Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.314
Filtrar
1.
Neurology ; 95(19): e2697-e2706, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33055277

RESUMO

OBJECTIVE: To investigate small fiber innervation of the skin and its relationships with clinicometry of autism and peripheral afferents for contact heat-evoked potential (CHEP) and psychophysical measures of thermal thresholds. METHODS: We recruited 32 men with autism (26.5 ± 5.9 years) and conducted small fiber assessments of skin biopsy with quantifying intraepidermal nerve fiber (IENF) density, CHEP, quantitative sensory testing, and large fiber physiology of nerve conduction studies. Results were compared with age-matched controls and analyzed with clinical measures of autism. RESULTS: Patients with autism showed a lower IENF density than controls (5.53 ± 2.09 vs 11.13 ± 3.49 fibers/mm, p < 0.0001). The IENF density was reduced in 17 (53.1%) men with autism classified as skin denervation group. On psychophysics, 9 (28%) men with autism had elevated thermal thresholds, and the warm threshold of the big toe was negatively correlated with IENF density (p = 0.0073), indicating functional impairments of small fiber sensory nerves. IENF density was negatively correlated with CHEP amplitude in autism (p = 0.003), in contrast to the pattern of positive correlation in controls, indicating different processing of nociceptive afferent in autism. Clinically, IENF density was related to distinct tactile symptom patterns in the skin denervation vs normal innervation group, respectively. Furthermore, IENF density was associated with autistic symptoms measured by the Autism Spectrum Quotient in a U-shaped model (p = 0.014). CONCLUSIONS: These observations indicated that a substantial portion of individuals with autism had small fiber pathology, which was associated with tactile and autistic symptoms, providing structural and physiologic evidence for the involvement of peripheral sensory nerves in autism.


Assuntos
Transtorno Autístico/fisiopatologia , Epiderme/patologia , Potenciais Somatossensoriais Evocados/fisiologia , Temperatura Alta , Fibras Nervosas/patologia , Condução Nervosa/fisiologia , Nociceptividade/fisiologia , Adulto , Estudos de Casos e Controles , Eletrodiagnóstico , Epiderme/inervação , Humanos , Masculino , Limiar da Dor , Limiar Sensorial , Adulto Jovem
2.
BMC Dermatol ; 20(1): 6, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32867747

RESUMO

BACKGROUND: Specific species of ceramides (Cer), major constituents of lipids in the stratum corneum (SC), are decreased and are correlated with SC barrier and water-holding functions in the skin of patients with atopic dermatitis (AD) or psoriasis (Pso). However, possible correlations between Cer subclass ratios and skin properties in barrier-disrupted skin and in healthy skin remain unclear. The objective of this study was to identify a new marker to evaluate skin properties and epidermal differentiation in SC not only in barrier-disrupted skin but also in healthy skin. METHODS: The Cer subclass ratios in the SC of healthy control subjects and in patients with AD or Pso were evaluated. Correlations with candidate markers and facial skin features of healthy Japanese females (20-74 years old, n = 210) were investigated. Variations of markers during epidermal differentiation were studied in human epidermis and in cultured keratinocytes. RESULTS: The ratios of Cer [NP]/[NS], Cer [NH]/[NS], Cer [NP]/[AS], Cer [NH]/[NS], Cer [NDS]/[AS], Cer [AH]/[AS] and Cer [EOP]/[AS] showed significant differences between non-lesional skin of AD patients and normal skin of healthy control subjects, as well as Pso patients and their healthy control subjects. The Cer [NP]/[NS] ratio was correlated with SC functional parameters (transepidermal water loss and capacitance) and with skin appearance (texture, scaling and color) even in the cheek skin of healthy female subjects. The Cer [NP]/[NS] ratio in the SC was approximately 18-times higher than in living keratinocytes, and it increased as they differentiated. CONCLUSIONS: The Cer [NP]/[NS] ratio in the SC is a potential marker for skin properties and epidermal differentiation in barrier-disrupted skin as well as in healthy skin.


