in melanocytes. Through functional experiments, it was determined that a subgroup of exosomal miRNAs had distinct impacts on melanogenesis. In the current study, we focused on hsa-miR-365b-5p which founded upregulated in UVB-irradiated keratinocyte exosomes and confirmed to exert enhancing effects on melanogenesis in human melanocyte. Hsa-miR-365b-5p is a specific, mature microRNA derived from the precursor hsa-miR-365. We demonstrated that the overexpression of hsa-miR-365b-5p in normal human epidermal melanocytes (NHEM) resulted in an approximate 50% increase in melanin content relative to the control group. Furthermore, treatment with an inhibitor of hsa-miR-365b-5p substantiated its specific regulatory role in melanogenesis, as inhibition resulted in a nearly 90% reduction in melanin production. Notably, hsa-miR-365b-5p upregulates the expression of genes associated with melanogenesis, including MITF, TYR, TRP1, and TRP2. Additionally, we established that GLI Family Zinc Finger 2 (GLI2) functions as a repressor of MITF, with its inhibition via siRNA leading to increased melanogenesis. Moreover, we constructed a luciferase reporter vector containing the 3' UTR of GLI2, confirming that hsa-miR-365b-5p specifically targets GLI2, a known repressor of MITF. These findings elucidate the regulatory pathways governing melanogenesis and underscore the significant role of hsa-miR-365b-5p in this biological process. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the effects of circRNA18_46222157_46248185 (named circRNA18) on goat melanogenesis, which differs significantly in goat skins isolated from white and brown coat-colored skins. Methods: Expression patterns of circRNA18 in goat skin and melanocytes were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. The circRNA18 interference vector was designed and synthesized to transfect melanocytes and detect the effect of circRNA18 interference on melanin production. Bioinformatics software was used to predict the targeted adsorption miRNAs of circRNA18, verified by luciferase assay. A miRNA expression vector was constructed and transfected into melanocytes to detect the effect of miRNA on melanin production, and the targeted regulatory genes were detected by luciferase assay. Target gene interference vector was constructed to detect the influence of target gene interference on melanin production. Results: qRT-PCR results unveiled distinct expression patterns of circRNA18 in diverse tissues of male and female goats, while in situ hybridization assays showed that circRNA18 is expressed in the cytoplasm of melanocytes. Functional analysis demonstrated that the downregulation of circRNA18 in melanocytes leads to a significant increase (p<0.01) in melanin production. Bioinformatics analysis identified a potential miR-211 binding site on circRNA18, and luciferase assay confirmed their interaction. Overexpression of miR-211 in melanocytes significantly augmented (p<0.01) melanin production. There were two potential miR-211 binding sites on adenoviral E1A-binding protein (EP300), and the overexpression of miR-211 in melanocytes significantly decreased (p<0.001) EP300 expression, with luciferase assay confirming their interaction. Downregulation of EP300 expression in melanocytes through siRNA-EP300 transfection results in a substantial increase (p<0.05) in melanin production. qRT-PCR results indicated that overexpression of mimics-circRNA18 in melanocytes markedly suppressed (p<0.0001) miR-211 expression, significantly elevated (p<0.01) EP300 expression, and significantly inhibited (p<0.001) melanin production. Conclusion: circRNA18_46222157_46248185 acted as a negative regulator of melanogenesis in goat melanocytes by targeting the miR-211/EP300 pathway, and guiding animal hair color breeding strategies. [ABSTRACT FROM AUTHOR]

Background/Objectives: Facial lesions, including lentigo maligna and lentigo maligna melanoma (LM/LMM), both malignant, present significant diagnostic challenges due to their clinical similarity to benign conditions. Although standard dermoscopy is a well-established tool for diagnosis, its inability to reveal cellular-level details highlights the necessity of new magnified techniques. This study aimed to assess the role of standard dermoscopy, high-magnification dermoscopy, and fluorescence-advanced videodermatoscopy (FAV) in diagnosing LM/LMM and differentiating them from benign facial lesions. Methods: This retrospective, observational, multicenter study evaluated 85 patients with facial skin lesions (including LM, LMM, basal-cell carcinoma, solar lentigo, seborrheic keratosis, actinic keratosis, and nevi) who underwent dermatological examination for skin tumor screening. Standard dermoscopy at 30× magnification (D30), high-magnification dermoscopy at 150× magnification (D150), and FAV examination were performed. Dermoscopic images were retrospectively evaluated for the presence of fifteen 30× and twenty-one 150× dermoscopic features, and their frequency was calculated. To compare D30 with D150 and D150 with FAV, the Gwet AC1 concordance index and the correct classification rate (CCR) were estimated. Results: Among 85 facial lesions analyzed, LM/LMM exhibited distinctive dermoscopic features at D30, including a blue–white veil (38.9% vs. 1.7%, p < 0.001), regression structures (55.6% vs. 21.7%, p = 0.013), irregular dots or globules (50.0% vs. 10%, p = 0.001), angulated lines (72.2% vs. 6.7%, p < 0.001), an annular granular pattern (61.1% vs. 20%, p = 0.002), asymmetrical pigmented follicular openings (100.0% vs. 21.7%; p < 0.001), and follicular obliteration (27.8% vs. 3.3%). At D150, roundish melanocytes (87.5% vs. 18.2%, p < 0.001) and melanophages (43.8% vs. 14.5%, p = 0.019) were predominant. FAV examination identified large dendritic cells, isolated melanocytes, and free melanin in LM/LMM (all p < 0.001) with high concordance to D150. Conclusions: Integrating D30, D150, and FAV into clinical practice may enhance diagnostic precision for facial lesions by combining macroscopic and cellular insights, thereby reducing unnecessary biopsies. However, future studies are essential to confirm these results. [ABSTRACT FROM AUTHOR]

