RESUMEN
Three-hydroxy-3-methylglutaryl coenzyme A synthase (HMGCS) 1 was identified to interact with Gal-7, a pro-apoptotic ß-galactosideâbinding protein, by yeast two-hybrid system. Their interaction was confirmed by in vitro ß-galactosidase, Biacore, and immunoprecipitation assays. A distinct interactive site of HMGCS1 was found to reside at phenylalanine 26. The expression of HMGCS1 in cultured keratinocytes was upregulated by exogenous Gal-7 and downregulated in LGALS7 small interfering RNAâtransfected cells. HMGCS1-overexpressing cells were found to induce Gal-7 expression, which suggests that Gal-7 and HMGCS1 expressions are both stimulated by positive feedback regulation. The amount of cholesterol, a final biosynthetic product of HMGCS1-involved pathway, was increased in Gal-7âtreated cells and was significantly reduced in LGALS7 small interfering RNAâtransfected cells. The increase of cholesterol level in Gal-7âtreated cells was inhibited by wild-type HMGCS1 peptide but not by phenylalanine 26âmutated peptide, suggesting that the interaction of Gal-7/HMGCS1 is related to cellular cholesterol level. Foam cells in granulomatous tissues of the specimens from normolipidemic cutaneous xanthoma showed positive reactions with the antibodies for Gal-7 and HMGCS1 as well as for lipid markers. These results are likely to indicate that Gal-7 induction in epidermal keratinocytes causes both apoptotic cell death and HMGCS1-mediated cholesterol accumulation, which will be phagocytized by macrophages. This mechanism may explain the pathogenesis of normolipidemic cutaneous xanthoma.
Asunto(s)
Hidroximetilglutaril-CoA Sintasa , Xantomatosis , Colesterol/metabolismo , Galectinas , Humanos , Hidroximetilglutaril-CoA Sintasa/metabolismo , Queratinocitos/metabolismo , Fenilalanina , ARN Interferente PequeñoRESUMEN
Photosensitivity is a skin reaction disorder mediated by phototoxic and/or photoallergic mechanisms. The accumulation of porphyrins is generally considered to induce phototoxicity. ATP-binding cassette subfamily G member 2 (ABCG2) has been identified as a transporter of porphyrins and its common variants-p.Gln126Ter (rs72552713) and p.Gln141Lys (rs2231142)-reportedly decrease the function of porphyrin transport in vitro; however, the physiological importance of ABCG2 as a porphyrin transporter remains to be fully elucidated. We herein investigated whether ABCG2 dysfunction could lead to porphyrin accumulation and photosensitivity in Japanese subjects, and found it to be significantly correlated with erythrocyte protoporphyrin levels (P = 0.012). This appears to be the first clinical finding of ABCG2 dysfunction-associated protoporphyrin accumulation in humans. We divided the patients into a chronic actinic dermatosis (CAD) group and a non-CAD group. CAD was diagnosed based on the criteria of reduced minimal erythema doses to ultraviolet B (UVB) and/or ultraviolet A (UVA). The non-CAD group was composed of patients who exhibited normal reactions to UVB and UVA on phototesting, but had histories of recurrent erythema/papules on sun-exposed areas. Estimated ABCG2 function according to ABCG2 genotypes in the non-CAD group was significantly lower than in the general Japanese population (P = 0.045). In contrast, no difference was found in ABCG2 function between the CAD group and the general population, suggesting that ABCG2 dysfunction might be a genetic factor in non-CAD patients with clinical photosensitivity. In this context, genetic dysfunction of ABCG2 might be an overlooked pathological etiology of "photosensitivity of unknown cause."
