RESUMO
Whole-exome and whole-genome sequencing have become widespread in approximately the last 15 years, and the predisposing factors and pathomechanisms of inflammatory keratinization diseases, which have been unknown for a long time, have gradually been revealed. Hence, various inflammatory keratinization diseases are recognized to cause innate immunity hyperactivation. Therefore, we have been advocating for the clinical entity, "autoinflammatory keratinization diseases (AiKDs)" since 2017. AiKDs are inflammatory keratinization diseases caused by autoinflammatory-related pathomechanisms in the skin. The aberrant activation of innate immunity and the resultant autoinflammation in the epidermis and the superficial dermis in AiKDs cause hyperkeratosis in the epidermis. Our initially proposed concept of AiKDs included generalized pustular psoriasis and related conditions, pityriasis rubra pilaris type V, and familial keratosis lichenoides chronica. Since then, the number of diseases known to be AiKDs has increased as previously unknown disease-causing factors and pathogenetic mechanisms of inflammatory keratinization diseases have been clarified one by one. To date, porokeratosis, hidradenitis suppurative, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs associated with epidermal growth factor receptor (EGFR) deficiency or with hepatitis and autism have been recognized as AiKDs. The concept of AiKDs is considered extremely useful in our precise understanding of the pathogeneses behind inflammatory keratinization diseases and our appropriate treatment method selection. The number of AiKDs is expected to grow with the clarification of the pathomechanisms of further inflammatory keratinization diseases.
Assuntos
Ceratose , Neoplasias Cutâneas , Humanos , Ceratose/complicações , Ceratose/metabolismo , Ceratose/patologia , Pele/metabolismo , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , SíndromeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The flower buds of Sophora japonica L. are a major traditional medicine in China, Japan, and Korea and are used to stop bleeding and 'cool the blood'. Accordingly, they are used to treat bleeding haemorrhoids, hypertension, and pyoderma. In addition, it was recently found that the flower buds of S. japonica (SJ) have cosmetic whitening properties. MATERIALS AND METHODS: Compounds in SJ and their targets and related diseases were investigated using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform. Target gene information was obtained from the UniProt database. Network construction was carried out using Cytoscape 3.72. Contact dermatitis (CD)-related gene searching was performed using the Cytoscape string App. Docking analysis was conducted using AutoDock Vina. Six-week-old Balb/c male mice with DNFB (1-fluoro-2,4-dinitrofluorobenzene)-induced CD were treated with a methanol extract of the flower buds of S. japonica (MESJ), and its effects on skin colour, lesions, and immune cell infiltration, and on histopathological abnormalities such as epidermal hyperplasia were investigated. RESULTS: Eleven compounds targeted 13 CD-related genes, that is, serum albumin (ALB), prostaglandin G/H synthase (COX) 2, C-X-C motif chemokine (CXCL) 2, CXCL10, ICAM1, IFN-γ, IL-10, IL-1α, IL-1ß, IL-2, IL-6, E-selectin, and TNF. In the murine DNFB model, MESJ significantly suppressed scaling, erythema, and skin thickening as compared with DNFB controls and epithelial hyperplasia and immune cell infiltrations induced by repeated DNFB application. CONCLUSIONS: Our animal study showed that the mode of action of MESJ was closely related to the prevention of epithelial hyperplasia and immune cell infiltration. The results obtained demonstrated that the flower buds of S. japonica offer a potential means of treating CD, and suggest that the therapeutic mechanism of CD is explained by relations between 11 major components of SJ, including kaempferol and quercetin, and 13 CD-related genes.
Assuntos
Dermatite de Contato/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Sophora/química , Animais , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Bases de Dados Factuais , Dermatite de Contato/etiologia , Dermatite de Contato/metabolismo , Dermatite de Contato/patologia , Dinitrofluorbenzeno/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Flores/química , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo , Hiperplasia/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Ceratose/induzido quimicamente , Ceratose/tratamento farmacológico , Ceratose/metabolismo , Ceratose/patologia , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento MolecularRESUMO
p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.