Hair follicle (HF) development and pigmentation are complex processes governed by various signaling pathways, such as TGF-β and FGF signaling pathways. Nestin + (neural crest like) stem cells are also expressed in HF stem cells, particularly in the bulge and dermal papilla region. However, the specific role and differentiation potential of these Nestin-positive cells within the HF remain unclear, especially regarding their contribution to melanocyte formation and hair pigmentation. Bone morphogenetic protein 4 (BMP4), members of the TGFβ family, has been implicated in regulating HF growth, coloration, and related cellular behaviors. Its role in directing Nestin-positive cells toward a melanocytic lineage has yet to be fully explored. In this study, mouse HF organoids were constructed and shown to be an ideal model for studying HF growth and development in vitro. Using this model as a basis, we demonstrated that BMP4 controls HF coloration as well as its length, number, and even size. Furthermore, Nestin-positive cells in the HF-especially those in the bulge region-differentiate into melanocytes, which produce the pigments that give HF its color under BMP4 stimulation. The resulting increase in pigmentation within the mouse HF organoids underscores that BMP4 has a major regulatory role in the formation of melanocytes from Nestin-positive stem cells. This research provides insights into the cellular mechanisms underlying hair pigmentation and suggests potential therapeutic applications for pigmentation disorders. [ABSTRACT FROM AUTHOR]

Background Hypothesis/Objective Materials and Methods Results Conclusions and Clinical Relevance In humans, the presence of an even distribution of melanocytes within the epidermal basal layer allows for uniform pigmentation in healthy and young individuals. Moreover, despite high variability in skin colours and tones, interindividual melanocyte density variability is low. However, dogs display a high intraindividual pigmentary variability in different anatomical areas.Data on canine melanocytes, including their distribution and density, are limited. This study aimed to assess melanocyte density across different anatomical areas in dogs of various breeds.Samples were harvested postmortem from 22 dogs of different breeds and ages. Samples were collected from the following: haired skin (back, ventral abdomen, head and pinnae), oral and conjunctival mucocutaneous junctions, oral mucosa (buccal mucosa, gingiva, palate) and nose. Immunohistochemical investigation using a cocktail containing Melan‐A and SOX‐10 antibodies was performed to evaluate the melanocytes:keratinocytes ratio (M:K ratio).Variable melanocyte density was recorded in different anatomical areas, with a higher M:K ratio on the eyelid (median: 1:4; interquartile range [IQR]: 1:3.8–1:5.1) and on the nose (median: 1:6.5; IQR: 1:5.2–1:9.6). Lower ratios were observed on the haired skin, particularly on the head (median: 1:113.6; IQR: 1:37.8–1:255.1).Together with different melanocyte densities in different anatomical areas, dogs showed a high interindividual variability, particularly on haired skin. This finding could be associated with colour phenotype, sun exposure, and breed. Variable densities of melanocytes also might justify different incidence of melanocytic tumours in hyperpigmented breeds and in different somatic areas, as well as provide an increased protective effect in chronically sun‐exposed areas. [ABSTRACT FROM AUTHOR]

Hair graying is one of the most intuitive phenotypes of human aging. Although the specific role of genetic factors in gray hair is still uncertain, studies have found that oxidative stress, emotional stress, neuroendocrine regulation, diseases, and trace elements contained in the body may all be related to the generation of white hair. Melanin production in hair follicles is strictly coupled to the nascent stage of the hair growth cycle. Melanin stem cell self-maintenance defects and melanocyte synthesis disorders under the regulation of various hormones and biological factors in the process of pigment synthesis may be the key to the generation of white hair. This article reviews the recent research on the mechanism of white hair formation and the future prospects for the prevention and treatment of white hair from different aspects. [ABSTRACT FROM AUTHOR]

Vitiligo, a chronic skin condition characterized by depigmentation, poses significant therapeutic challenges. Various medical therapies have been explored to address this disorder, aiming to halt its progression and promote repigmentation. Recent advancements in medical therapies have shown promising results in managing this condition. This abstract reviews the latest therapeutic approaches, including the use of Janus kinase inhibitors such as ruxolitinib. Additionally, traditional treatments such as corticosteroids, calcineurin inhibitors, and phototherapy continue to play a crucial role in vitiligo management. This review highlights the importance of a multifaceted approach, combining new and established therapies to optimize patient outcomes and improve quality of life.

Vitiligo is a dermatological condition affecting 1% of the global population, characterized by the loss of skin pigmentation. It appears in two main forms: nonsegmental (symmetrical depigmentation) and segmental (localized depigmentation). Oxidative stress and mitochondrial dysfunction in melanocytes cause vitiligo, while immune privilege protects hair follicle melanocytes, allowing for possible repigmentation. Genetic factors and associations with other autoimmune diseases, such as type 1 diabetes and thyroiditis, suggest a heritable autoimmune component. CD8+ T cells play a crucial role in vitiligo, targeting melanocytes and promoting apoptosis. These cells, along with IFN-γ signaling, contribute to disease progression. Therapies targeting these pathways, such as JAK inhibitors, have shown promise in repigmentation, particularly when combined with narrowband UVB phototherapy, a gold standard treatment. Surgical interventions, including punch grafting and suction blister grafting, show high efficiency but bring high risks of skin damage and hyperpigmentation. Vitiligo patients experience significant emotional suffering, requiring both a psychological and medical treatment approach. Dietary interventions, specifically those rich in antioxidants, may support disease treatment. Vitamin D, in particular, is a promising therapeutic agent by protecting melanocytes from oxidative stress via the WNT/β-catenin pathway. This review points out the need for more research on targeted therapies that combine immune regulation, phototherapy, and dietary strategies for effective vitiligo treatment.

