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1.
Gene ; 759: 144964, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32717308

RESUMO

BACKGROUND: Mucosal melanoma is a tumor caused by the malignant transformation of pigment-producing cells and can arise from any mucosal tissue where melanocytes are present. Due to its rarity, the mucosal melanoma subtype is poorly described, and its genetic characteristics are infrequently studied. The discovery or confirmation of new mucosal melanoma susceptibility genes will provide important insights for the study of its pathogenesis. MATERIALS AND METHODS: We performed deep targeted sequencing of 100 previously reported melanoma-related genes in 39 mucosal melanoma samples and a gene-level loss-of-function (LOF) variant enrichment analysis for mucosal melanoma from different incidence sites. RESULTS: We detected 7,589 variants in these samples, and 484 were LOF variants (gain or loss of a stop codon, missense, and splice site). Four different gene-level enrichment analyses revealed that FSIP1 (fibrous sheath interacting protein 1) is a susceptibility gene for oral mucosal melanoma (OR = 0.33, PChi = 4.05 × 10-2, Pburden = 3.06 × 10-2, Pskat = 3.01 × 10-2, Pskato = 3.01 × 10-2), whereas the different methods did not detect a significant susceptibility gene for the other subtypes. CONCLUSIONS: In our study, a susceptibility gene for oral mucosal melanoma was confirmed in a Chinese Han population, and these findings contribute to a better genetic understanding of mucosal melanoma of different subtypes.


Assuntos
Proteínas de Transporte/genética , Mutação com Perda de Função , Melanoma/genética , Proteínas de Plasma Seminal/genética , Idoso , Feminino , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/classificação , Melanoma/patologia , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia
2.
Mol Cell ; 79(3): 472-487.e10, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32531202

RESUMO

It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genoma , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Processamento de Proteína Pós-Traducional , Neoplasias Cutâneas/genética , Acetilação , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sequência Conservada , Elementos Facilitadores Genéticos , Feminino , Xenoenxertos , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Nus , Fator de Transcrição Associado à Microftalmia/química , Fator de Transcrição Associado à Microftalmia/metabolismo , Motivos de Nucleotídeos , Regiões Promotoras Genéticas , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Peixe-Zebra
3.
Clin Dermatol ; 38(3): 354-356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32563349

RESUMO

Although pityriasis alba is a common dermatologic condition, its pathogenesis is poorly understood, and there are many discrepancies in the literature. To assess the effect of the duration of disease on the histologic findings, a search of cases labeled "pityriasis alba" was performed on any cases submitted to our dermatopathology laboratory. Of 179 cases of pityriasis alba, five cases identified the duration of the disease, when the biopsy was taken. A biopsy for a lesion of only 1-month duration demonstrated groups of large, prominent melanocytes heaped up upon one another. Compared with biopsies from patients who had the lesions for increasingly longer periods of time, it was apparent that the melanocytes became progressively less abundant and smaller with less prominent dendritic processes. The time that the biopsy is taken may affect the histologic findings of pityriasis alba. Additionally, an abundance of melanosomes was observed between the melanocytes in all sections examined which may reflect a problem with the transfer of melanosomes into keratinocytes in this condition.


Assuntos
Pitiríase/patologia , Pele/patologia , Adolescente , Biópsia , Criança , Feminino , Humanos , Queratinócitos/patologia , Masculino , Melanócitos/patologia , Melanossomas/patologia , Fatores de Tempo
5.
Virchows Arch ; 477(1): 121-130, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388720

