RESUMO
Islet transplantation for type 1 diabetes is limited by a shortage of donor islets and requirement for immunosuppression. We approached this problem by inducing in vivo islet neogenesis in non-obese diabetic (NOD) diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus carrying neurogenin3 (Ngn3), an islet lineage-defining transcription factor, and betacellulin (Btc), an islet growth factor, leads to the induction of periportal insulin-positive cell clusters in the liver, which are rapidly destroyed. To specifically accord protection to these 'neo-islets' from cytokine-mediated destruction, we overexpressed suppressor of cytokine signaling 1 (SOCS1) gene, using a rat insulin promoter in combination with Ngn3 and Btc. With this approach, about half of diabetic mice attained euglycemia sustained for over 4 months, regain glucose tolerance and appropriate glucose-stimulated insulin secretion. Histological analysis revealed periportal islet hormone-expressing 'neo-islets' in treated mouse livers. Despite evidence of persistent 'insulitis' with activated T cells, these 'neo-islets' persist to maintain euglycemia. This therapy does not affect diabetogenicity of splenocytes, as they retain the ability to transfer diabetes. This study thus provides a proof-of-concept for engineering in vivo islet neogenesis with targeted resistance to cytokine-mediated destruction to provide a long-term reversal of diabetes in NOD mice.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Betacelulina/genética , Diabetes Mellitus Experimental/terapia , Terapia Genética/métodos , Proteínas do Tecido Nervoso/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Adenoviridae/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Betacelulina/biossíntese , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Feminino , Terapia de Imunossupressão , Insulina/biossíntese , Insulina/genética , Ilhotas Pancreáticas/fisiologia , Transplante das Ilhotas Pancreáticas/métodos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Proteínas do Tecido Nervoso/biossíntese , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/biossínteseRESUMO
Silica is a commonly used filler in dental materials and as a reinforcing agent in industry. The aim of this study was to further investigate the effect of the addition of untreated and a novel surface treated silica on the transverse bend and impact strength of acrylic resin denture base material. It was hypothesized that the silica/resin composite materials would have an improved flexural and impact strength than the conventional heat-cured acrylic resin. Three types of untreated and two of treated silica powder were used in this study. The range of percentages used were 1%, 0.5%, 0.2%, 0.1%. The treated particles were coated with hexamethyldisilazane or dimethyldichloridesilazane. Conventional heat cured acrylic resin was used as a control. The modulus of rupture for all groups of acrylic resin containing silica was significantly lower than for the control. The modulus of elasticity was not significantly greater than the control group. For the impact strength statistical analysis revealed a significant difference between the groups. There was a nonsignificant increase in the impact strength for specimens compared to the control. In conclusion the addition of silica to poly(methyl methacrylate) denture base materials did not produce a significant improvement in the transverse bend or impact strength compared to conventional heat-cured acrylic resin. The incorporation of untreated and surface treated silica cannot be recommended as a method of reinforcement.