Assuntos
Ceramidas/análise , Dermatite Atópica/patologia , Epiderme/química , Psoríase/patologia , Adulto , Idoso , Biomarcadores/análise , Estudos de Casos e Controles , Diferenciação Celular , Células Cultivadas , Dermatite Atópica/diagnóstico , Epiderme/patologia , Feminino , Humanos , Queratinócitos/química , Queratinócitos/citologia , Lipídeos/análise , Pessoa de Meia-Idade , Psoríase/diagnóstico , Adulto Jovem
3.
J Vis Exp ; (162)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32894272

RESUMO

The murine excisional wound model has been used extensively to study each of the sequentially overlapping phases of wound healing: inflammation, proliferation and remodeling. Murine wounds have a histologically well-defined and easily recognizable wound bed over which these different phases of the healing process are measurable. Within the field, it is common to use an arbitrarily defined "middle" of the wound for histological analyses. However, wounds are a three-dimensional entity and often not histologically symmetrical, supporting the need for a well-defined and robust method of quantification to detect morphometric defects with a small effect size. In this protocol, we describe the procedure for creating bilateral, full-thickness excisional wounds in mice as well as a detailed instruction on how to measure morphometric parameters using an image processing program on select serial sections. The two-dimension measurements of wound length, epidermal length, epidermal area, and wound area are used in combination with the known distance between sections to extrapolate the three-dimension epidermal area covering the wound, overall wound area, epidermal volume and wound volume. Although this detailed histological analysis is more time and resource consuming than conventional analyses, its rigor increases the likelihood of detecting novel phenotypes in an inherently complex wound healing process.


Assuntos
Ferida Cirúrgica/reabilitação , Cicatrização/fisiologia , Animais , Modelos Animais de Doenças , Epiderme/crescimento & desenvolvimento , Epiderme/patologia , Epiderme/fisiologia , Inflamação , Camundongos , Ferida Cirúrgica/patologia
4.
Nat Commun ; 11(1): 4788, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963234

RESUMO

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes.


Assuntos
Proliferação de Células , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , GTP Fosfo-Hidrolases , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hiperplasia/patologia , Queratinócitos/patologia , Camundongos , Camundongos Knockout , Membrana Mucosa/metabolismo , Prognóstico , RNA Mensageiro/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transcriptoma
5.
Scand J Immunol ; 92(5): e12953, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32757303

RESUMO

Psoriasis is an inflammatory disease that arises in genetically predisposed individuals. Chronic skin lesions that contain activated immune cells can persist for years. Systemic inhibition of TNF, IL-17 and IL-23 cytokines has revolutionized psoriasis care during the recent decades. Unfortunately, local relapse of disease is common at previously inflamed sites after cessation of treatment. This highlights that fundamental pathologic alterations of the affected tissues are not completely resolved during clinical remission. Here, we present arguments for a local disease memory located in both dermis and epidermis in psoriasis skin. We decipher different cellular components and intercellular crosstalk that sustain local disease memory and amplify disease relapse in human psoriasis. Decrypting the mechanisms underlying the establishment and persistence of pathogenic memory cells in resolved psoriasis may provide new therapeutic perspectives aimed at long-term remission of psoriasis.


Assuntos
Cicatriz/imunologia , Citocinas/imunologia , Interleucina-17/imunologia , Queratinócitos/imunologia , Psoríase/imunologia , Pele/imunologia , Cicatriz/metabolismo , Citocinas/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Humanos , Memória Imunológica/imunologia , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Psoríase/metabolismo , Recidiva , Pele/metabolismo , Pele/patologia
6.
Oncogene ; 39(36): 5855-5866, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32616890

RESUMO

Epidermal squamous cell carcinoma (SCC) is a common and highly invasive form of cancer. SCC arises due to ultraviolet light exposure and is associated with increased expression of pro-cancer genes and reduced expression of cancer suppressors. Actin-Like Protein 6A (ACTL6A, BAF53a) is an important protein subunit of the SWI/SNF epigenetic chromatin regulatory complex. ACTL6A is elevated in cancer cells and has been implicated as a driver of cancer cell proliferation and tumor growth. In the present study, we show that ACTL6A drives SCC cell proliferation, spheroid formation, invasion and migration, and that these activities are markedly reduced by ACTL6A knockdown. We further show that ACTL6A expression is associated with reduced levels of the p21Cip1 cyclin-dependent kinase inhibitor and tumor suppressor protein. Molecular studies show that ACTL6A interacts with p53 DNA response elements in the p21Cip1 gene promoter to suppress p21Cip1 promoter activity and mRNA and protein level. Additional studies show that an increase in p21Cip1 expression in ACTL6A knockdown cells is required for suppression of the SCC cell phenotype, suggesting that p21Cip1 is a mediator of ACTL6A action. We further show that this regulation is p53 independent. These findings suggest that ACTL6A suppresses p21Cip1 promoter activity to reduce p21Cip1 protein as a mechanism to maintain the aggressive epidermal SCC phenotype.


