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Ageing Research Reviews Aug 2023Hair graying is an early and obvious phenotypic and physiological trait with age in humans. Several recent advances in molecular biology and genetics have increased our... (Review)
Review
Hair graying is an early and obvious phenotypic and physiological trait with age in humans. Several recent advances in molecular biology and genetics have increased our understanding of the mechanisms of hair graying, which elucidate genes related to the synthesis, transport, and distribution of melanin in hair follicles, as well as genes regulating these processes above. Therefore, we review these advances and examine the trends in the genetic aspects of hair graying from enrichment theory, Genome-Wide association studies, whole exome sequencing, gene expression studies, and animal models for hair graying with age, aiming to overview the changes in hair graying at the genetic level and establish the foundation for future research. Meanwhile, by summarizing the genetics, it's of great value to explore the possible mechanism, treatment, or even prevention of hair graying with age.
Topics: Animals; Humans; Aging; Hair Color; Genome-Wide Association Study; Melanocytes; Hair
PubMed: 37276979
DOI: 10.1016/j.arr.2023.101977 -
Cancer Discovery Oct 2023Oncogenes can initiate tumors only in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can...
UNLABELLED
Oncogenes can initiate tumors only in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors in keratinocytes. Electron microscopy demonstrates specialized cell-cell junctions between keratinocytes and melanoma cells, and multielectrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte cocultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that GABAergic signaling across the skin microenvironment regulates the ability of oncogenes to initiate melanoma.
SIGNIFICANCE
This study shows evidence of GABA-mediated regulation of electrical activity between melanoma cells and keratinocytes, providing a new mechanism by which the microenvironment promotes tumor initiation. This provides insights into the role of the skin microenvironment in early melanomas while identifying GABA as a potential therapeutic target in melanoma. See related commentary by Ceol, p. 2128. This article is featured in Selected Articles from This Issue, p. 2109.
Topics: Animals; Humans; Melanoma; Zebrafish; Melanocytes; Skin; Keratinocytes; Cell Transformation, Neoplastic; gamma-Aminobutyric Acid; Tumor Microenvironment
PubMed: 37553760
DOI: 10.1158/2159-8290.CD-23-0389 -
Frontiers in Cell and Developmental... 2023Melanocytes, which originate from the neuroectoderm, are specialized cells responsible for producing pigments and possessing a dendritic morphology. These cells migrate... (Review)
Review
Melanocytes, which originate from the neuroectoderm, are specialized cells responsible for producing pigments and possessing a dendritic morphology. These cells migrate to the epidermis and follicles, contributing to skin and hair pigmentation during embryonic development. The remarkable self-renewal capacity of melanocytes enables them to effectively restore hair and skin pigmentation. The synthesis of melanin to safeguard the skin against damage caused by ultraviolet radiation, as well as the enigmatic immune function of melanocytes, demonstrate their indispensable contributions to maintaining cutaneous homeostasis. The regulation of cutaneous pigmentation involves an intricate network influenced by intrinsic cellular signals within melanocytes and extracellular cues. Therefore, this paper provides a comprehensive review of the role of melanocytes in skin biology. This in-depth analysis could open novel avenues for research aimed at the prevention and treatment of skin disorders.
PubMed: 38078014
DOI: 10.3389/fcell.2023.1309557 -
Frontiers in Cell and Developmental... 2023Hair follicle (HF) homeostasis is regulated by various signaling pathways. Disruption of such homeostasis leads to HF disorders, such as alopecia, pigment loss, and hair... (Review)
Review
Hair follicle (HF) homeostasis is regulated by various signaling pathways. Disruption of such homeostasis leads to HF disorders, such as alopecia, pigment loss, and hair aging, which is causing severe health problems and aesthetic concerns. Among these disorders, hair aging is characterized by hair graying, hair loss, hair follicle miniaturization (HFM), and structural changes to the hair shaft. Hair aging occurs under physiological conditions, while premature hair aging is often associated with certain pathological conditions. Numerous investigations have been made to determine the mechanisms and explore treatments to prevent hair aging. The most well-known hypotheses about hair aging include oxidative stress, hormonal disorders, inflammation, as well as DNA damage and repair defects. Ultimately, these factors pose threats to HF cells, especially stem cells such as hair follicle stem cells, melanocyte stem cells, and mesenchymal stem cells, which hamper hair regeneration and pigmentation. Here, we summarize previous studies investigating the above mechanisms and the existing therapeutic methods for hair aging. We also provide insights into hair aging research and discuss the limitations and outlook.
PubMed: 38033857
DOI: 10.3389/fcell.2023.1278278 -
The Journal of Allergy and Clinical... Jan 2024Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated.
OBJECTIVE
This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV).
METHODS
Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry.
RESULTS
Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3/CD8 T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P < .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P < .05). T1 and T2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P < .05). Changes in immune biomarkers correlated with clinical response.
CONCLUSIONS
Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.
Topics: Adult; Humans; Vitiligo; Proteomics; Melanocytes; Skin; Biomarkers; Janus Kinase 3
PubMed: 37777018
DOI: 10.1016/j.jaci.2023.09.021 -
Current Ophthalmology Reports Dec 2023To provide an up-to-date review of the epidemiology, presentation, diagnosis, and treatment options for conjunctival nevi (CN).
PURPOSE OF REVIEW
To provide an up-to-date review of the epidemiology, presentation, diagnosis, and treatment options for conjunctival nevi (CN).
RECENT FINDINGS
Around 17.2%-42% of all conjunctival tumors have been found to be CN, which most frequently present in White individuals between the first to early third decade of life, with equal distribution between males and females. CN commonly occur in the interpalpebral bulbar conjunctiva with pigmentation ranging from amelanotic to dark. Diagnosis is typically made through slit lamp examination, visualized by a well circumscribed, variably elevated, variably pigmented, solitary lesion with clear cysts distributed throughout the pigment. In ambiguous cases, anterior segment optical coherence tomography (AS-OCT) can highlight the presence of sub-clinical cysts, whose presence points to a diagnosis of nevus. However, excisional biopsy with histopathology examination is the gold standard for identifying CN.
SUMMARY
CN are benign, variably pigmented lesions. They are the most common of the conjunctival melanocytic tumors. Due to the extremely low risk of transformation to malignant melanoma (MM), CN are usually managed with routine observation and photo documentation.
PubMed: 38390435
DOI: 10.1007/s40135-023-00315-w