Simple Summary: Two-pore channel 2 (TPC2) is a protein mediating Ca2+ and Na+ flux across the membranes of intracellular vesicles, including melanosomes. Melanosomes produce pigment (melanin), giving hair and skin their color. Blond or red hair and fair skin, in particular in combination with extensive UV light exposure, are bona fide risk factors for melanoma development. While TPC2 gain-of-function variants decrease melanin production, resulting in an increased likelihood for carriers to have light/blond hair, loss of TPC2 function increases melanin production. Here, we will discuss recent evidence for TPC2 and its effector Rab7a as proteins involved in melanin production and their implications for melanoma development. Two-pore channel 2 (TPC2) is expressed in endolysosomes throughout the human body, as well as in melanosomes of melanocytes. Melanocytes produce pigment, i.e., melanin, which determines hair and skin color but also protects from UV light. Extensive exposure to UV light is one of the major risk factors for the development of melanoma, which develops from pigment-producing cells, i.e., melanocytes. In recent years, several human TPC2 single nucleotide polymorphisms have been identified to increase the likelihood of carriers presenting with blond hair and hypopigmentation. These variants were all characterized as gain-of-function versions of TPC2. Vice versa, the loss of function of TPC2 increases melanin production and reduces cancer hallmarks such as proliferation, migration, invasion, tumor growth, and metastasis formation. The activity of TPC2 is controlled in a complex manner, with several endogenous ligands as well as a number of interacting proteins being involved. We will discuss here the role of TPC2 in pigmentation and its potential to impact melanoma development and progression and highlight recent findings on Rab7a as an enhancer of TPC2 activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine oral melanoma is an aggressive cancer in dogs that may respond to new treatments designed to boost the immune system's ability to fight the disease. In this study, we investigated whether mesenchymal stem cells derived from fat tissue could stimulate the immune system against this cancer. Mesenchymal stem cells are known to produce proteins called cytokines that help support immune functions. We tested whether combining these stem cells with another type of immune cell could inhibit cancer cell viability and migration. We also examined three key interleukins—2, 8, and 12—associated with immune responses to understand how they might reduce cancer cell growth and migration. Our findings showed that mesenchymal stem cells indeed reduced cancer cell migration and survival, although the effects varied depending on the cancer cell type, suggesting that some cells respond better than others. These results could aid in developing new, less invasive therapies that harness the immune system to fight cancer in dogs, potentially reducing the need for more aggressive treatments and improving patient outcomes. Canine oral melanoma (COM) is a promising target for immunomodulatory therapies aimed at enhancing the immune system's antitumor response. Given that adipose-derived mesenchymal stem cells (Ad-MSCs) possess immunomodulatory properties through cytokine release, we hypothesized that co-culturing Ad-MSCs and canine peripheral blood mononuclear cells (PBMCs) could stimulate interleukin (IL) production against melanoma cell lines (MCCLs) and help identify therapeutic targets. This study evaluated IL-2, IL-8, and IL-12 expressions in co-culture with MCCL, Ad-MSCs, and PBMCs and assessed the relationship between gene expression, cell viability, and migration. Using four experimental groups in a Transwell insert system to separate cell types, we found that Ad-MSCs can reduce MCCL migration and viability, though the effect may vary depending on each cell line's susceptibility. Furthermore, Ad-MSCs modified IL expression profiles in co-cultured cells. Our findings suggest that Ad-MSCs could have therapeutic potential for COM by inhibiting cell migration and reducing viability. However, deeper insights into Ad-MSC interactions with the tumor microenvironment and melanoma-specific factors will be essential to optimize therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Melanoma, a type of cancer, has the ability to metastasize and can be fatal. The lack of success in the treatment of melanoma with chemotherapeutic agents and the side effects have led to the search for new agents. Moreover, developing systems that will provide reduce side effects by using biocompatible carriers, may be beneficial. Naringin (NAR), from Citrus plants, has anticancer and anti-inflammatory properties. NAR is useful in formulations where it is used with a carrier due to its low water solubility and bioavailability with few toxicity. This study aimed to evaluate the effects of NAR-loaded peptide based Fmoc-FF nanogels on human melanoma (SK-MEL-30) cells. Characterization of NAR-loaded Fmoc-FF nanogels was carried out. The biocompatibility properties of Fmoc-FF and NAR-loaded nanogels were evaluated in mouse fibroblast (L929) cells, and their cytotoxic effects were evaluated in human melanoma (SK-MEL-30) cells by the MTT method. While the DCF-DA method was used to measure the effects on reactive oxygen species (ROS) release, the changes in oxidative stress biomarkers were examined by spectrophotometric analysis, tyrosinase enzyme activity and inflammation biomarkers were investigated by ELISA method. Comet method was used to evaluate antigenotoxic effects. It has been observed that loading NAR into Fmoc peptide gels may be effective in causing cytotoxic, genotoxic, anti-inflammatory and anti-tyrosinase effects and an increase in ROS release in melanoma cells. These results indicate that NAR-loaded Fmoc-FF gels, which have the feature of easy application to the skin, may be effective in the treatment of melanoma without causing toxic effects. [ABSTRACT FROM AUTHOR]