Assuntos
Actinas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Actinas/genética , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , Fenótipo , Regiões Promotoras Genéticas , Neoplasias Cutâneas/patologia , Ativação Transcricional , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
7.
Toxicol Appl Pharmacol ; 401: 115078, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479919

RESUMO

Sulfur mustard (SM) is a highly toxic blistering agent thought to mediate its action, in part, by activating matrix metalloproteinases (MMPs) in the skin and disrupting components of the basement membrane zone (BMZ). Type IV collagenases (MMP-9) degrade type IV collagen in the skin, a major component of the BMZ at the dermal-epidermal junction. In the present studies, a type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), was tested for its ability to protect the skin against injury induced by SM in the mouse ear vesicant model. SM induced inflammation, epidermal hyperplasia and microblistering at the dermal/epidermal junction of mouse ears 24-168 h post-exposure. This was associated with upregulation of MMP-9 mRNA and protein in the skin. Dual immunofluorescence labeling showed increases in MMP-9 in the epidermis and in the adjacent dermal matrix of the SM injured skin, as well as breakdown of type IV collagen in the basement membrane. Pretreatment of the skin with BiPS reduced signs of SM-induced cutaneous toxicity; expression of MMP-9 mRNA and protein was also downregulated in the skin by BiPS. Following BiPS pretreatment, type IV collagen appeared intact and was similar to control skin. These results demonstrate that inhibiting type IV collagenases in the skin improves basement membrane integrity after exposure to SM. BiPS may hold promise as a potential protective agent to mitigate SM induced skin injury.


Assuntos
Benzopiranos/uso terapêutico , Substâncias para a Guerra Química/toxicidade , Colágeno Tipo IV/antagonistas & inibidores , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Gás de Mostarda/toxicidade , Dermatopatias/tratamento farmacológico , Animais , Benzopiranos/farmacologia , Colágeno Tipo IV/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Masculino , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Dermatopatias/induzido quimicamente , Dermatopatias/metabolismo , Dermatopatias/patologia
8.
J Leukoc Biol ; 108(1): 267-281, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32421901

RESUMO

Psoriasis is a common, chronic multifactorial inflammatory skin disease with both genetic and environmental components. A number of studies have suggested that psoriasis episodes are often preceded by stressful life events. Nevertheless, the underline mechanisms of stress in psoriasis remain unexplored. To address this question, we established an emotional stress mouse model induced by empty bottle stimulation, and applied imiquimod (IMQ), a ligand of TLR7/8 and effective potent immune activator, on the dorsal skin to induce psoriasis-like lesions. We found that empty bottles induced emotional stress exaggerated and prolonged psoriasiform dermatitis, which appeared as more prominent epidermal hyperplasia in the emotional stress mice compared with the control mice. Higher mRNA expression of Il-1ß, Il-17a, and Il-22, as well as higher secretion of IL-1ß, IL-12p40, IL-17, and IL-22 were observed in the skin lesion of emotional stress mice. The emotional stress condition and IMQ treatment synergistically led to higher expression levels of neurotransmitters and their receptors in the skin, especially substance P (SP), we also found that SP could stimulate DCs to secrete more IL-23p40 in vitro. In addition, NK-1R antagonist partially abrogated enhanced epidermal thickness and the level of neurotransmitters in emotional stress mice. Taken together, these results indicate that stress exacerbates and prolongs psoriasiform dermatitis in mice by up-regulating IL-1ß and IL-23p40, which were related to local DCs stimulated by abnormal SP.