RESUMO

Overlapping histological features between benign and malignant lesions and a lack of firm diagnostic criteria for malignancy result in high rates of inter-observer variation in the diagnosis of melanocytic lesions. We aimed to investigate the differential expression of five miRNAs (21, 200c, 204, 205, and 211) in benign naevi (n = 42), dysplastic naevi (n = 41), melanoma in situ (n = 42), and melanoma (n = 42) and evaluate their potential as diagnostic biomarkers of melanocytic lesions. Real-time PCR showed differential miRNA expression profiles between benign naevi; dysplastic naevi and melanoma in situ; and invasive melanoma. We applied a random forest machine learning algorithm to classify cases based on their miRNA expression profiles, which resulted in a ROC curve analysis of 0.99 for malignant melanoma and greater than 0.9 for all other groups. This indicates an overall very high accuracy of our panel of miRNAs as a diagnostic biomarker of benign, dysplastic, and malignant melanocytic lesions. However, the impact of variable lesion percentage and spatial expression patterns of miRNAs on these real-time PCR results was also considered. In situ hybridisation confirmed the expression of miRNA 21 and 211 in melanocytes, while demonstrating expression of miRNA 205 only in keratinocytes, thus calling into question its value as a biomarker of melanocytic lesions. In conclusion, we have validated some miRNAs, including miRNA 21 and 211, as potential diagnostic biomarkers of benign, dysplastic, and malignant melanocytic lesions. However, we also highlight the crucial importance of considering tissue morphology and spatial expression patterns when using molecular techniques for the discovery and validation of new biomarkers.


Assuntos
Biomarcadores/análise , Síndrome do Nevo Displásico/patologia , Hiperplasia/patologia , Melanoma/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Diagnóstico Diferencial , Síndrome do Nevo Displásico/diagnóstico , Síndrome do Nevo Displásico/metabolismo , Humanos , Hiperplasia/diagnóstico , Hiperplasia/metabolismo , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/patologia , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia
6.
Clin Sci (Lond) ; 134(10): 1127-1141, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32400851

RESUMO

Vitiligo is a depigmentation disorder that develops as a result of the progressive disappearance of epidermal melanocytes. The elevated level of amino acid metabolite homocysteine (Hcy) has been identified as circulating marker of oxidative stress and known as a risk factor for vitiligo. However, the mechanism underlying Hcy-regulated melanocytic destruction is currently unknown. The present study aims to elucidate the effect of Hcy on melanocytic destruction and its involvement in the pathogenesis of vitiligo. Our results showed that Hcy level was significantly elevated in the serum of progressive vitiligo patients. Notably, Hcy induced cell apoptosis in melanocytes via activating reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. More importantly, folic acid, functioning in the transformation of Hcy, could lower the intracellular Hcy level and further reverse the apoptotic effect of Hcy on melanocytes. Additionally, Hcy disrupted melanogenesis whereas folic acid supplementation could reverse the melanogenesis defect induced by Hcy in melanocytes. Taken together, Hcy is highly increased in vitiligo patients at progressive stage, and our in vitro studies revealed that folic acid could protect melanocytes from Hcy-induced apoptosis and melanin synthesis inhibition, indicating folic acid as a potential benefit agent for patients with progressive vitiligo.


Assuntos
Apoptose , Fator de Iniciação 2 em Eucariotos/metabolismo , Homocisteína/metabolismo , Melanócitos/metabolismo , Melanócitos/patologia , Fator de Transcrição CHOP/metabolismo , Vitiligo/metabolismo , eIF-2 Quinase/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Ácido Fólico/farmacologia , Homocisteína/sangue , Humanos , Masculino , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos , Vitiligo/sangue
7.
Anticancer Res ; 40(4): 1931-1942, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234882