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Variación Genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Trastornos por Fotosensibilidad/etiología , Trastornos por Fotosensibilidad/genética , Porfirinas/metabolismo , Adulto , Anciano , Pueblo Asiatico , Eritrocitos/metabolismo , Genotipo , Humanos , Persona de Mediana Edad , Trastornos por Fotosensibilidad/metabolismo , Protoporfirinas/sangreAsunto(s)
Hepatitis/inmunología , Psoriasis/complicaciones , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colecalciferol/análogos & derivados , Colecalciferol/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Hepatitis/tratamiento farmacológico , Hepatitis/patología , Hepatitis/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Psoriasis/tratamiento farmacológico , Psoriasis/patologíaRESUMEN
Fusarium onychomycosis is uncommon in the temperate climate zone of Japan. Based on the morphological characteristics and a gene analysis, we diagnosed a patient with ungual hyalohyphomycosis caused by Fusarium cugenangense belonging to the F oxysporum complex. This intractable disease was cured by 6-month treatment with efinaconazole 10% solution.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Inmunoglobulina A/metabolismo , Complicaciones del Embarazo , Enfermedades Cutáneas Vesiculoampollosas/inmunología , Enfermedades Cutáneas Vesiculoampollosas/patología , Adulto , Dermis/metabolismo , Femenino , Humanos , Neutrófilos/metabolismo , EmbarazoAsunto(s)
Artritis Psoriásica/tratamiento farmacológico , Fármacos Dermatológicos/efectos adversos , Infliximab/efectos adversos , Piodermia Gangrenosa/tratamiento farmacológico , Uveítis/inducido químicamente , Adalimumab/uso terapéutico , Sustitución de Medicamentos , Femenino , Humanos , Persona de Mediana Edad , Resultado del TratamientoAsunto(s)
Edema/etiología , Dermatosis del Pie/etiología , Dermatosis de la Mano/etiología , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/diagnóstico , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/diagnóstico , Eritema/etiología , Fiebre/etiología , Humanos , Linfadenopatía/etiología , Masculino , Persona de Mediana Edad , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Enfermedades de la Lengua/etiologíaAsunto(s)
Celulitis (Flemón)/virología , Infecciones por Coxsackievirus/virología , Enterovirus/patogenicidad , Eosinofilia/virología , Piel/virología , Administración Oral , Biopsia , Celulitis (Flemón)/diagnóstico , Celulitis (Flemón)/tratamiento farmacológico , Celulitis (Flemón)/inmunología , Infecciones por Coxsackievirus/diagnóstico , Infecciones por Coxsackievirus/inmunología , Enterovirus/inmunología , Eosinofilia/diagnóstico , Eosinofilia/tratamiento farmacológico , Eosinofilia/inmunología , Glucocorticoides/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Resultado del TratamientoAsunto(s)
Pénfigo/tratamiento farmacológico , Prednisolona/efectos adversos , Psoriasis/inducido químicamente , Azatioprina/efectos adversos , Azatioprina/uso terapéutico , Biopsia , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos , Quimioterapia Combinada , Humanos , Masculino , Persona de Mediana Edad , Pénfigo/patología , Prednisolona/uso terapéutico , Psoriasis/patología , Piel/efectos de los fármacos , Piel/patología , Células Th17/efectos de los fármacosRESUMEN
BACKGROUND: C-reactive protein (CRP) is a prototypic acute phase protein which increases dramatically in the blood during the first 48h of tissue inflammation and has been recognized as a risk factor for atherosclerosis. CRP interacts with a variety of proteins. OBJECTIVE: To know the role of accumulated CRP in the skin. METHODS: Interaction of CRP with basal keratinocytes was studied using immunohistochemical method and keratinocyte culture system. RESULTS: We found an immunohistochemical deposition of CRP on the basal keratinocyte membrane in some normal human skins (23 out of 46 skins). When added to cultured keratinocytes, heat-denatured but not native CRP was found to adhere to keratinocyte cell membrane after 1h, then internalized into cytoplasm after 24h. The heat-denatured CRP recognized at least four keratinocyte polypeptides with the molecular weights of 56, 42, 32 and 24kDa. Ligand binding assays suggested that multiple populations of receptor-ligand interactions were involved in the binding between CRP and keratinocyte. Cultured dermal microvascular endothelial cells were found to express CRP of which expression was greatly induced by interleukin-1ß (IL-1ß) treatment, suggesting that the deposited CRP in the basal keratinocytes can be derived from local dermal microvasculatures as well as from systemic circulation (serum). Treatment of cultured keratinocytes with heat-denatured CRP induced interleukin-8 (IL-8) expression, a potent leukocyte chemotactic cytokine. CRP in the medium (liquid phase) and CRP-coated dishes (solid phase) both inhibited the adhesion of keratinocytes in culture. CONCLUSION: Accumulation of CRP may regulate the skin inflammation and keratinocyte proliferation by modulating keratinocyte cytokine expression and adhesion to substrate.
Asunto(s)
Proteína C-Reactiva/metabolismo , Dermatitis/metabolismo , Epidermis/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Queratinocitos/metabolismo , Adhesión Celular , Proliferación Celular , Células Cultivadas , Humanos , Inmunohistoquímica , Queratinocitos/fisiología , Microvasos/metabolismoRESUMEN
BACKGROUND: There is no reliable marker to estimate the degree of skin aging in vivo. It now has become possible to quantitatively determine the dermal characteristics of the extracellular matrix (ECM) in vivo using multiphoton laser tomography (MLT). METHODS: Fifty-seven healthy Japanese female volunteers, aged from 20 to 60 years old, were examined using multiphoton depth-resolved measurements of autofluorescence (AF) and second harmonic generation (SHG) at three sites on their right cheek. Paraffin-embedded skin specimens obtained from the faces of 12 normal individuals aged 38-68 years old were stained with Elastica van Gieson (EVG). RESULTS: We found unique elastic aggregates at a 20 µm depth from the dermo-epidermal junction (DEJ) in vivo which increased in size with aging of subjects from 20 to 60 years old. SHG fibers seemed to surround those elastic aggregates. Histological examination of specimens from normal individuals stained with EVG confirmed the occurrence of elastic aggregates with varied sizes just beneath the epidermis or hair follicles. CONCLUSIONS: The elastic aggregates are morphologically similar to previously described 'elastic globes' and can serve as a marker of the early stage of photoaging. MLT will contribute to determine age-related dermal changes using a non-invasive technique.