Assuntos
Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Epiderme/metabolismo , Via de Sinalização Wnt/genética , Animais , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologiaAssuntos
Alopecia/genética , Colesterol/metabolismo , Ceratose/genética , Anormalidades da Pele/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Alopecia/diagnóstico , Alopecia/metabolismo , Alopecia/patologia , Arginina/genética , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Ceratose/diagnóstico , Ceratose/metabolismo , Ceratose/patologia , Metabolismo dos Lipídeos/genética , Masculino , Mucosa/metabolismo , Mucosa/patologia , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Pele/patologia , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/metabolismo , Anormalidades da Pele/patologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could be more related to altered barrier function and consequently disorders that affect epithelial cells, such as psoriasis, atopic dermatitis (AD), erythrokeratoderma, loricrin keratoderma (LK) and periodontitis. The aim of this review is to summarize what is known about the association between loricrin downregulation and epithelial-related disorders (ERDs). A search was performed on the following databases: Medline, Cochrane Library, PubMed, EMBASE, Lilacs, Scopus and Google Scholar, resulting in 16 included articles. Loricrin keratoderma was the ERD most frequently associated with loricrin mutations (730insG, 709insC and 578insG; 5/7 cases - 71.44 %). Atopic dermatitis was the ERD most frequently associated with loricrin downregulation (2/7 cases - 28.6 %). Mutilating palmoplantar keratoderma, progressive symmetrical erythrokeratoderma and a new type of erythrokeratoderma were not associated with any mutations. At the gene level, periodontitis patients showed the highest decrease (-6.89x), followed by AD (-6.5x) and psoriasis patients (-0.5x). In summary, loricrin mutation and downregulation were associated with several ERDs. The diversity in disease presentation is likely related to whether there is a total loss of loricrin, mislocalization and/or if the mutant form of loricrin causes dysfunction of other proteins and/or changes in cornification.
Assuntos
Proteínas de Membrana/metabolismo , Mutação , Dermatopatias/metabolismo , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Ceratose/genética , Ceratose/metabolismo , Masculino , Proteínas de Membrana/genética , Mucosa/metabolismo , Psoríase/genética , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Dermatopatias/genéticaAssuntos
Aquaporina 3/metabolismo , Ceratose/metabolismo , Pele/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Antebraço , Humanos , Masculino , Adulto JovemAssuntos
Ceratose/patologia , Mamilos/patologia , Adapaleno/uso terapêutico , Antígenos CD7/metabolismo , Complexo CD3/metabolismo , Fármacos Dermatológicos/uso terapêutico , Diagnóstico Diferencial , Feminino , Rearranjo Gênico do Linfócito T , Humanos , Imuno-Histoquímica , Ceratolíticos/uso terapêutico , Ceratose/diagnóstico , Ceratose/tratamento farmacológico , Ceratose/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Micose Fungoide/diagnóstico , Mamilos/metabolismo , Ácido Salicílico/uso terapêutico , Neoplasias Cutâneas/diagnóstico , Adulto JovemRESUMO
RATIONALE: Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes). OBJECTIVE: To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. METHODS AND RESULTS: Expression of CSPG4 (chondroitin sulfate proteoglycan 4) was detected in epidermal keratinocytes and the cardiac conduction system. CSPG4pos cells constituted ≈5.6±3.3% of the nonmyocyte cells in the mouse heart. Inducible postnatal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibroadipocytes, as in human arrhythmogenic cardiomyopathy. The mice exhibited palmoplantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP. CONCLUSIONS: Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in patients with arrhythmogenic cardiomyopathy and cardiocutaneous syndromes.