ABSTRACT In 1973, Dr. Martin C. Mihm, Jr. presented the finding that congenital melanocytic nevi, when viewed at low magnification, resemble superficial and deep perivascular dermatitis, forming the so‐called “pseudoinflammatory” pattern. One year earlier, Dr. Richard A. Sagebiel had put forward the concept of “pseudovascular spaces” in melanocytic nevi. A retrospective look at these early studies confirms that alert observation at the microscope can lead to a deeper understanding of the fundamental biology underlying melanocytic tumors. [ABSTRACT FROM AUTHOR]

Vitiligo is characterized by the depletion of melanocytes due to the activation of CD8+ T cells. Taurine‐upregulated gene 1 (TUG1), a long noncoding RNA, is involved in melanogenesis. This study aimed to explore the role and mechanism of TUG1 in vitiligo. RT‐qPCR and western blot analyses demonstrated decreased TUG1 levels and increased miR‐375 levels in patients with vitiligo. MTT and transwell assays indicated that TUG1 upregulation facilitated melanocyte survival and inhibited CD8+ T cell migration. Dual luciferase reporter and chromatin immunoprecipitation assays verified that Forkhead box O3 (FOXO3) directly interacted with the TUG1 promoter, leading to the positive regulation of TUG1 expression. In addition, FOXO3 promoted melanocyte survival by enhancing the transcription of TUG1. Luciferase reporter assay and RNA immunoprecipitation assay confirmed that TUG1 upregulated GATA binding protein 3 (GATA3) expression by targeting miR‐375. TUG1 facilitated melanocyte survival by regulating the miR‐375/GATA3 axis. In vitiligo, melanocyte survival is promoted by the induction of the TUG1‐mediated miR‐375/GATA3 axis by FOXO3, which offers new therapeutic targets for vitiligo treatment. [ABSTRACT FROM AUTHOR]

The treatment of melanoma has witnessed groundbreaking changes over the last decade, transforming the standard of care for patients with high-risk, advanced or metastatic disease. Whilst the treatment approach depends on the stage of disease, the management of primary melanoma remains complete wide excision of the primary. Sentinel node biopsy is offered in selected higher risk melanoma and complete nodal dissection is performed in patients who present with palpable nodal disease. Tumour genetic analysis for BRAF mutation should be performed in all patients with stage IIB to IV disease as this will determine if patients are suitable for targeted treatment with BRAF and MEK inhibitors. Systemic treatment with targeted treatment with BRAF and MEK inhibitors and immunotherapy are recommended as adjuvant treatment options and in metastatic settings. Patients with a personal or family history of three or more melanomas require genetic assessment. [ABSTRACT FROM AUTHOR]

Melittin is a major active ingredient of the bee venom produced by honeybees (Apis mellifera) that exerts various biological effects, such as anti-inflammatory, anti-tumor, anti-microbial, and antioxidant. The role of melittin in modulating melanin production by melanocytes is not known. Therefore, the present study aimed to study the effect of melittin on melanin production by human melanocytes along with its antioxidant status. Cultured human melanocytes were treated with melittin in a dose- and time-dependent manner, followed by the study of the cell viability, cell proliferation, and total melanin content. The effects of melittin in combination with narrow-band ultraviolet B (NB-UVB) on the total melanin content, melanocyte dendricity, oxidative stress, and the expression of genes associated with melanogenesis were investigated. An increased melanin content was observed with a low dose of melittin (LDM) (alone or in combination with NB-UVB), and there was a corresponding increase in the tyrosinase activity, melanocyte dendricity, and melanogenesis-associated genes. The present study concluded that LDM alone or LDM (+NB-UVB) can induce melanin synthesis by increasing the tyrosinase activity in melanocytes by limiting the oxidative stress, and this may be therapeutically exploited as an adjuvant therapy for vitiligo. [ABSTRACT FROM AUTHOR]

Vitiligo is a disease characterised by the autoimmune destruction of melanocytes, manifesting as depigmentation of the skin. We present the case of a female patient with a history of breast cancer who developed vitiligo in the area of the treatment field 12 months after the end of radiotherapy. It has been reported in the literature that vitiligo can occur in patients with a history of vitiligo after radiotherapy, attributable to the Koebner phenomenon, where some treatments can induce new vitiligo lesions in the patient. [ABSTRACT FROM AUTHOR]

Vitiligo, an autoimmune skin disorder characterized by melanocyte loss, has long been associated with sympathetic nervous system activity. Clinical observations have suggested links between psychological stress, sympathetic activation, and vitiligo progression. However, direct experimental evidence for the role of sympathetic nerves in vitiligo development has been lacking. Herein, we employed 6-hydroxydopamine (6-OHDA) to induce sympathetic nerve depletion in mice before vitiligo induction. Sympathetic nerve ablation was confirmed through immunofluorescent staining of tyrosine hydroxylase. Vitiligo progression was assessed by quantifying epidermal melanocytes and CD8+ T cells using whole-mount immunofluorescence staining. The loss of melanocytes and infiltration of CD8+ T cells in vitiligo lesions were comparable between sympathectomized and control mice. Overall, our study suggested that previously observed associations between sympathetic nervous system activity and vitiligo may be concomitant effects rather than causative factors, challenging long-held clinical hypotheses.

Abstract In humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest‐derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10‐driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle‐deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development.