Asunto(s)
Tejido Elástico/ultraestructura , Envejecimiento de la Piel/patología , Piel/ultraestructura , Tomografía , Adulto , Anciano , Biomarcadores , Cara , Femenino , Humanos , Rayos Láser , Persona de Mediana Edad , Imagen Óptica , Adulto JovenRESUMEN
Photomechanical waves (PMWs), which were generated by irradiation of a light-absorbing material (laser target) with nanosecond laser pulses, were used for targeted transvascular drug delivery in rats. An Evans blue (EB) solution was injected into the tail vein, and laser targets were placed on the skin, muscle and brain. Each laser target was irradiated with a laser pulse(s) and 4h later, the rat was perfused and the distribution of EB fluorescence in the targeted tissues was examined. We observed laser fluence-dependent and hence PMW pressure-dependent extravasation of EB selectively in the tissues that had been exposed to a PMW(s). Uptake of leaked EB into cells in extravascular space was also observed in the targeted tissues. Tissue damage or hemorrhage was not apparent except in the brain exposed to the highest laser fluence used. The results for the brain indicated opening of the blood-brain barrier (BBB). Reverse-order (PMW application before EB injection) experiments showed that the BBB was closed in the duration from 8h to 12h after PMW application at a laser fluence of 0.5J/cm(2). Since EB molecules are strongly bound with serum albumin in blood, the results indicate that the present method can be applied not only to small molecules but also to macromolecules.
Asunto(s)
Sistemas de Liberación de Medicamentos/instrumentación , Azul de Evans/administración & dosificación , Animales , Barrera Hematoencefálica/metabolismo , Diseño de Equipo , Rayos Láser , Masculino , Músculos/metabolismo , Ratas , Ratas Sprague-Dawley , Piel/metabolismoRESUMEN
Pathogenesis of primary localized cutaneous amyloidosis (PLCA) is unclear, but pathogenic relationship to keratinocyte apoptosis has been implicated. We have previously identified galectin-7, actin, and cytokeratins as the major constituents of PLCA. Determination of the amyloidogenetic potential of these proteins by thioflavin T (ThT) method demonstrated that galectin-7 molecule incubated at pH 2.0 was capable of binding to the dye, but failed to form amyloid fibrils. When a series of galectin-7 fragments containing ß-strand peptides were prepared to compare their amyloidogenesis, Ser(31)-Gln(67) and Arg(120)-Phe(136) were aggregated to form amyloid fibrils at pH 2.0. The rates of aggregation of Ser(31)-Gln(67) and Arg(120)-Phe(136) were dose-dependent with maximal ThT levels after 3 and 48 h, respectively. Their synthetic analogs, Phe(33)-Lys(65) and Leu(121)-Arg(134), which are both putative tryptic peptides, showed comparable amyloidogenesis. The addition of sonicated fibrous form of Ser(31)-Gln(67) or Phe(33)-Lys(65) to monomeric Ser(31)-Gln(67) or Phe(33)-Lys(65) solution, respectively, resulted in an increased rate of aggregation and extension of amyloid fibrils. Amyloidogenic potentials of Ser(31)-Gln(67) and Phe(33)-Lys(65) were inhibited by actin and cytokeratin fragments, whereas those of Arg(120)-Phe(136) and Leu(121)-Arg(134) were enhanced in the presence of Gly(84)-Arg(113), a putative tryptic peptide of galectin-7. Degraded fragments of the galectin-7 molecule produced by limited trypsin digestion, formed amyloid fibrils after incubation at pH 2.0. These results suggest that the tryptic peptides of galectin-7 released at neutral pH, may lead to amyloid fibril formation of PLCA in the intracellular acidified conditions during keratinocyte apoptosis via regulation by the galectin-7 peptide as well as actin and cytokeratins.
Asunto(s)
Amiloide/metabolismo , Amiloidosis Familiar/metabolismo , Galectinas/metabolismo , Péptidos/metabolismo , Enfermedades Cutáneas Genéticas/metabolismo , Actinas/metabolismo , Secuencia de Aminoácidos , Apoptosis , Humanos , Queratinocitos/metabolismo , Queratinas/metabolismo , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Proteínas Recombinantes/metabolismo , Tripsina/metabolismoRESUMEN
BACKGROUND: Lichen sclerosus et atrophicus (LSA) is histopathologically characterized by upper dermal hyalinization with vacuolar alteration, whereas no particular microscopic change in the mid to lower dermis has been described. The purpose of this study was to investigate any histopathologic changes involving elastic fibers in the mid to lower dermis in patients with LSA. METHODS: We surveyed 22 paraffin-embedded specimens of vulval (18 cases) and extragenital (4 cases) LSA. The sliced skin sections were stained with elastic van Gieson (EVG), and then the degree of elastic fiber change was determined. RESULTS: We found an increase in elastic fibers in the mid to lower dermis in contrast to a decrease or disappearance of elastic fibers in the superficial hyalinized dermis. The level of increase of elastic fibers varies from normal (8/22 cases) to moderate (7/22 cases) to advanced (7/22 cases) levels. CONCLUSIONS: An increase in elastic fibers in the mid to lower dermis may reflect a repairing process in response to the degraded upper dermal elastic fibers, which could be related to the pathogenesis of LSA.