Assuntos
Displasia Arritmogênica Ventricular Direita/metabolismo , Desmoplaquinas/metabolismo , Ceratose/metabolismo , Fenótipo , Animais , Antígenos/genética , Displasia Arritmogênica Ventricular Direita/genética , Células Cultivadas , Desmoplaquinas/genética , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Ceratose/genética , Camundongos , Mutação , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteoglicanas/genética , SíndromeRESUMO
BACKGROUND: Symmetrical acrokeratoderma (SAK) is characterized by brown to black hyperkeratotic patches on acral regions. Although epidermal hyperkeratosis and acanthosis are consistent pathological changes, the nature of epidermal hyperplasia is unknown. AIM: To evaluate epidermal proliferation and differentiation and melanocytic density in skin lesions of SAK. METHODS: Expression of keratin 10 (K10), K14, K16, involucrin, filaggrin, Ki-67, and Melan-A was detected by immunohistochemistry in eight patients with SAK, seven patients with ichthyosis vulgaris (IV) and six healthy controls (HCs). RESULTS: Expression of K14, K16, involucrin and filaggrin was upregulated in patients with SAK compared with patients with IV and the HCs (P < 0.01-0.05), but K10 expression was similar for the three groups (P > 0.05). Numbers of Ki-67+ and Melan-A+ cells were higher in patients with SAK than in patients with IV and the HCs (P < 0.05). CONCLUSIONS: These results demonstrate that excessive keratinocyte proliferation and abnormal differentiation contribute to epidermal hyperplasia, while melanocytic proliferation is responsible for the pigmented lesions in SAK.
Assuntos
Diferenciação Celular , Proliferação de Células , Células Epidérmicas , Queratinócitos/citologia , Queratinas/metabolismo , Ceratose/patologia , Melanócitos/citologia , Adolescente , Adulto , Epiderme/metabolismo , Feminino , Proteínas Filagrinas , Humanos , Imuno-Histoquímica , Proteínas de Filamentos Intermediários/metabolismo , Queratinócitos/metabolismo , Ceratose/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Precursores de Proteínas/metabolismo , Pele/metabolismo , Pele/patologia , Regulação para Cima , Adulto JovemAssuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Citarabina/efeitos adversos , Doenças do Cabelo/induzido quimicamente , Proteínas Hedgehog/metabolismo , Ceratose/induzido quimicamente , Idoso , Biópsia , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/metabolismo , Folículo Piloso/patologia , Proteínas Hedgehog/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Ceratose/diagnóstico , Ceratose/metabolismo , Masculino , Pele/patologiaRESUMO
OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory disease of unknown etiology with antigen-specific and non-specific mechanisms. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel activated by noxious stimuli such as oxidative stress products evoking pain and release of proinflammatory mediators from sensory nerve endings culminating in neurogenic inflammation. Extraneuronal TRPA1s, for example, on immune cells possess yet unknown functions. SUBJECTS AND METHODS: We studied the buccal mRNA expression (qPCR) and protein localization (immunohistochemistry) of TRPA1 receptors and key OLP mediator transcripts in oral mucosa samples of healthy volunteers (n = 9), OLP patients (n = 43), and OLP-like hyperkeratotic patients (n = 12). RESULTS: We measured 27.7- and 25.5-fold TRPA1 mRNA increase in OLP and OLP-like hyperkeratotic patients compared to healthy controls. TRPA1 transcripts elevated 2.4-fold in hypertensive OLP but not in hyperkeratotic patients compared to counterparts, reduced by 1.6-fold by angiotensin-convertase inhibitor intake. TRPA1 messenger RNA was more coexpressed with transcripts of tumor necrosis factor α than with interferon γ. Keratinocytes, macrophages but not T cells expressed TRPA1. CONCLUSIONS: We provided evidence for the extraneuronal presence and upregulation of the proinflammatory TRPA1 receptor in buccal samples of patients with OLP. This may implicate the ion channel in the pathomechanism of OLP.
