RESUMO
BACKGROUND: Chronic skin ulcers are a major complication and a therapeutic challenge in patients with diabetes mellitus. Glucose-induced accumulation of reactive oxygen species (ROS) is considered to be an important pathogenetic factor in diabetes. OBJECTIVES: To characterize the impact of high glucose (HG) on normal human keratinocytes (NHKs) and examine if Lys-d-Pro-Thr (KdPT), a tripeptide derived from α-melanocyte-stimulating-hormone, has protective effects. METHODS: We investigated the key functions of NHKs under HG conditions with or without KdPT in vitro as well as ex vivo employing a skin organ culture model. RESULTS: HG impaired metabolic activity, cell proliferation, viability and migration of NHKs. As shown by atomic force microscopy HG altered the biophysical properties of NHKs, i.e. cell size and elasticity. Glucotoxicity in NHKs was paralleled by the induction of intracellular ROS and endoplasmic reticulum stress. KdPT attenuated HG-induced oxidative stress and antagonized the effects of glucose on cell viability, metabolic activity and migration. Importantly, KdPT also antagonized the suppressive effect of HG on epidermal migration in wounded human skin organ cultures. CONCLUSIONS: Our findings highlight a novel effect of KdPT that could be exploited for the future therapy of diabetic skin ulcers.
Assuntos
Pé Diabético/prevenção & controle , Epiderme/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Cicatrização/efeitos dos fármacos , Glicemia/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Pé Diabético/sangue , Pé Diabético/etiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Epiderme/fisiologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/ultraestrutura , Microscopia de Força Atômica , Oligopeptídeos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.
Assuntos
Interleucinas/genética , Mutação/genética , Psoríase/genética , Adulto , Proteínas Adaptadoras de Sinalização CARD/genética , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos , Guanilato Ciclase/genética , Heterozigoto , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Transporte Vesicular/genéticaRESUMO
Chronic venous insufficiency is very common and has an important socioeconomic impact. It is associated with a high morbidity for the patients and causes high costs for the healthcare systems. In recent years novel treatment modalities have evolved and their efficacy has been evaluated in many studies. Knowledge of pathophysiology, the diagnostic procedures and therapeutic options for chronic venous insufficiency is important for effective treatment of affected patients.
Assuntos
Angiografia/métodos , Ablação por Cateter/métodos , Fotopletismografia/métodos , Modalidades de Fisioterapia , Insuficiência Venosa/diagnóstico , Insuficiência Venosa/terapia , Doença Crônica , Bandagens Compressivas , Humanos , Flebografia/métodos , Escleroterapia/métodos , Resultado do Tratamento , Insuficiência Venosa/etiologiaRESUMO
Being the largest organ of the human body, skin is frequently affected in many rheumatic diseases. Thus, it can serve as an important indicator for the correct diagnosis of a rheumatic disease and also as a marker of disease activity in distinct rheumatic disorders. In this review we will highlight the clinical features of these cutaneous manifestations of the major rheumatic diseases. We will also provide an update on the complex pathobiology of these diseases based on the most recent developments in clinical and translational research.