RESUMO

BACKGROUND: RhoA and its downstream effectors Rho-associated coiled-coil kinases (ROCK) 1 and 2 are central controllers of cytoskeleton dynamics, and therefore influence cell shape, adhesion and migration. Since modulation of these processes holds promise for an effective anticancer strategy, effects of ROCK inhibition have been evaluated in a number of malignancies. MATERIALS AND METHODS: Using immunohistochemistry, ROCK1 and ROCK2 expression was semi-quantitatively assessed in 129 patient-derived primary melanomas. RESULTS: There was a striking predilection for low melanocytic expression of both kinases in thick, ulcerated and mitogenic tumors, as well as in nodular histological type. ROCK1 and -2 expression in tumor-infiltrating lymphocytes (TILs) was preferentially down-regulated in advanced and aggressive tumors. Moreover, diminished ROCK2 reactivity in melanoma cells and TILs was associated with shorter melanoma-specific and recurrence-free survival. CONCLUSION: This is the first analysis of ROCK1 and -2 protein expression in clinical melanoma samples and the results indicated the suppression of ROCK signaling in melanocytes of aggressive and late-stage tumors. Functional models that more accurately represent the clinical setting are necessary to dissect the role of ROCK1 and -2 in melanoma. Additionally, our study indicates that ROCK activity in TILs may be involved in the pathogenesis of cancer, and thus merits further investigations.


Assuntos
Melanoma/genética , Neoplasias Cutâneas/genética , Quinases Associadas a rho/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/epidemiologia , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Transdução de Sinais/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Adulto Jovem
8.
An Bras Dermatol ; 95(3): 351-354, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32265056

RESUMO

Secondary osteoma cutis is a phenomenon that may occur in several conditions. When it occurs in a melanocytic nevus it is named osteonevus of Nanta, an event considered uncommon and characterized by the presence of bone formation adjacent or interposed with melanocytic cells. There are reports of its occurrence in various melanocytic lesions, being more frequently associated with intradermal nevus. We report a case of osteonevus of Nanta in combined nevus, possibly the first description of this association.


Assuntos
Doenças Ósseas Metabólicas/patologia , Nevo Intradérmico/patologia , Nevo Pigmentado/patologia , Ossificação Heterotópica/patologia , Dermatoses do Couro Cabeludo/patologia , Dermatopatias Genéticas/patologia , Neoplasias Cutâneas/patologia , Adulto , Doenças Ósseas Metabólicas/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Melanócitos/patologia , Nevo Intradérmico/cirurgia , Nevo Pigmentado/cirurgia , Ossificação Heterotópica/cirurgia , Dermatoses do Couro Cabeludo/cirurgia , Dermatopatias Genéticas/cirurgia , Neoplasias Cutâneas/cirurgia
9.
Orv Hetil ; 161(15): 563-574, 2020 04 01.
Artigo em Húngaro | MEDLINE | ID: mdl-32320191

RESUMO

Our purpose is to summarize the actual knowledge about melanocytic lesions of the ocular surface (conjunctival nevus, primary acquired melanosis and conjunctival melanoma),especially their clinical appearance, differential diagnosis and treatment. Conjunctival nevus is the most common benign, conjunctival melanocytic lesion. Primary acquired melanosis mainly presents in middle-aged or elderly individuals, characterized by proliferation of melanocytes of the conjunctival epithelial layer. Conjunctival melanoma is a rare tumor, it is the second most common malignant ocular surface tumor after ocular surface squamous neoplasia and the third most common ocular malignancy following choroideal malignant melanoma and ocular surface squamous neoplasia. Early recognition and proper management of conjunctival melanoma is indispensable due to its high malignant and metastatic potential. Due to frequent recurrences, the knowledge and use of intra- and postoperative adjuvant treatment modalities, and regular follow-up are necessary. Orv Hetil. 2020; 161(15): 563­574.


Assuntos
Neoplasias da Túnica Conjuntiva/patologia , Melanócitos/patologia , Melanoma/patologia , Nevo Pigmentado/patologia , Nevo/patologia , Neoplasias Cutâneas/patologia , Idoso , Diagnóstico Diferencial , Humanos , Pessoa de Meia-Idade
10.
Nat Cell Biol ; 22(4): 372-379, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231306