Assuntos
Canais de Cálcio/análise , Canais de Cálcio/genética , Líquen Plano Bucal/genética , Mucosa Bucal/química , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/metabolismo , Canais de Potencial de Receptor Transitório/análise , Canais de Potencial de Receptor Transitório/genética , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão/complicações , Hipertensão/genética , Hipertensão/metabolismo , Interferon gama/genética , Ceratose/genética , Ceratose/metabolismo , Líquen Plano Bucal/complicações , Líquen Plano Bucal/metabolismo , Masculino , Canal de Cátion TRPA1 , Fator de Necrose Tumoral alfa/genética , Regulação para CimaRESUMO
BACKGROUND: Distinguishing regressed lichen planus-like keratosis (LPLK) from regressed melanoma can be difficult on histopathologic examination, potentially resulting in mismanagement of patients. OBJECTIVE: We aimed to identify histopathologic features by which regressed melanoma can be differentiated from regressed LPLK. METHODS: Twenty actively inflamed LPLK, 12 LPLK with regression and 15 melanomas with regression were compared and evaluated by hematoxylin and eosin staining as well as Melan-A, microphthalmia transcription factor (MiTF) and cytokeratin (AE1/AE3) immunostaining. RESULTS: (1) A total of 40% of regressed melanomas showed complete or near complete loss of melanocytes within the epidermis with Melan-A and MiTF immunostaining, while 8% of regressed LPLK exhibited this finding. (2) Necrotic keratinocytes were seen in the epidermis in 33% regressed melanomas as opposed to all of the regressed LPLK. (3) A dense infiltrate of melanophages in the papillary dermis was seen in 40% of regressed melanomas, a feature not seen in regressed LPLK. CONCLUSIONS: In summary, our findings suggest that a complete or near complete loss of melanocytes within the epidermis strongly favors a regressed melanoma over a regressed LPLK. In addition, necrotic epidermal keratinocytes and the presence of a dense band-like distribution of dermal melanophages can be helpful in differentiating these lesions.
Assuntos
Ceratose , Erupções Liquenoides , Melanoma , Neoplasias Cutâneas , Diagnóstico Diferencial , Feminino , Humanos , Ceratose/metabolismo , Ceratose/patologia , Erupções Liquenoides/metabolismo , Erupções Liquenoides/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Proteomics technology is an attractive biomarker candidate discovery tool that can be applied to study large sets of biological molecules. To identify novel biomarkers and molecular targets in arsenic-induced skin lesions, we have determined the protein profile of arsenic-affected human epidermal stratum corneum by shotgun proteomics. Samples of palm and foot sole from healthy subjects were analyzed, demonstrating similar protein patterns in palm and sole. Samples were collected from the palms of subjects with arsenic keratosis (lesional and adjacent non-lesional samples) and arsenic-exposed subjects without lesions (normal). Samples from non-exposed healthy individuals served as controls. We found that three proteins in arsenic-exposed lesional epidermis were consistently distinguishably expressed from the unaffected epidermis. One of these proteins, the cadherin-like transmembrane glycoprotein, desmoglein 1 (DSG1) was suppressed. Down-regulation of DSG1 may lead to reduced cell-cell adhesion, resulting in abnormal epidermal differentiation. The expression of keratin 6c (KRT6C) and fatty acid binding protein 5 (FABP5) were significantly increased. FABP5 is an intracellular lipid chaperone that plays an essential role in fatty acid metabolism in human skin. This raises a possibility that overexpression of FABP5 may affect the proliferation or differentiation of keratinocytes by altering lipid metabolism. KRT6C is a constituent of the cytoskeleton that maintains epidermal integrity and cohesion. Abnormal expression of KRT6C may affect its structural role in the epidermis. Our findings suggest an important approach for future studies of arsenic-mediated toxicity and skin cancer, where certain proteins may represent useful biomarkers of early diagnoses in high-risk populations and hopefully new treatment targets. Further studies are required to understand the biological role of these markers in skin pathogenesis from arsenic exposure.
Assuntos
Intoxicação por Arsênico/metabolismo , Desmogleína 1/metabolismo , Epiderme/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Queratina-6/metabolismo , Ceratose/metabolismo , Adulto , Idoso , Intoxicação por Arsênico/complicações , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Desmogleína 1/genética , Regulação para Baixo , Epiderme/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Queratina-6/genética , Ceratose/etiologia , Masculino , Pessoa de Meia-Idade , Proteômica/métodosRESUMO
A validated animal model would assist with research on the immunological consequences of the chronic expression of stress keratins KRT6, KRT16, and KRT17, as observed in human pre-malignant hyperproliferative epithelium. Here we examine keratin gene expression profile in skin from mice expressing the E7 oncoprotein of HPV16 (K14E7) demonstrating persistently hyperproliferative epithelium, in nontransgenic mouse skin, and in hyperproliferative actinic keratosis lesions from human skin. We demonstrate that K14E7 mouse skin overexpresses stress keratins in a similar manner to human actinic keratoses, that overexpression is a consequence of epithelial hyperproliferation induced by E7, and that overexpression further increases in response to injury. As stress keratins modify local immunity and epithelial cell function and differentiation, the K14E7 mouse model should permit study of how continued overexpression of stress keratins impacts on epithelial tumor development and on local innate and adaptive immunity.
