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Indian Journal of Dermatology,... 2020Melasma is a common, acquired, symmetrical hypermelanosis. It negatively impacts the patient's quality of life and responds poorly to treatment. Although earlier... (Review)
Review
Melasma is a common, acquired, symmetrical hypermelanosis. It negatively impacts the patient's quality of life and responds poorly to treatment. Although earlier classified as epidermal and dermal, melasma is now thought to be a complex interaction between epidermal melanocytes, keratinocytes, dermal fibroblasts, mast cells, and vascular endothelial cells. Factors influencing melasma may include inflammation, reactive oxygen species, ultraviolet radiation, genetic factors, and hormones. With a better understanding of the pathogenesis of melasma and the realization that targeting melanin synthesis alone is not very effective, treatments focussing on newly implicated factors have been developed. These include agents targeting hyperactive melanocytes, melanosomal transfer to keratinocytes, defective skin barrier, the mast cells, vasculature, and estrogen receptors as well as drugs with anti-inflammatory and antioxidant activity. Many of these newer agents are botanicals with multimodal mechanisms of action that offer a better safety profile when compared with the conventional drugs. There has also been a focus on oral agents such as tranexamic acid, flutamide, and ascorbic acid. It has been suggested that the "triple therapy of the future" may be a combination of hydroquinone, an antiestrogen and a vascular endothelial growth factor inhibitor, as the "ideal" skin-lightening agent.
Topics: Humans; Melanosis
PubMed: 31793496
DOI: 10.4103/ijdvl.IJDVL_633_18 -
Science (New York, N.Y.) Aug 2023Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering...
Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine.
Topics: Humans; Melanins; Melanocytes; Melanosomes; Skin Pigmentation; Genome-Wide Association Study; Adaptor Proteins, Signal Transducing; Kruppel-Like Factor 6; Endosomes; Animals; Mice; Cell Line, Tumor
PubMed: 37561850
DOI: 10.1126/science.ade6289 -
Dermatology and Therapy Sep 2017Melasma is a common acquired condition of symmetric hyperpigmentation, typically occurring on the face, with higher prevalence in females and darker skin types. Multiple... (Review)
Review
Melasma is a common acquired condition of symmetric hyperpigmentation, typically occurring on the face, with higher prevalence in females and darker skin types. Multiple etiologies, including light exposure, hormonal influences, and family history, have been implicated in the pathogenesis of this disorder. Overall prevalence ranges widely at 1-50%, since values are typically calculated within a specific ethnic population within a geographic region. Histologically, melasma can display increased epidermal and/or dermal pigmentation, enlarged melanocytes, increased melanosomes, solar elastosis, dermal blood vessels, and, occasionally, perivascular lymphohistiocytic infiltrates. Various topical, oral, and procedural therapies have been successfully used to treat melasma. Traditional topical therapies including hydroquinone, tretinoin, corticosteroids, and triple combination creams; however, other synthetic and natural topical compounds have also shown varying efficacies. Promising oral therapies for melasma include tranexamic acid, Polypodium leucotomos, and glutathione. Procedures, including chemical peels, microneedling, radiofrequency, and lasers, are also often used as primary or adjunctive treatments for melasma. Notably, combination therapies within or across treatment modalities generally result in better efficacies than monotherapies. This review serves as a comprehensive update on the current understanding of the epidemiology, pathogenesis, clinical and histologic features of melasma, as well as treatments for this common, yet therapeutically challenging, condition.
PubMed: 28726212
DOI: 10.1007/s13555-017-0194-1 -
Postepy Higieny I Medycyny... Jun 2016Melanins are natural pigments of skin, hair and eyes and can be classified into two main types: brown to black eumelanin and yellow to reddish-brown pheomelanin.... (Review)
Review
Melanins are natural pigments of skin, hair and eyes and can be classified into two main types: brown to black eumelanin and yellow to reddish-brown pheomelanin. Biosynthesis of melanins takes place in melanosomes, which are specialized cytoplasmic organelles of melanocytes - dendritic cells located in the basal layer of the epidermis, uveal tract of the eye, hair follicles, as well as in the inner ear, central nervous system and heart. Melanogenesis is a multistep process and begins with the conversion of amino acid L-tyrosine to DOPAquinone. The addition of cysteine or glutathione to DOPAquinone leads to the intermediates formation, followed by subsequent transformations and polymerization to the final product, pheomelanin. In the absence of thiol compounds DOPAquinone undergoes an intramolecular cyclization and oxidation to form DOPAchrome, which is then converted to 5,6-dihydroksyindole (DHI) or 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Eumelanin is formed by polymerization of DHI and DHICA and their quinones. Regulation of melanogenesis is achieved by physical and biochemical factors. The article presents the intracellular signaling pathways: cAMP/PKA/CREB/MITF cascade, MAP kinases cascade, PLC/DAG/PKCβ cascade and NO/cGMP/PKG cascade, which are involved in the regulation of expression and activity of the melanogenesis-related proteins by ultraviolet radiation and endogenous agents (cytokines, hormones). Activity of the key melanogenic enzyme, tyrosinase, is also affected by pH and temperature. Many pharmacologically active substances are able to inhibit or stimulate melanin biosynthesis, as evidenced by in vitro studies on cultured pigment cells.