Simple Summary: Asinara donkeys are unique worldwide for expressing a particular form of albinism spread to all individuals of the breed. This peculiar condition of oculo-cutaneous albinism of type 1 (OCA1) is a rare condition from a recessive autosomic mutation, fixed through generations, thanks to the isolation of donkeys on Asinara Island (from which the breed name originates) favoring inbreeding. Asinara island is a small island of Sardinia, one of the biggest islands in the Mediterranean sea. Asinara donkeys have shown good adaptation to the Mediterranean climate through various metabolic strategies, one of which relies on endogenous retinol mobilization during the positive photoperiod for protective effect and adequate circulating vitamin E. Indeed, their exposure to sun radiation and high temperature on one hand, and the lack of melanin in the coat, skin, iris and mucocutaneous junctions on the other, require them to overcome such an extended lack of photoprotective pigment (melanin) in alternative ways to prevent UV radiation damage. In this investigation, our interest was oriented toward screening the complete blood cell count to understand whether metabolic adaptation to the environment involved blood cell lines. Such an idea comes from the fact that in humans, a particular condition of albinism is reported to share the same gene with other mutations involving hemoglobin synthesis. In our case, significant differences were observed in relation to red blood cells (RBCs), in terms of their average volume (MCV), width distribution (RDW-CV), and width deviation (RDW-SD), in comparison to pigmented (gray) Sardo donkeys. The complete blood cell count (CBC) was screened in a group of 15 donkeys, of which 8 were of Asinara breed (oculocutaneous albinism type 1, OCA1) and 7 of Sardo breed (gray coat). All donkeys were kept under same management and dietary conditions and underwent periodic health monitoring in the month of June 2024, at the peak of the positive photoperiod, at Mediterranean latitudes. One aliquot of whole blood, drawn from each individual into K2-EDTA containing tubes, was analyzed for the complete blood cell count through an automatic analyzer, within two hours of sampling. Data were analyzed and compared by one-way ANOVA, where the breed was an independent variable. All animals appeared clinically healthy, though mild eosinophilia was observed in Sardo donkeys. The red blood cell line showed peculiar traits for Asinara donkeys, which displayed significantly higher circulating red blood cell numbers than gray coat Sardo donkeys (RBC, 5.19 vs. 3.80 1012/mL ± 0.98 pooled-St. Dev, respectively; p = 0.017). RBCs also exhibited a smaller diameter and higher degree of anisocytosis in Asinara donkeys, along with lower hematocrit value, albeit within physiological ranges. Taken all together, such hematological profile depicts a peculiar trait of the red blood cell line in albino donkeys during the positive photoperiod. [ABSTRACT FROM AUTHOR]

Benign dendritic melanocytic proliferation is usually observed in the skin. We report an extremely rare case of a melanocytic lesion in the middle ear mucosa. Only 3 cases of melanocytic lesions in the middle ear have been reported. Our report is the only one that describes an adult with a melanocytic lesion in the middle ear that extended to the inner ear and nasopharyngeal mucosa. A 23-year-old female presented with profound sensory neural hearing loss and recurrent discharge from the right ear. Examination revealed a blue right tympanic membrane with a small perforation. Computed tomography scans and magnetic resonance imaging were performed. After surgical exploration and histopathological examination, the patient was found to have a benign melanocytic lesion in the right middle ear. Melanocytic lesions are commonly found in the skin. There are no previous reports have described adult patients with melanocytic lesions in the middle ear that extend to the inner ear and nasopharynx, which cause profound hearing loss with recurrent ear discharge. These patients require regular follow-up to assess the progression of the lesion and to watch for any malignant behavior. [ABSTRACT FROM AUTHOR]

This study investigated the dominant blue eyes (DBE) trait linked to hearing impairment and variable white spotting in Maine Coon cats. Fifty-eight animals descending from 2 different DBE lineages, the Dutch and the Topaz lines, were sampled. They comprised 48 cats from the Dutch bloodline, including 9 green-eyed and 31 blue-eyed cats, with some individuals exhibiting signs of deafness, and 8 stillborn kittens. Samples from the Topaz lineage included 10 blue-eyed animals. A brainstem auditory evoked response test revealed a reduced to absent response to auditory stimuli and absent physiological waveforms in all of the 8 examined DBE animals. We sequenced the genome of 2 affected cats from the Dutch line and searched for variants in 19 candidate genes for the human Waardenburg syndrome and pigmentary disorders. This search yielded 9 private protein-changing candidate variants in the genes PAX3 , EDN3 , KIT , OCA2 , SLC24A5 , HERC2 , and TYRP1. The genotype–phenotype cosegregation was observed for the PAX3 variant within all animals from the Dutch lineage. The mutant allele was absent from 461 control genomes and 241 additionally genotyped green-eyed Maine Coons. We considered the PAX3 variant as the most plausible candidate—a heterozygous nonsense single base pair substitution in exon 6 of PAX3 (NC_051841.1:g.205,787,310G>A, XM_019838731.3:c.937C>T, XP_019694290.1:p.Gln313*), predicted to result in a premature stop codon. PAX3 variants cause auditory–pigmentary syndrome in humans, horses, and mice. Together with the comparative data from other species, our findings strongly suggest PAX3 :c.937C>T (OMIA:001688-9685) as the most likely candidate variant for the DBE, deafness, and minimal white spotting in the Maine Coon Dutch line. Finally, we propose the designation of DBERE (Rociri Elvis Dominant Blue Eyes) allele in the domestic cat. [ABSTRACT FROM AUTHOR]