Assuntos
Queratinas/metabolismo , Ceratose/patologia , Pele/metabolismo , Animais , Diferenciação Celular , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Papillomavirus Humano 16/genética , Humanos , Queratina-14/genética , Ceratose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Proteínas E7 de Papillomavirus/genética , Regiões Promotoras Genéticas , Transplante HomólogoRESUMO
The Merkel cell-neurite complex initiates the perception of touch and mediates Aß slowly adapting type I responses. Lichen planus is a chronic inflammatory autoimmune disease with T-cell-mediated inflammation, whereas hyperkeratosis is characterized with or without epithelial dysplasia in the oral mucosa. To determine the effects of lichen planus and hyperkeratosis on the Merkel cell-neurite complex, healthy oral mucosal epithelium and lesional oral mucosal epithelium of lichen planus and hyperkeratosis patients were stained by immunohistochemistry (the avidin-biotin-peroxidase complex and double immunofluorescence methods) using pan cytokeratin, cytokeratin 20 (K20, a Merkel cell marker), and neurofilament 200 (NF200, a myelinated Aß- and Aδ-nerve fibre marker) antibodies. NF200-immunoreactive (ir) nerve fibres in healthy tissues and in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis were counted and statistically analysed. In the healthy oral mucosa, K20-positive Merkel cells with and without close association to the intraepithelial NF200-ir nerve fibres were detected. In the lesional oral mucosa of lichen planus and hyperkeratosis patients, extremely rare NF200-ir nerve fibres were detected only in the lamina propria. Compared with healthy tissues, lichen planus and hyperkeratosis tissues had significantly decreased numbers of NF200-ir nerve fibres in the oral mucosal epithelium. Lichen planus and hyperkeratosis were associated with the absence of Aß-nerve endings in the oral mucosal epithelium. Thus, we conclude that mechanosensation mediated by the Merkel cell-neurite complex in the oral mucosal epithelium is impaired in lichen planus and hyperkeratosis.
Assuntos
Ceratose/patologia , Líquen Plano Bucal/patologia , Células de Merkel/metabolismo , Mucosa Bucal/patologia , Terminações Nervosas/metabolismo , Neuritos/metabolismo , Humanos , Técnicas Imunoenzimáticas , Queratinas/metabolismo , Ceratose/metabolismo , Líquen Plano Bucal/metabolismo , Microscopia Confocal , Mucosa Bucal/metabolismoRESUMO
BACKGROUND: Some examples of Bowen disease lack the characteristic broad parakeratosis making their histopathologic diagnosis particularly difficult in small and incomplete biopsies. MATERIALS AND METHODS: The archives of our dermatopathology laboratory were searched for cases of Bowen disease with >75% orthokeratosis (orthokeratotic Bowen disease) and classic Bowen disease (>25% parakeratosis). Selected specimens were evaluated histopathologically, using immunohistochemical stains (CK10, CK7, Bcl-2, p16 and Ki-67) and by DNA amplification/sequencing for human papilloma virus (HPV) subtypes. RESULTS: Among 102 consecutive samples 14 cases of orthokeratotic Bowen disease were identified. In comparison with 24 examples of classic Bowen disease, the orthokeratotic examples occurred more frequently in female and younger patients (p = 0.04 and 0.008, respectively) but shared most of the histopathologic features of classic Bowen disease except a preserved granular layer and relative absence of the eyeliner sign (p < 0.0001 and p = 0.042, respectively). Immunohistochemical staining patterns were similar between the two groups. HPV types 11, 16 and 58 were identified from five cases of orthokeratotic Bowen disease. CONCLUSION: Orthokeratotic Bowen disease is a distinct variant of squamous cell carcinoma in situ associated with HPV infection in less than half of the cases studied.