RESUMO

The availability of nucleotides has a direct impact on transcription. The inhibition of dihydroorotate dehydrogenase (DHODH) with leflunomide impacts nucleotide pools by reducing pyrimidine levels. Leflunomide abrogates the effective transcription elongation of genes required for neural crest development and melanoma growth in vivo1. To define the mechanism of action, we undertook an in vivo chemical suppressor screen for restoration of neural crest after leflunomide treatment. Surprisingly, we found that alterations in progesterone and progesterone receptor (Pgr) signalling strongly suppressed leflunomide-mediated neural crest effects in zebrafish. In addition, progesterone bypasses the transcriptional elongation block resulting from Paf complex deficiency, rescuing neural crest defects in ctr9 morphant and paf1(alnz24) mutant embryos. Using proteomics, we found that Pgr binds the RNA helicase protein Ddx21. ddx21-deficient zebrafish show resistance to leflunomide-induced stress. At a molecular level, nucleotide depletion reduced the chromatin occupancy of DDX21 in human A375 melanoma cells. Nucleotide supplementation reversed the gene expression signature and DDX21 occupancy changes prompted by leflunomide. Together, our results show that DDX21 acts as a sensor and mediator of transcription during nucleotide stress.


Assuntos
RNA Helicases DEAD-box/genética , Melanócitos/metabolismo , Crista Neural/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Receptores de Progesterona/genética , Proteínas de Peixe-Zebra/genética , Animais , Linhagem Celular Tumoral , RNA Helicases DEAD-box/metabolismo , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Leflunomida/farmacologia , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Crista Neural/efeitos dos fármacos , Crista Neural/crescimento & desenvolvimento , Nucleotídeos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Progesterona/metabolismo , Ligação Proteica , Receptores de Progesterona/metabolismo , Transdução de Sinais , Estresse Fisiológico/genética , Elongação da Transcrição Genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
11.
PLoS One ; 15(1): e0227909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31986193

RESUMO

Vitiligo is a T-cell mediated skin disorder characterized by progressive loss of skin color. In individuals genetically predisposed to the disease, various triggers contribute to the initiation of vitiligo. Precipitating factors can stress the skin, leading to T-cell activation and recruitment. Though hereditary factors are implicated in the pathogenesis of vitiligo, it is unknown whether precipitating, stressful events play a role in vitiligo. To understand this, we utilized a validated perceived stress scale (PSS) to measure this parameter in vitiligo patients compared to persons without vitiligo. Additionally, we probed a clinical database, using a knowledge linking software called ROCKET, to gauge stress-related conditions in the vitiligo patient population. From a pool of patients in an existing database, a hundred individuals with vitiligo and twenty-five age- and sex-matched comparison group of individuals without vitiligo completed an online survey to quantify their levels of perceived stress. In parallel, patients described specifics of their disease condition, including the affected body sites, the extent, duration and activity of their vitiligo. Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo. ROCKET analyses suggested signs of metabolic-related disease (i.e., 'stress') preceding vitiligo development. No correlation was found between perceived stress and the stage or the extent of disease, suggesting that elevated stress may not be a consequence of pigment loss alone. The data provide further support for stress as a precipitating factor in vitiligo development.


Assuntos
Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Vitiligo/fisiopatologia , Vitiligo/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Resposta ao Choque Térmico/genética , Humanos , Lactente , Recém-Nascido , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Pessoa de Meia-Idade , Pacientes/psicologia , Estresse Psicológico/complicações , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Inquéritos e Questionários , Linfócitos T/metabolismo , Linfócitos T/patologia , Vitiligo/complicações , Vitiligo/metabolismo , Adulto Jovem
12.
An Bras Dermatol ; 95(1): 71-74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31899063

RESUMO

Spitz nevus is a benign melanocytic lesion, which presents in several ways: solitary, agminated, or disseminated. The disseminated variant is uncommon; it may have a rapid evolution (the eruptive form) and be difficult to manage. This report presents the case of a 24-year-old patient with multiple papules on his limbs, which had appeared four years previously. On physical examination, 120 pink and skin-colored papules were seen, which under dermoscopy were observed to be homogeneous, pink vascular lesions. Histopathologic study revealed epithelioid cells arranged in groups or singly in the dermis and dermo-epidermal junction. They were HMB-45 positive in the superficial dermis, and Ki-67<1%. Given these findings, a diagnosis of eruptive disseminated Spitz nevi was made.