It has been 30 (!!) years since I began working on zebrafish pigment cells, as a postdoc in the laboratory of Prof. Christiane Nüsslein‐Volhard. There, I participated in the first large‐scale mutagenesis screen in zebrafish, focusing on pigment cell mutant phenotypes. The isolation of colourless, shady, parade and choker mutants allowed us (as a postdoc in Prof. Judith Eisen's laboratory, and then in my own laboratory at the University of Bath since 1997) to pursue my ambition to address long‐standing problems in the neural crest field. Thus, we have studied how neural crest cells choose individual fates, resulting in our recent proposal of a new, and potentially unifying, model which we call Cyclical Fate Restriction, as well as addressing how pigment cell patterns are generated. A key feature of our work in the last 10 years has been the use of mathematical modelling approaches to clarify our biological models and to refine our interpretations. None of this would have been possible without a hugely talented group of laboratory members and other collaborators from around the world—it has been, and I am sure will continue to be, a pleasure and privilege to work with you all! [ABSTRACT FROM AUTHOR]

Photobiomodulation (PBM) using 830 nm light‐emitting diode (LED) benefits tissue regeneration, wound healing and neural stimulation. However, there is not much exploration of its effect on melanocytes and ex vivo skin model. This study aims to investigate the mechanism behind the anti‐melanogenic activity of 830 nm LED and provides evidence for its activity in human ex vivo skin model. Our results showed that 830 nm LED at fluences ranging from 5 to 20 J/cm2 inhibited melanosome maturation and reduced melanin content, tyrosinase activity and melanogenesis‐related proteins. 830 nm LED inhibited the phosphorylation of AKT and its downstream FOXO3a, leading to nuclear translocation of FOXO3a. Furthermore, FOXO3a knockdown and AKT activator like SC79 could reverse the melanogenesis inhibition phenotype induced by 830 nm LED. In human ex vivo skin model, Fontana–Masson staining revealed a decrease in epidermal basal pigmentation after 830 nm LED irradiation. Taken together, 830 nm LED demonstrated the anti‐melanogenic activity via FOXO3a. [ABSTRACT FROM AUTHOR]

Intercellular communication is a cell‐type and stimulus‐dependent event driven not only by soluble factors but also by extracellular vesicles (EVs). EVs include vesicles of different size and origin that contain a myriad of molecules. Among them, small EVs (sEV; <200 nm) have been shown to modulate not just regional cell responses but also distant organ behavior. In cancer, distant organ modulation by sEVs has been associated to disease dissemination, which is one of the main concerns in melanoma. Description of broadly conserved alterations in sEV‐contained molecules represents a strategy to identify key modifications in cellular communication as well as new disease biomarkers. Here, we characterize proteomes of cutaneous melanocyte and melanoma‐derived sEVs to deepen on the landscape of normal and disease‐related cell communication. Results reveal the presence of unique protein signatures for melanocytes and melanoma cells that reflect cellular transformation‐related profound modifications. Melanocyte‐derived sEVs are enriched in oxidative metabolism (e.g., aconitase 2, ACO2) or pigmentation (e.g., tyrosinase, TYR) related proteins while melanoma‐derived sEVs reflect a generalized decrease in mature melanocytic markers (e.g., melanoma antigen recognized by T‐cells 1, MART‐1, also known as MLANA) and an increase in epithelial to mesenchymal transition (EMT)‐related adhesion molecules such as tenascin C (TNC). [ABSTRACT FROM AUTHOR]

Vitiligo, a chronic skin condition characterized by depigmentation, poses significant therapeutic challenges. Various medical therapies have been explored to address this disorder, aiming to halt its progression and promote repigmentation. Recent advancements in medical therapies have shown promising results in managing this condition. This abstract reviews the latest therapeutic approaches, including the use of Janus kinase inhibitors such as ruxolitinib. Additionally, traditional treatments such as corticosteroids, calcineurin inhibitors, and phototherapy continue to play a crucial role in vitiligo management. This review highlights the importance of a multifaceted approach, combining new and established therapies to optimize patient outcomes and improve quality of life. [ABSTRACT FROM AUTHOR]

The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin β1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

In humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest‐derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10‐driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle‐deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development. [ABSTRACT FROM AUTHOR]

Myosin Va (Myo Va) is one of three protein complexes involved in melanosome transport. In this study, we identified BMP-2 as an up-regulator of Myo Va expression using 2-methyl-naphtho[1,2,3-de]quinolin-8-one (MNQO). Our results showed that MNQO reduced the mRNA and protein expression of Myo Va and BMP-2 in melanocytes. Knockdown of BMP-2 by siRNA also affected Myo Va mRNA and protein expression, confirming that MNQO regulates Myo Va through BMP-2. Furthermore, phosphorylation of Smad1/5/8 by BMP2 treatment confirmed that the BMP-2/Smad signaling pathway regulates Myo Va expression in Melan-a melanocytes. Smad-binding elements were found in the Myo Va promoter and phosphorylated Smad1/5/8 bind directly to the Myo Va promoter to activate Myo Va transcription and BMP-2 enhances this binding. These findings provide insight into a new role for BMP-2 in Melan-a melanocytes and a mechanism of regulation of Myo Va expression that may be beneficial in the treatment of albinism or hyperpigmentation disorders. [ABSTRACT FROM AUTHOR]

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne‐related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk‐benefit profile. [ABSTRACT FROM AUTHOR]

