RESUMO
AIMS: The present report aimed to clarify the clinical characteristics in a girl at the age of 12 and her mother with partial lipodystrophy and Type A insulin resistance syndrome. METHODS: We examined fat distribution in the patients using dual-energy X-ray absorptiometry, magnetic resonance imaging, and computed tomography. We performed genetic analysis to examine the causal gene for lipodystrophy and insulin resistance. RESULTS: Both patients had partial lipodystrophy and a novel heterozygous missense mutation (Asn1137â¯ââ¯Lys1137) in the insulin receptor gene. Because Asn1137 in the catalytic loop is conserved in all protein kinases, this mutation was thought to impair insulin receptor function. By whole-exome sequencing, we found the proband had neither mutations in candidate genes known to be associated with familial partial lipodystrophy nor novel likely candidate causal genes. Taken together, we thought that fat loss in these two patients might be caused by insulin receptor dysfunction. The proband had amenorrhea due to polycystic ovary syndrome. Her menstruation improved, as fat loss was restored during adolescence. This might be caused by improving insulin resistance due to increased levels of leptin and fat mass. CONCLUSIONS: This case might help to understand the mechanisms insulin receptor dysfunction that cause lipodystrophy.
Assuntos
Antígenos CD/genética , Lipodistrofia Parcial Familiar/genética , Síndrome Metabólica/genética , Mutação de Sentido Incorreto , Receptor de Insulina/genética , Adulto , Estudos de Casos e Controles , Criança , Feminino , Testes Genéticos , Heterozigoto , Humanos , Resistência à Insulina/genética , Lipodistrofia Parcial Familiar/complicações , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Núcleo Familiar , Linhagem , Fenótipo , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/genéticaRESUMO
Increased A disintegrin and metalloprotease 17 (ADAM17) expression in vascular smooth muscle cells (VSMC) is implicated in the development of cardiovascular diseases including atherosclerosis and hypertension. Although cilostazol, type III phosphodiesterase (PDE III) inhibitor, has recently been found to inhibit VSMC proliferation, the mechanisms remain largely unclear. Here, we hypothesized that cilostazol regulates the ADAM17 expression in VSMC. In cultured VSMC, interleukin (IL)-1α and IL-1ß significantly increased ADAM17 expression. MEK inhibitor U0126, NF-κB inhibitor BAY-11-7085, and siRNA targeting p65/RelA significantly inhibited IL-1α or IL-ß-induced ADAM17 expression. Cilostazol significantly inhibited IL-1α or IL-1ß-induced extracellular signal-regulated kinase (ERK) phosphorylation and ADAM17 expression. Unexpectedly, cilostamide, dibutryl cAMP, and forskolin did not affect IL-1-induced ADAM17 expression. Our results clearly demonstrated that IL-1 induces ADAM17 expression through ERK/NF-κB activation in VSMCs. Moreover, the inhibitory effects of cilostazol on IL-1-induced ADAM17 expression may be independent of the cAMP signaling pathway in VSMC. These novel findings may provide important clues to understanding the expression mechanisms of ADAM17 and the inhibitory mechanisms of cilostazol in VSMC proliferation.
Assuntos
Proteína ADAM17/metabolismo , AMP Cíclico/metabolismo , Interleucina-1/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Células Cultivadas , Cilostazol , MAP Quinases Reguladas por Sinal Extracelular , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismoRESUMO
A neonatal case of provisional neurocutaneous melanosis presenting with lissencephaly is reported. Several congenital nevi were observed on the trunk and extremities of the infant, including a giant congenital hairy nevus over the skull. Brain magnetic resonance imaging revealed a marked ventricular dilatation with pachygyria and an absent corpus callosum; however, an injection of gadolinium did not demonstrate any enhanced lesions. Histopathological investigations by a brain biopsy showed a disorganized and anomalous embryonic cerebral architecture, suggesting lissencephaly. The detailed mechanism of this combined pathology is difficult to explain; however, a developmental disturbance was suggested to be present in both the neural crest cells and the neuroepithelial cells, resulting in the development of neurocutaneous melanosis accompanied with lissencephaly.
Assuntos
Agenesia do Corpo Caloso , Lisencefalia/complicações , Nevo Pigmentado/congênito , Humanos , Recém-Nascido , Lisencefalia/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Nevo Pigmentado/complicaçõesRESUMO
Cyclosporin A (CsA) is an immunosuppressant with severe side effects including gingival overgrowth. We have previously reported that CsA impairs the activity of the lysosomal enzymes cathepsin B and L in human gingival fibroblasts (HGFs). Here, we have examined the effects of CsA on the DNA-binding activity of the cyclic AMP response element-binding protein (CREB) and cell viability, and the effects of CREB on cathepsin B and L synthesis and activity in HGFs. We have confirmed that CsA down-regulates cathepsin B and L synthesis. Further, CsA has no effect on cell viability and dramatically impairs CREB-DNA binding activity. Importantly, the synthesis of cathepsin B and L is down-regulated, and their activity is also significantly impaired in HGFs transfected with plasmid expressing dominant-negative CREB. These results suggest that CREB is essential for the CsA-mediated down-regulation of cathepsin B and L synthesis in HGFs.
Assuntos
Proteína de Ligação a CREB/fisiologia , Catepsina B/biossíntese , Catepsinas/biossíntese , Ciclosporina/farmacologia , Cisteína Endopeptidases/biossíntese , Catepsina B/efeitos dos fármacos , Catepsina L , Catepsinas/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisteína Endopeptidases/efeitos dos fármacos , Regulação para Baixo , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Gengiva/efeitos dos fármacos , Gengiva/enzimologia , Humanos , Proteínas de Membrana Lisossomal/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/enzimologia , TransfecçãoRESUMO
We report a neonatal case of Peters' anomaly with bilateral perisylvian polymicrogyria and abdominal calcification. The male infant was born after a normal labor. Bilateral central corneal opacities with iridocorneal strands indicated Peters' anomaly. The X-ray and abdominal computed tomography demonstrated multiple calcifications beneath the diaphragma around the liver and the spleen. TORCH serology was negative. Intracranial calcification was not detected. Brain magnetic resonance imaging demonstrated bilateral perisylvian polymicrogyria. Abdominal calcification was suspected to be related to vascular disruption. Bilateral perisylvian polymicrogyria has been thought to result from ischemic events such as intrauterine hypotension or vascular occlusions. Based on these considerations, we conclude that a vascular disruption sequence may an important pathogenetic mechanism of Peters' anomaly.