Assuntos
Nevo de Células Epitelioides e Fusiformes/patologia , Neoplasias Cutâneas/patologia , Biópsia , Dermoscopia , Humanos , Imuno-Histoquímica , Masculino , Melanócitos/patologia , Adulto Jovem
13.
Biochem Pharmacol ; 174: 113816, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972168

RESUMO

In spite of its toxic effects, N-acetyl-p-aminophenol (APAP), also commonly known as acetaminophen or paracetamol, is one of the most widely used analgesic and antipyretic agents. It can be obtained without a medical prescription. To test the effect over the zebrafish embryonic development, a Fish Embryo acute Toxicity (FET) test was carried out with acetaminophen to establish the range of concentrations that cause a harmful effect on the zebrafish development. Diminished pigmentation (in embryos treated from 0 h post-fertilization) and blockage of melanin synthesis (in larvae treated from 72 h post-fertilization) were detected, suggesting the involvement of this compound in the development of black pigment cells as described recently for human epidermal melanocytes. Morphological abnormalities such as aberrant craniofacial structures, pericardial edemas, and blood accumulation were also found. All these effects could be due to higher levels of apoptotic cells detected in treated embryos. Therefore, teratogenic effects of acetaminophen cannot be ruled out, and its wide use should be taken with caution.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Anormalidades Craniofaciais/induzido quimicamente , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Pigmentação/efeitos dos fármacos , Animais , Anormalidades Craniofaciais/patologia , Embrião não Mamífero/anormalidades , Desenvolvimento Embrionário/fisiologia , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanócitos/fisiologia , Pigmentação/fisiologia , Peixe-Zebra
14.
Mol Med Rep ; 21(2): 858-866, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974624

RESUMO

Vitiligo is a common localized or generalized skin pigmentation disorder. Endoplasmic reticulum (ER) stress may be implicated in the development of vitiligo. microRNA­421 (miR­421) has been reported to be dysregulated in various human tumors. However, there is no report to date on the role of miR­421 in vitiligo development. The present study demonstrated that 3 µM tunicamycin (TM) increased the expression of the ER stress­related proteins protein kinase RNA­like endoplasmic reticulum kinase (PERK), α subunit of eukaryotic translation initiation factor 2 (eIF2α) and C/EBP homologous protein (CHOP) in human primary epidermal melanocytes. Moreover, TM suppressed melanocyte viability and induced apoptosis. Reverse transcription­quantitative PCR analysis demonstrated that TM promoted miR­421 expression in human melanocytes. Next, TargetScan and dual luciferase reporter gene assay indicated that receptor­interacting serine/threonine kinase 1 (RIPK1) was a direct target of miR­421. RIPK1 expression was significantly downregulated in TM­induced human melanocytes. Subsequently, the effect of miR­421 downregulation on the damage of human melanocytes induced by ER stress was investigated. Human melanocytes were transfected with inhibitor control, miR­421 inhibitor, miR­421 inhibitor + control­short hairpin (sh)RNA, or miR­421 inhibitor + RIPK1­shRNA for 24 h and then treated with TM (3 µM) for 48 h. TM was found to upregulate PERK, eIF2α and CHOP protein expression in human melanocytes, which was reduced by an miR­421 inhibitor. In addition, the miR­421 inhibitor increased viability and reduced apoptosis in TM­treated melanocytes. Furthermore, all these effects of the miR­421 inhibitor on TM­induced human melanocytes were reversed by RIPK1­shRNA. Further analyses revealed that the miR­421 inhibitor activated the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin signaling pathway in TM­induced human melanocytes. These data collectively suggest that miR­421 may serve as a new treatment target in vitiligo development.