Human pigmentary disorders encompass a broad spectrum of phenotypic changes arising from disruptions in various stages of melanocyte formation, the melanogenesis process, or the transfer of pigment from melanocytes to keratinocytes. A large number of pigmentation genes associated with pigmentary disorders have been identified, many of them awaiting in vivo confirmation. A more comprehensive understanding of the molecular basis of pigmentary disorders requires a vertebrate animal model where changes in pigmentation are easily observable in vivo and can be combined to genomic modifications and gain/loss‐of‐function tools. Here we present the amphibian Xenopus with its unique features that fulfill these requirements. Changes in pigmentation are particularly easy to score in Xenopus embryos, allowing whole‐organism based phenotypic screening. The development and behavior of Xenopus melanocytes closely mimic those observed in mammals. Interestingly, both Xenopus and mammalian skins exhibit comparable reactions to ultraviolet radiation. This review highlights how Xenopus constitutes an alternative and complementary model to the more commonly used mouse and zebrafish, contributing to the advancement of knowledge in melanocyte cell biology and related diseases. [ABSTRACT FROM AUTHOR]

Background: Transient Receptor Potential Mucolipin 1 (TRPML1) serves as a pivotal reactive oxygen species (ROS) sensor in cells, which is implicated in the regulation of autophagy. However, its function in melanocyte autophagy under oxidative stress remains elusive. Methods: The expression and ion channel function of TRPML1 were investigated using immunofluorescence and calcium imaging in primary human melanocytes (MCs). After activating TRPML1 with MLSA1 (TRPML1 agonist), autophagy‐related molecules were investigated via western blot. ROS level, apoptosis‐ and autophagy‐related molecules were investigated after pretreatment with MLSA1. After interference with TRPML1 expression, mitochondrial structures were visualized by electron microscopy with hydrogen peroxide (H2O2）treatment. Results: TRPML1 was expressed and functionally active in primary human MCs, and its activation promotes elevated expression of LC3‐II and reduced apoptosis and ROS levels under oxidative stress. TRPML1 downregulation caused mitochondrial swelling and disruption of cristae structures under oxidative stress in primary human MCs. Conclusions: TRPML1 might mediate lysosomal autophagy in primary human MCs under oxidative stress, participating in mechanisms that maintain the oxidative and antioxidant systems in balance. [ABSTRACT FROM AUTHOR]

The skin–brain axis has been suggested to play a role in several pathophysiological conditions, including opioid addiction, Parkinson's disease and many others. Recent evidence suggests that pathways regulating skin pigmentation may directly and indirectly regulate behaviour. Conversely, CNS-driven neural and hormonal responses have been demonstrated to regulate pigmentation, e.g., under stress. Additionally, due to the shared neuroectodermal origins of the melanocytes and neurons in the CNS, certain CNS diseases may be linked to pigmentation-related changes due to common regulators, e.g., MC1R variations. Furthermore, the HPA analogue of the skin connects skin pigmentation to the endocrine system, thereby allowing the skin to index possible hormonal abnormalities visibly. In this review, insight is provided into skin pigment production and neuromelanin synthesis in the brain and recent findings are summarised on how signalling pathways in the skin, with a particular focus on pigmentation, are interconnected with the central nervous system. Thus, this review may supply a better understanding of the mechanism of several skin–brain associations in health and disease. [ABSTRACT FROM AUTHOR]

This study presents the effects of treating polystyrene (PS) cell culture plastic with oxidoreductase enzyme laccase and the catechol substrates caffeic acid (CA), L-DOPA, and dopamine on the culturing of normal human epidermal melanocytes (NHEMs) and human embryonal carcinoma cells (NTERA-2). The laccase–substrate treatment improved PS hydrophilicity and roughness, increasing NHEM and NTERA-2 adherence, proliferation, and NHEM melanogenesis to a level comparable with conventional plasma treatment. Cell adherence dynamics and proliferation were evaluated. The NHEM endpoint function was quantified by measuring melanin content. PS surfaces treated with laccase and its substrates demonstrated the forming of polymer-like structures. The surface texture roughness gradient and the peak curvature were higher on PS treated with a combination of laccase and substrates than laccase alone. The number of adherent NHEM and NTERA-2 was significantly higher than on the untreated surface. The proliferation of NHEM and NTERA-2 correspondingly increased on treated surfaces. NHEM melanin content was enhanced 6-10-fold on treated surfaces. In summary, laccase- and laccase–substrate-modified PS possess improved PS surface chemistry/hydrophilicity and altered roughness compared to untreated and plasma-treated surfaces, facilitating cellular adherence, subsequent proliferation, and exertion of the melanotic phenotype. The presented technology is easy to apply and creates a promising custom-made, substrate-based, cell-type-specific platform for both 2D and 3D cell culture. [ABSTRACT FROM AUTHOR]

The whitening effect of thymol trimethoxycinnamate was studied based on skin cell model. CCK-8 method and cell state observation were used to detect the effect of thymol trimethoxycinnamate on the viability of B16-F10 cells. NaOH lysis method and dopa oxidation method were used to analyze the changes of melanin content and tyrosinase activity in B16-F10 cells. Cell scratch method and Transwell chamber method were used to determine the migration ability of B16-F10 cells. Fluorescence analysis was used to detect the changes of fluorescent AGEs content in the saccharification experiment in vitro. The results show that thymol trimethoxycinnamate has no significant effect on cell viability at or below 10 µg/mL, and has the highest inhibition rate on melanin synthesis, tyrosinase activity and cell migration at 10 µg/mL. The inhibition rate of fluorescent AGEs production in vitro is 97.75% at 200 µg/mL. The results show that thymol trimethoxycinnamate can obviously inhibit the formation of melanin and tyrosinase activity, and has a good whitening effect. Because of its good anti-saccharification ability, it can be used as a potential anti-aging material. [ABSTRACT FROM AUTHOR]