Topics: Animals; Benzoquinones; Cytokines; Dihydroxyphenylalanine; Gene Expression Regulation, Enzymologic; Hormones; Humans; Indolequinones; Indoles; Melanins; Melanosomes; Monophenol Monooxygenase; Signal Transduction; Tyrosine; Ultraviolet Rays
PubMed: 27356601
DOI: 10.5604/17322693.1208033 -
Cell Aug 2021Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated...
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
Topics: Animals; Cell Line; Cohort Studies; Cyclic AMP; DNA Damage; Enzyme Inhibitors; Genetic Predisposition to Disease; Humans; Melanocytes; Melanosomes; Mice; Mice, Inbred C57BL; Microphthalmia-Associated Transcription Factor; Mitochondria; Monophenol Monooxygenase; NADP Transhydrogenases; Oxidation-Reduction; Polymorphism, Single Nucleotide; Proteasome Endopeptidase Complex; Proteolysis; RNA, Messenger; Skin Pigmentation; Ubiquitin; Ultraviolet Rays; Zebrafish
PubMed: 34233163
DOI: 10.1016/j.cell.2021.06.022 -
Progress in Retinal and Eye Research Nov 2022Albinism is a pigment disorder affecting eye, skin and/or hair. Patients usually have decreased melanin in affected tissues and suffer from severe visual abnormalities,... (Review)
Review
Albinism is a pigment disorder affecting eye, skin and/or hair. Patients usually have decreased melanin in affected tissues and suffer from severe visual abnormalities, including foveal hypoplasia and chiasmal misrouting. Combining our data with those of the literature, we propose a single functional genetic retinal signalling pathway that includes all 22 currently known human albinism disease genes. We hypothesise that defects affecting the genesis or function of different intra-cellular organelles, including melanosomes, cause syndromic forms of albinism (Hermansky-Pudlak (HPS) and Chediak-Higashi syndrome (CHS)). We put forward that specific melanosome impairments cause different forms of oculocutaneous albinism (OCA1-8). Further, we incorporate GPR143 that has been implicated in ocular albinism (OA1), characterised by a phenotype limited to the eye. Finally, we include the SLC38A8-associated disorder FHONDA that causes an even more restricted "albinism-related" ocular phenotype with foveal hypoplasia and chiasmal misrouting but without pigmentation defects. We propose the following retinal pigmentation pathway, with increasingly specific genetic and cellular defects causing an increasingly specific ocular phenotype: (HPS1-11/CHS: syndromic forms of albinism)-(OCA1-8: OCA)-(GPR143: OA1)-(SLC38A8: FHONDA). Beyond disease genes involvement, we also evaluate a range of (candidate) regulatory and signalling mechanisms affecting the activity of the pathway in retinal development, retinal pigmentation and albinism. We further suggest that the proposed pigmentation pathway is also involved in other retinal disorders, such as age-related macular degeneration. The hypotheses put forward in this report provide a framework for further systematic studies in albinism and melanin pigmentation disorders.
Topics: Humans; Melanins; Mutation; Albinism; Retina; Pigmentation
PubMed: 35729001
DOI: 10.1016/j.preteyeres.2022.101091 -
Redox Biology Aug 2021Pterostilbene (Pt) is a natural polyphenol found in blueberries and several grape varieties. Pt's pharmacological importance was well documented. Nevertheless, the...
The in vitro and in vivo depigmenting activity of pterostilbene through induction of autophagy in melanocytes and inhibition of UVA-irradiated α-MSH in keratinocytes via Nrf2-mediated antioxidant pathways.