Assuntos
Melanócitos/patologia , MicroRNAs/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Vitiligo/genética , Vitiligo/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tunicamicina/farmacologia
15.
Nature ; 577(7792): 676-681, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31969699

RESUMO

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs)1,2, but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics3,4, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.


Assuntos
Vias Autônomas/fisiopatologia , Cor de Cabelo/fisiologia , Melanócitos/patologia , Nicho de Células-Tronco/fisiologia , Células-Tronco/patologia , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Glândulas Suprarrenais/metabolismo , Adrenalectomia , Animais , Vias Autônomas/patologia , Proliferação de Células , Células Cultivadas , Denervação , Feminino , Humanos , Masculino , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Norepinefrina/metabolismo , Trauma Psicológico/patologia , Trauma Psicológico/fisiopatologia , Receptores Adrenérgicos beta 2/deficiência , Receptores Adrenérgicos beta 2/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Estresse Psicológico/patologia , Sistema Nervoso Simpático/patologia
16.
Mol Cell Biochem ; 465(1-2): 141-153, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31823188

RESUMO

Ultraviolet radiations (UVR) are responsible for a wide variety of acute and chronic effects on the animal skin. However, the effect of UVR-induced oxidative stress and protection through paracrine factors on animal skin has received little attention. We previously demonstrated how heat stress-induced adaptation in Bos indicus melanocytes was dependent on the level of melanin and reduction of apoptosis. Therefore, in the present investigation, the survival mechanisms adopted by melanocytes under UV stress and the role of α-MSH in cell survival under in vitro conditions were studied. After the treatment of melanocyte cells with UVR (using Osram ultravitalux 300 W lamp), analysis of Gene expression using Real-Time PCR was done to study the adopted molecular pathways under stressful conditions. In addition, α-MSH was used to assess its modulating role in cell survival under stress. This study revealed the increase in the expression of genes related to melanogenesis, cell cycle, heat shock proteins, and apoptosis of the cells after UVR stress and demonstrated the role of paracrine factor (α-MSH) in elevating the protection response to stressful conditions like UVR stress by increasing the melanogenesis and decreasing the mitochondrial-mediated apoptosis. Based on the results of the present study, it can be stated that α-MSH can play a pivotal role in the protection of animal skin cells under stressful conditions in climate-changing scenario.


Assuntos
Apoptose/efeitos da radiação , Melaninas/metabolismo , Melanócitos/metabolismo , Estresse Fisiológico/efeitos da radiação , Raios Ultravioleta/efeitos adversos , alfa-MSH/metabolismo , Animais , Bovinos , Melanócitos/patologia , Pele/metabolismo , Pele/patologia
17.
Virchows Arch ; 476(3): 439-443, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31754815

RESUMO

We report a series of 21 compound blue nevi, a rare variant in the vast clinical and morphological spectrum of blue melanocytic proliferations. Clinically, they presented in young adults, with a slight female predominance. One-third were located on the dorsum of the foot. Morphologically, all cases displayed large dendritic melanocytes restricted to the deep layers of the epidermis. The compound component was central and evenly distributed. Melanocytic density ranged from scarce isolated cells to a confluent lentiginous architecture. In 12 of the 21 cases, junctional nests of small, bland, weakly pigmented melanocytes were associated. These nests became confluent in the most cellular cases. In all cases, a dermal component was immediately present underneath, mainly of cellular blue nevus-type. All cases were genetically confirmed to harbor either a GNAQ or GNA11 hotspot mutation. This study expands the morphological spectrum of blue nevi that should not be restricted to a strictly intradermal melanocytic proliferation.