Assuntos
Epiderme/patologia , Imiquimode/efeitos adversos , Subunidade p40 da Interleucina-12/biossíntese , Interleucina-1beta/biossíntese , Psoríase/induzido quimicamente , Estresse Psicológico/complicações , Animais , Ansiedade/etiologia , Ansiedade/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Dermatite/etiologia , Dermatite/patologia , Emoções , Epiderme/efeitos dos fármacos , Hiperplasia , Inflamação/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Neurotransmissores/metabolismo , Nociceptores/metabolismo , Psoríase/complicações , Psoríase/patologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Cell Mol Life Sci ; 77(22): 4601-4614, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32462404

RESUMO

Long non-coding RNAs (lncRNAs) are a largely uncharacterized group of non-coding RNAs with diverse regulatory roles in various biological processes. Recent observations have elucidated the functional roles of lncRNAs in cutaneous biology, e.g. in proliferation and differentiation of epidermal keratinocytes and in cutaneous wound repair. Furthermore, the role of lncRNAs in keratinocyte-derived skin cancers is emerging, especially in cutaneous squamous cell carcinoma (cSCC), which presents a significant burden to health care services worldwide and causes high mortality as metastatic disease. Elucidation of the functions of keratinocyte-specific lncRNAs will improve understanding of the molecular pathogenesis of epidermal disorders and skin cancers and can be exploited in development of new diagnostic and therapeutic applications for keratinocyte carcinomas. In this review, we summarize the current evidence of functionally important lncRNAs in cutaneous biology and in keratinocyte carcinomas.


Assuntos
Carcinoma de Células Escamosas/genética , Queratinócitos/patologia , RNA Longo não Codificante/genética , Neoplasias Cutâneas/genética , Pele/patologia , Animais , Carcinoma de Células Escamosas/patologia , Epiderme/patologia , Humanos , Neoplasias Cutâneas/patologia
10.
Oncogene ; 39(24): 4756-4769, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32427988

RESUMO

Pak1 (serine/threonine p21-activated kinases) was previously reported to have oncogenic activity in several cancers. However, its roles in the cancer microenvironment are poorly understood. We demonstrated that Pak1 expression in Langerhans cells (LCs) is essential for the maintenance of epidermal stem cells and skin tumor development. We found that PAK1 is localized in LCs by immunohistochemistry. Furthermore, the number of LCs significantly decreased in MSM/Ms Pak1 homozygous knockout mice (MSM/Ms-Pak1-/-). F1 hybrid (FVB/N×MSM/Ms) Pak1 heterozygous knockout mice (F1-Pak1+/-) had increased numbers of Th17 cells in the skin. Therefore, Pak1 knockdown cells were prepared using LC-derived XS52 cells (XS52-Pak1KD) and co-cultured with keratinocyte-derived C5N cells. As a result, XS52-Pak1KD cell supernatants promoted C5N cell proliferation. We then carried out DMBA/TPA skin carcinogenesis experiments using F1-Pak1+/- mice. Of note, F1-Pak1+/- mice exhibited stronger resistance to skin tumors than control mice. F1-Pak1+/- mice had fewer epidermal stem cells in the skin bulge. Our study suggested that Pak1 regulates the epidermal stem cell number by changing the properties of LCs and functions in skin carcinogenesis. We clarified a novel role of Pak1 in regulating LCs as a potential therapeutic target in skin immune disease and carcinogenesis.


Assuntos
Carcinogênese/metabolismo , Epiderme/metabolismo , Células de Langerhans/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas/metabolismo , Células-Tronco/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Epiderme/patologia , Células de Langerhans/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Células-Tronco/patologia , Quinases Ativadas por p21/genética
11.
Exp Mol Pathol ; 115: 104470, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32445752