Pterostilbene (Pt) is a natural polyphenol found in blueberries and several grape varieties. Pt's pharmacological importance was well documented. Nevertheless, the depigmenting effects are not demonstrated. We evaluated the Pt's depigmenting effects through autophagy induction in B16F10 cells and inhibition of UVA (3 J/cm)-irradiated α-MSH in keratinocyte HaCaT cells via Nrf2-mediated antioxidant pathways. Pt (2.5-5μM) attenuated ROS production and downregulated the POMC/α-MSH pathway in HaCaT cells. The conditioned medium-derived from UVA-irradiated HaCaT pretreated with Pt suppressed melanogenesis in B16F10 through MITF-CREB-tyrosinase pathway downregulation. Interestingly, Pt-induced HaCaT autophagy was revealed by enhanced LC3-II accumulation, p62/SQSTM1 activation, and AVO formation. Pt significantly decreased melanosome gp100 but increased LC3-II levels in HaCaT cells exposed to B16F10-derived melanin. Pt activated and facilitated the Nrf2 antioxidant pathway in HaCaT cells leading to increased HO-1, γ-GCLC, and NQO-1 antioxidant protein expression. ERK, AMPK, and ROS pathways mediate the Nrf2 activation. However, Nrf2 knockdown suppressed Pt's antioxidant ability leading to uncontrolled ROS and α-MSH levels after UVA-irradiation suggested the essentiality of the Nrf2 pathway. Moreover, in α-MSH-stimulated B16F10 cells, Pt (10-30 μM) downregulated the MC1R, MITF, tyrosinase, TRP-1/-2, and melanin expression. Further, Pt showed potent anti-melanogenic effects through autophagy induction mechanism in B16F10 cells, verified by increased LC3-II/p62 levels, AVO formation, and Beclin-1/Bcl-2 ratio, decreased ATG4B levels and PI3K/AKT/mTOR pathway. Transmission electron microscopy provided direct evidence by showing autophagosomes engulfing melanosomes following Pt treatment in α-MSH-stimulated B16F10 cells. Moreover, Pt-induced anti-melanogenic activity through the downregulation of CREB-MITF pathway-mediated TRP-1/-2, tyrosinase expressions, melanosome formation, and melanin synthesis was substantially reversed due to 3-MA (autophagy inhibitor) pretreatment or LC3 silencing in B16F10 cells. In vivo results also confirmed that Pt-inhibited tyrosinase expression/activity and endogenous pigmentation in the zebrafish model. Therefore, pterostilbene is a potent skin-whitening and antioxidant agent and could be used in skin-whitening formulations as a topical applicant.
Topics: Animals; Antioxidants; Autophagy; Cell Line, Tumor; Keratinocytes; Melanins; Melanocytes; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Stilbenes; Zebrafish; alpha-MSH
PubMed: 34049220
DOI: 10.1016/j.redox.2021.102007 -
Science Advances Oct 2022During embryonic development, reciprocal interactions between epidermal and mesenchymal layers trigger hair follicle morphogenesis. This study revealed that...
During embryonic development, reciprocal interactions between epidermal and mesenchymal layers trigger hair follicle morphogenesis. This study revealed that microenvironmental reprogramming via control over these interactions enabled hair follicle induction in vitro. A key approach is to modulate spatial distributions of epithelial and mesenchymal cells in their spontaneous organization. The de novo hair follicles with typical morphological features emerged in aggregates of the two cell types, termed hair follicloids, and hair shafts sprouted with near 100% efficiency in vitro. The hair shaft length reached ~3 mm in culture. Typical trichogenic signaling pathways were up-regulated in hair follicloids. Owing to replication of hair follicle morphogenesis in vitro, melanosome production and transportation were also monitored in the hair bulb region. This in vitro hair follicle model might be valuable for better understanding hair follicle induction, evaluating hair growth and inhibition of hair growth by drugs, and modeling gray hairs in a well-defined environment.
PubMed: 36269827
DOI: 10.1126/sciadv.add4603 -
Nature Dec 2020Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the...
Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the lysosome, that synthesizes pigment-but have unclear functions. Here we describe MelanoIP, a method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use this method to study MFSD12, a transmembrane protein of unknown molecular function that, when suppressed, causes darker pigmentation in mice and humans. We find that MFSD12 is required to maintain normal levels of cystine-the oxidized dimer of cysteine-in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter cystinosin. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes.
Topics: Biological Transport; Cell Fractionation; Cell Line; Cysteine; Cystine; Cystinosis; Fibroblasts; Humans; Lysosomes; Melanins; Melanosomes; Membrane Proteins; Oxidation-Reduction
PubMed: 33208952
DOI: 10.1038/s41586-020-2937-x