Assuntos
Nevo Azul/genética , Nevo Azul/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Humanos , Masculino , Melanócitos/patologia , Pessoa de Meia-Idade , Mutação , Adulto Jovem
18.
World Neurosurg ; 134: 90-93, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31678313

RESUMO

BACKGROUND: Meningeal melanocytoma is a rare benign lesion found in the central nervous system. Preoperative diagnosis of meningeal melanocytoma is often a diagnostic challenge, as the clinical and neurologic features are often nonspecific. Various characteristics, including the natural course of this tumor, remain poorly understood. We report a case of a rapidly growing dumbbell-shaped melanocytoma compressing the spinal cord that manifested 2 years after a tumor was identified at the right C2-C3 foramen. CASE DESCRIPTION: A 40-year-old, right-handed man presented with a 2-month history of right palm and left leg numbness. Magnetic resonance imaging of the cervical spine showed a dumbbell-shaped tumor at the right C2-C3 foramen with extension into the central canal. The lesion was hyperintense on T1-weighted images and hypointense to isointense on T2-weighted images. Contrast enhancement was not visualized clearly. Fluorodeoxyglucose-positron emission tomography with computed tomography showed intense uptake in the lesion. The patient's history included a small lesion that had been localized at the right C2-C3 foramen 2 years before admission. The pathologic findings were consistent with melanocytoma. CONCLUSIONS: It is important to include meningeal melanocytoma in the differential diagnosis of dumbbell tumors, as meningeal melanocytomas may show rapid progression.


Assuntos
Melanócitos/patologia , Neoplasias Meníngeas/patologia , Adulto , Humanos , Masculino
19.
An Bras Dermatol ; 94(6): 747-750, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31789261

RESUMO

Melanoacanthoma is a rare variant of seborrheic keratosis, which is notable for dark pigmentation and fast radial growth, making it difficult to distinguish from melanoma. Histologically, it is characterized by proliferation of keratinocytes and dendritic melanocytes. The authors report a scalp lesion, fast growing, suspected by dermoscopy and confocal microscopy examination, with dendritic cells distributed throughout the lesion. Based on these findings, it was not possible to classify this lesion as clearly benign, so it was excised. Histopathologic evaluation and immunostain were consistent with melanoacanthoma.


Assuntos
Acantoma/patologia , Ceratose Seborreica/patologia , Dermatoses do Couro Cabeludo/patologia , Neoplasias Cutâneas/patologia , Idoso , Células Dendríticas/patologia , Dermoscopia , Humanos , Masculino , Melanócitos/patologia , Microscopia Confocal/métodos
20.
Biomed Res Int ; 2019: 7623607, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828129

RESUMO

Background: Noncultured epidermal suspension (NCES) is a surgical technique which employs cellular grafting onto depigmented lesions. However, scarring and dyschromia at the donor site often occurs. Objective: To assess the outcome of reusing the same donor site in subsequent sessions of NCES procedures. Methods: Electronic records of vitiligo patients who had undergone two sessions of NCES procedures were retrospectively reviewed. Information on the first and second NCES was retrieved for analyses. Results: A total of 30 patients (female 19 and male 11) were included. The majority of patients had nonsegmental vitiligo (66.7%). The median donor-to-recipient ratios were 1 : 3 (1 : 1-1 : 20) for the first session and 1 : 3 (1 : 1-1 : 13.5) for the second session (p=0.661). The mean melanocyte count was 220.7 ± 65.5 cells/mm2 vs. 242.4 ± 55.3 cells/mm2 on the first and second sessions, respectively (p=0.440). The mean repigmentation rate was 84.2% (±21.1%) and 82.3 (±22.1%) for the first and second NCESs, respectively (p=0.645). The frequency of color mismatch and pigment loss were similar between both sessions (p=0.706 and p=1.000). Conclusions: Repeated use of donor sites in subsequent NCES sessions gave comparable repigmentation.


Assuntos
Cicatriz/terapia , Células Epidérmicas/transplante , Pigmentação da Pele/fisiologia , Vitiligo/terapia , Adulto , Cicatriz/fisiopatologia , Células Epidérmicas/patologia , Epiderme/patologia , Epiderme/transplante , Células Epiteliais/transplante , Feminino , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento , Vitiligo/fisiopatologia
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