RESUMO

Sulfur mustard (SM), a dermal vesicant that has been used in chemical warfare, causes inflammation, edema and epidermal erosions depending on the dose and time following exposure. Herein, a minipig model was used to characterize wound healing following dermal exposure to SM. Saturated SM vapor caps were placed on the dorsal flanks of 3-month-old male Gottingen minipigs for 30 min. After 48 h the control and SM wounded sites were debrided daily for 7 days with wet to wet saline gauze soaks. Animals were then euthanized, and full thickness skin biopsies prepared for histology and immunohistochemistry. Control skin contained a well differentiated epidermis with a prominent stratum corneum. A well-developed eschar covered the skin of SM treated animals, however, the epidermis beneath the eschar displayed significant wound healing with a hyperplastic epidermis. Stratum corneum shedding and a multilayered basal epithelium consisting of cuboidal and columnar cells were also evident in the neoepidermis. Nuclear expression of proliferating cell nuclear antigen (PCNA) was contiguous in cells along the basal epidermal layer of control and SM exposed skin; SM caused a significant increase in PCNA expression in basal and suprabasal cells. SM exposure was also associated with marked changes in expression of markers of wound healing including increases in keratin 10, keratin 17 and loricrin and decreases in E-cadherin. Trichrome staining of control skin showed a well-developed collagen network with no delineation between the papillary and reticular dermis. Conversely, a major delineation was observed in SM-exposed skin including a web-like papillary dermis composed of filamentous extracellular matrix, and compact collagen fibrils in the lower reticular dermis. Although the dermis below the wound site was disrupted, there was substantive epidermal regeneration following SM-induced injury. Further studies analyzing the wound healing process in minipig skin will be important to provide a model to evaluate potential vesicant countermeasures.


Assuntos
Gás de Mostarda/toxicidade , Pele/patologia , Cicatrização , Animais , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Epiderme/patologia , Proteínas de Membrana/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Pele/efeitos dos fármacos , Suínos , Porco Miniatura , Cicatrização/efeitos dos fármacos
12.
Oncogene ; 39(21): 4241-4256, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32286519

RESUMO

T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, has been shown to function as a tumor suppressor during skin carcinogenesis. In the current study, we generated a novel epidermal-specific TC-PTP-overexpressing (K5HA.Ptpn2) mouse model to show that TC-PTP contributes to the attenuation of chemically induced skin carcinogenesis through the synergistic regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling. We found overexpression of TC-PTP increased epidermal sensitivity to DMBA-induced apoptosis and it decreased TPA-mediated hyperproliferation, coinciding with reduced epidermal thickness. Inhibition of STAT1, STAT3, STAT5, or AKT reversed the effects of TC-PTP overexpression on epidermal survival and proliferation. Mice overexpressing TC-PTP in the epidermis developed significantly reduced numbers of tumors during skin carcinogenesis and presented a prolonged latency of tumor initiation. Examination of human papillomas and squamous cell carcinomas (SCCs) revealed that TC-PTP expression was significantly reduced and TC-PTP expression was inversely correlated with the increased grade of SCCs. Our findings demonstrate that TC-PTP is a potential therapeutic target for the prevention of human skin cancer given that it is a major negative regulator of oncogenic signaling.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Epiderme/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Papiloma/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/biossíntese , Transdução de Sinais , Neoplasias Cutâneas/enzimologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Sobrevivência Celular , Epiderme/patologia , Humanos , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Papiloma/genética , Papiloma/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
13.
Am J Physiol Cell Physiol ; 318(6): C1144-C1153, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267715

RESUMO

The skin is essential for terrestrial life. It is responsible for regulating water permeability and functions as a mechanical barrier that protects against environmental insults such as microbial infection, ultraviolet light, injury, and heat and cold, which could damage the cells of the body and compromise survival of the organism. This barrier is provided by the outer layer, the epidermis, which is composed predominantly of keratinocytes; keratinocytes undergo a program of differentiation to form the stratum corneum comprising the cornified squame "bricks" and lipid "mortar." Dysregulation of this differentiation program can result in skin diseases, including psoriasis and nonmelanoma skin cancers, among others. Accumulating evidence in the literature indicates that the water-, glycerol-, and hydrogen peroxide-transporting channel aquaporin-3 (AQP3) plays a key role in various processes involved in keratinocyte function, and abnormalities in this channel have been observed in several human skin diseases. Here, we discuss the data linking AQP3 to keratinocyte proliferation, migration, differentiation, and survival as well as its role in skin properties and functions like hydration, water retention, wound healing, and barrier repair. We also discuss the mechanisms regulating AQP3 levels, localization, and function and the anomalies in AQP3 that are associated with various skin diseases.