Assuntos
Doença de Bowen/metabolismo , Doença de Bowen/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Idoso , Doença de Bowen/virologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Ceratose/metabolismo , Ceratose/patologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Estudos Retrospectivos , Neoplasias Cutâneas/virologiaRESUMO
BACKGROUND: K1 and K2 are the main type II keratins in the suprabasal epidermis where each of them heterodimerizes with the type I keratin K10 to form intermediate filaments. In regions of the ears, tail, and soles of the mouse, only K2 is co-expressed with K10, suggesting that these keratins suffice to form a mechanically resilient cytoskeleton. OBJECTIVE: To determine the effects of the suppression of both main keratins, K2 and K10, in the suprabasal plantar epidermis of the mouse. METHODS: Krt2(-/-) Krt10(-/-) mice were generated by crossing Krt2(-/-) and Krt10(-/-) mice. Epidermal morphology of soles of hind-paws was examined macroscopically and histologically. Immunofluorescence analysis and quantitative PCR analysis were performed to analyze the expression of keratins in sole skin of wildtype and Krt2(-/-) Krt10(-/-) mice. Highly abundant proteins of the sole stratum corneum were determined by electrophoretic and chromatographic separation and subsequent mass spectrometry. RESULTS: K2 and K10 are the most prominent suprabasal keratins in normal mouse soles with the exception of the footpads where K1, K9 and K10 predominate. Mice lacking both K2 and K10 were viable and developed epidermal acanthosis and hyperkeratosis in inter-footpad epidermis of the soles. The expression of keratins K1, K9 and K16 was massively increased at the RNA and protein levels in the soles of Krt2(-/-) Krt10(-/-) mice. CONCLUSIONS: This study demonstrates that the loss of the main cytoskeletal components of plantar epidermis, i.e. K2 and K10, can be only partly compensated by the upregulation of other keratins. The thickening of the epidermis in the soles of Krt2(-/-) Krt10(-/-) mice may serve as a model for pathomechanistic aspects of palmoplantar keratoderma.
Assuntos
Epiderme/fisiologia , Queratina-10/fisiologia , Queratina-2/fisiologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Epiderme/anatomia & histologia , Extremidades , Humanos , Queratina-1/genética , Queratina-1/metabolismo , Queratina-10/genética , Queratina-16/genética , Queratina-16/metabolismo , Queratina-2/deficiência , Queratina-2/genética , Queratina-9/genética , Queratina-9/metabolismo , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/metabolismo , Ceratodermia Palmar e Plantar/patologia , Ceratose/genética , Ceratose/metabolismo , Ceratose/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: To prepare and optimize the topical elastic liposome (EL)-loaded carbopol-980 gel of 5-Fluorouracil (5-FU) containing permeation enhancers (azone, propylene glycol (PG) and lauryl alcohol (LA)) and further evaluation for permeation flux of 5-FU, the activation energy and irritation in the rat skin. METHODS: EL formulations were prepared using phosphatidylcholine and varied surfactants (Span 60, Span 80 and Tween-80) by rotator evaporation method and optimized by experimental design. In vitro characterizations dictated the EL containing Span 80 (lipid:surfactant = 7:3) (EL3-S80) for further optimization of gel. Different gel formulations (5% w/w) with varying concentration (1-3%) of permeation enhancers were prepared and evaluated for viscosity, spreadability, the 5-FU permeation and deposition. The activation energy using the Franz diffusion cell and the plausible irritation using the Draize test were assessed on the albino rat and rabbit, respectively. RESULTS AND DISCUSSION: EL3-S80 was selected as an optimized EL owing to maximum desirability (0.99) and enhanced 5-FU flux (187.86 ± 14.1 µg/cm(2)/h). EL3-S80 suspension loaded gels (0.5%) revealed reduced viscosity leading to higher spreadability than blank gel. EL containing 3% azone in gel, EL containing 3% LA in gel and EL containing 3% PG in gel portrayed 187.86 ± 14.1, 117.7 ± 13.4 and 106.7 ± 7.3 µg/cm(2)/h as enhanced 5-FU flux values, respectively as compared to drug solution (8.8 ± 0.76 µg/cm(2)/h). Furthermore, reduced value of activation energy (2.63-folds) and the non-irritancy of gel could be effective and safe. CONCLUSION: ELA-3 gel formulation could be used as an effective and economic gel in cutaneous cancer and skin-related keratoses.