Objective s : To identify canine breeds at risk for ocular melanosis and to compare the clinical and histologic features between affected Cairn Terriers (CTs) and non‐Cairn Terriers (NCTs). Design: Relative risk (RR) analysis and retrospective cohort study of dogs histologically diagnosed with ocular melanosis. Procedures: The COPLOW archive was searched for globe submissions diagnosed with ocular melanosis. Six hundred fifty globes were included, and RR analysis was performed to identify at‐risk NCT breeds. A cohort of 360 CT and NCT globes diagnosed from 2013 to 2023 were included in the retrospective cohort study. Clinical data were collected from submission forms, medical records, and follow‐up surveys. One hundred fifty‐seven submissions underwent masked histologic review. Immunohistochemical staining for CD204 was performed to determine the predominance of melanophages in affected uvea from five NCTs. Results: At‐risk NCT breeds included the Boxer, Labrador Retriever, and French Bulldog. Glaucoma was the reported reason for enucleation in 79.4% of submissions. At enucleation, clinical features less prevalent in NCTs than CTs included pigmentary abnormalities in the contralateral eye (33.7% vs. 63.1%, p =.0008) and abnormal episcleral/scleral pigmentation in the enucleated globe (25.4% vs. 53.6%, p =.0008). Histologic involvement of the episclera was also less frequent in NCTs than in CTs (39.7% vs. 76.9%, p =.008). Concurrent melanocytic neoplasms arising in melanosis were more common in NCTs (24.4%) than CTs (3.9%). Melanophages were not predominant in any samples evaluated immunohistochemically. Conclusions: Several popular NCT breeds carry risk for ocular melanosis, and some clinicopathologic disease features may differ from those described in CTs. [ABSTRACT FROM AUTHOR]

In our series of studies, the changes in the skin characteristics of mice caused by aging were investigated in correlation with the stem cells for keratinocytes and melanocytes in the natural hair cycle until middle age. The aim of the present review was to investigate these characteristics of hair follicles (HFs) at older age and complete the analysis of these changes as a study throughout the mouse lifetime. In addition, stem cells for keratinocytes and melanocytes were evaluated for changes in skin characteristics caused by aging. Postnatal day 200 (P200) appears to be the age of complete maturation of skin and the onset of aging with regard to HFs. Keratin 15-positive keratinocyte stem cells complete their localization as a quantitatively sufficient amount of progenitor in the hair bulge region and orchestrate the regeneration of hairs in every anagen phase thereafter. Although their frequency is low, an unusual structure of HFs, curved HFs, appear for the first time at P200. Thereafter, abnormal hair curvature continues to increase throughout life. In contrast, HF characteristics derived from melanocytes begin to show a high frequency of hypopigmented hair bulbs at P200 and appear to lead to a significant increase in the number of white hairs. Curved HFs and white hairs were considered biomarkers of aging in mice. The number of tyrosinase-related protein 2-positive melanocyte stem cells in the hair bulge is extremely low and may be one cause underlying not only the induction of melanocyte-derived characteristics by aging but possibly also that of keratinocyte-derived characteristics. These results provide insight into the mechanisms of the actions of stem cells on hair regeneration through the aging process. [ABSTRACT FROM AUTHOR]

We have discovered that human vitiligo patients treated with narrow‐band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery‐stage RNA‐Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non‐responding) and compared them with repigmented (responding) lesions from the same patient. Non‐responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non‐responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/β‐catenin repigmentation pathway. Vitiligo‐responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro‐melanogenic effect of α‐MSH. Understanding the pathways that govern lack of NBUVB‐induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo. [ABSTRACT FROM AUTHOR]

Background: Treatment of vitiligo seeks to achieve three goals: cessation of disease progression, regeneration of pigmentation, and prevention of recurrence. Summary: Number of nonsurgical interventions are available that suppress the autoimmune response and regenerate the melanocytes from the reservoir: phototherapy including psoralen and ultraviolet A, narrowband ultraviolet B, and 308-nm excimer and 311-nm Titanium:Sapphire lasers; topical agents including topical calcineurin inhibitors, topical corticosteroids, and topical 5-fluorouracil; and systemic agents including corticosteorids, mycophenolate mofetil, cyclosporine, methotrexate, minocycline, afamelanotide, and antioxidants. In recent years, a great advance has been made in the understanding of pathogenesis of vitiligo, and JAK inhibitors are being investigated as a new treatment. Minimally invasive procedures such as fractional lasers or microneedling can help achieve the optimal treatment outcome when used properly. Key Messages: Our review describes various treatment modalities for vitiligo based on their molecular mechanism of action. Bridging the gap between molecular mechanisms and therapeutic options would be a valuable reference for physicians in clinical practice. [ABSTRACT FROM AUTHOR]

Mammalian melanin is produced in melanocytes and accumulated in melanosomes. Melanogenesis is supported by many factors derived from the surrounding tissue environment, such as the epidermis, dermis, and subcutaneous tissue, in addition to numerous melanogenesis-related genes. The roles of these genes have been fully investigated and the molecular analysis has been performed. Moreover, the role of paracrine factors derived from epidermis has also been studied. However, the role of dermis has not been fully studied. Thus, in this review, dermis-derived factors including soluble and insoluble components were overviewed and discussed in normal and abnormal circumstances. Dermal factors play an important role in the regulation of melanogenesis in the normal and abnormal mammalian skin. [ABSTRACT FROM AUTHOR]