Assuntos
Aquaporina 3/metabolismo , Epiderme/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Água/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Epiderme/patologia , Humanos , Queratinócitos/patologia , Estado de Hidratação do Organismo , Permeabilidade , Psoríase/patologia , Transdução de Sinais , Cicatrização
14.
Res Vet Sci ; 130: 93-97, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32155472

RESUMO

Cutaneous papilloma (CP) and cutaneous squamous cell carcinoma (CSCC) are frequent epidermal tumours in dogs. In this regard, the study of the deregulated activity of signalling molecules during the epidermal tumourigenesis process could be the basis for the development of novel molecular mechanism-based antitumour treatments for CP and CSCC canine patients. Recent evidence suggests that the development and progression of CP and CSCC involve the dysregulated activation of the Hippo signalling pathway effector YAP. Thus, in the present study, we evaluated the immunohistochemical expression pattern of YAP in sections of tissue microarrays constructed from canine samples of normal epidermis, CP, preneoplastic epidermis, and CSCC. In samples of CP, preneoplastic epidermis, and CSCC, YAP expression was significantly increased relative to normal epidermis. This emerging evidence suggests that the dysregulated activity of the Hippo signalling pathway effector YAP represents a frequent event during canine epidermal tumourigenesis, pointing to this protein as a potential therapeutic target for the treatment of CP and CSCC in dogs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/genética , Carcinoma de Células Escamosas/veterinária , Doenças do Cão/genética , Epiderme/patologia , Papiloma/veterinária , Neoplasias Cutâneas/veterinária , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma de Células Escamosas/genética , Cães , Perfilação da Expressão Gênica/veterinária , Papiloma/genética , Transdução de Sinais , Neoplasias Cutâneas/genética , Análise Serial de Tecidos
16.
Sci Rep ; 10(1): 4930, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188902

RESUMO

GPNMB is involved in multiple cellular functions including cell adhesion, stress protection and stem cell maintenance. In skin, melanocyte-GPNMB is suggested to mediate pigmentation through melanosome formation, but details of keratinocyte-GPNMB have yet to be well understood. We confirmed the expression of GPNMB in normal human epidermal keratinocytes (NHEKs) by reducing the expression using siRNA. A higher calcium concentration of over 1.25 mM decreased the GPNMB expression. Histological staining showed that GPNMB was expressed in the basal layer of normal skins but completely absent in vitiligo skins. The normal expression of GPNMB in nevus depigmentosus skin suggested that lack of GPNMB is characteristic of vitiligo lesional skins. IFN-γ and IL-17A, two cytokines with possible causal roles in vitiligo development, inhibited GPNMB expression in vitro. Approximately 4-8% of the total GPNMB expressed on NHEKs were released possibly by ADAM 10 as a soluble form, but the process of release was not affected by the cytokines. The suppressive effect of IFN-γ on GPNMB was partially via IFN-γ/JAK2/STAT1 signaling axis. Decreased GPNMB expression in keratinocytes may affect melanocyte maintenance or survival against oxidative stress although further studies are needed. These findings indicate a new target for vitiligo treatment, focusing on the novel role of IFN-γ and IL-17 in downregulating keratinocyte-GPNMB.


Assuntos
Regulação da Expressão Gênica , Queratinócitos/metabolismo , Glicoproteínas de Membrana/genética , Vitiligo/genética , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Cálcio/metabolismo , Adesão Celular , Citocinas/metabolismo , Epiderme/metabolismo , Epiderme/patologia , Humanos , Janus Quinase 2/metabolismo , Glicoproteínas de Membrana/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Vitiligo/metabolismo , Vitiligo/patologia
17.
PLoS One ; 15(3): e0222619, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32150577

RESUMO

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-ß1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-ß1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.


Assuntos
Eczema/genética , Epiderme/patologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Ceratose/genética , Pele/metabolismo , Transgenes , Acetamidas/farmacologia , Animais , Citocinas/metabolismo , Doxiciclina/farmacologia , Eczema/tratamento farmacológico , Feminino , Homeostase/genética , Hiperplasia/tratamento farmacológico , Hiperplasia/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Queratinócitos/metabolismo , Ceratose/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transativadores/metabolismo , Compostos de Tritil/farmacologia
18.
An Bras Dermatol ; 95(2): 238-240, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32146012

RESUMO

Some epidermal alterations in measles has been described, such as keratinocytes apoptotic, parakeratosis, giant-cell formation, intranuclear and cytoplasmic inclusions, dyskeratosis, spongiosis, and intracellular edema. The authors report for the first time in human a case of measles with the presence of multinucleated giant cells in the hair follicle and dyskeratosis in acrosyringium.


Assuntos
Epiderme/patologia , Folículo Piloso/patologia , Sarampo/patologia , Biópsia , Criança , Células Gigantes/patologia , Humanos , Queratinócitos/patologia , Masculino , Paraceratose/patologia
19.
Sci Rep ; 10(1): 2024, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029783

RESUMO

The transmembrane protein claudin-1 is a major component of epidermal tight junctions (TJs), which create a dynamic paracellular barrier in the epidermis. Claudin-1 downregulation has been linked to atopic dermatitis (AD) pathogenesis but variable levels of claudin-1 have also been observed in healthy skin. To elucidate the impact of different levels of claudin-1 in healthy and diseased skin we determined claudin-1 levels in AD patients and controls and correlated them to TJ and skin barrier function. We observed a strikingly broad range of claudin-1 levels with stable TJ and overall skin barrier function in healthy and non-lesional skin. However, a significant decrease in TJ barrier function was detected in lesional AD skin where claudin-1 levels were further reduced. Investigations on reconstructed human epidermis expressing different levels of claudin-1 revealed that claudin-1 levels correlated with inside-out and outside-in barrier function, with a higher coherence for smaller molecular tracers. Claudin-1 decrease induced keratinocyte-autonomous IL-1ß expression and fostered inflammatory epidermal responses to non-pathogenic Staphylococci. In conclusion, claudin-1 decrease beyond a threshold level results in TJ and epidermal barrier function impairment and induces inflammation in human epidermis. Increasing claudin-1 levels might improve barrier function and decrease inflammation and therefore be a target for AD treatment.


Assuntos
Claudina-1/metabolismo , Dermatite Atópica/imunologia , Epiderme/patologia , Junções Íntimas/patologia , Adulto , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Claudina-1/análise , Claudina-1/genética , Dermatite Atópica/microbiologia , Dermatite Atópica/patologia , Regulação para Baixo , Epiderme/imunologia , Epiderme/microbiologia , Feminino , Técnicas de Silenciamento de Genes , Voluntários Saudáveis , Humanos , Interleucina-1beta/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Staphylococcus/imunologia , Staphylococcus/isolamento & purificação , Perda Insensível de Água/imunologia , Adulto Jovem
20.
Muscle Nerve ; 61(5): 595-599, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32034782

RESUMO

BACKGROUND: We aimed to evaluate the significance of electromyographic findings in the intrinsic foot muscles (IFMs) of patients with skin biopsy proven small fiber neuropathy (SFN). METHODS: This was a single-center retrospective analysis of patients who underwent skin biopsy for intra-epidermal nerve fiber density (IENFD) measurement and electrodiagnostic (EDX) study for evaluation of polyneuropathy. RESULTS: A total of 1416 patents with normal lower extremity EDX studies proximal to the foot were included. Active denervation was seen in 16.1% of IFMs in patients with skin biopsy proven SFN and 4.1% of patients without SFN (P < .0001). Reinnervation changes without active denervation were observed in 30.4% of SFN patients and 23.8% of patients without SFN (P = .01). IENFD was lower in SFN patients with active denervation in IFMs than without (P < .0001). CONCLUSIONS: Evaluation of active denervation in the IFMs can reveal large fiber dysfunction in SFN patients with otherwise normal routine EDX findings.


Assuntos
Pé/inervação , Músculo Esquelético/inervação , Condução Nervosa/fisiologia , Neuropatia de Pequenas Fibras/fisiopatologia , Nervo Sural/fisiopatologia , Potenciais de Ação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletrodiagnóstico , Eletromiografia , Epiderme/patologia , Feminino , Pé/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Fibras Nervosas/patologia , Estudos Retrospectivos , Neuropatia de Pequenas Fibras/patologia , Coxa da Perna , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA