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Med Sci Monit ; 25: 9679-9689, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31848329


BACKGROUND The aim of this study was to determine the association between white matter lesions (WML) and diabetes-associated cognitive decline (DACD) in rat models of type 2 diabetes (T2DM). MATERIAL AND METHODS Sixty Sprague-Dawley male rats were divided into 4 groups: control, control+metformin, T2DM, and T2DM+metformin groups. The T2DM groups were fed a diet high in fat and glucose to induce impaired glucose tolerance (IGT) and then were injected with streptozotocin to induce T2DM. The Morris water maze test was used to evaluate cognitive function. Brain diffusion tensor imaging scans were performed for WML. The expression of myelin basic protein (MBP), oligodendrocyte transcription factor 1 (OLIG1), and OLIG2 (markers of brain damage and repair) was determined using immunofluorescence. After IGT, the fractional anisotropy (FA) values of the right thalamus area were significantly lower in both T2DM groups compared with controls. RESULTS Eight weeks after streptozotocin injection, the FA values of the thalamus were lower in the T2DM (bilateral thalamus) group and T2DM+metformin (left thalamus) group than in controls, while the FA values in the left thalamus area were lower in the T2DM+metformin group than in the control and control+metformin groups. The maze escape latency was longer and the number of rats passing through the platform was smaller in the T2DM and T2DM+metformin groups than in the control group. MBP levels were lower and OLIG1 and OLIG2 levels were higher in both T2DM groups than in controls. CONCLUSIONS WML is associated with DACD and appears before the onset of T2DM and signs of DACD and plays a role in diabetes-associated cognitive decline. Metformin reduces WMLs but does not rescue cognitive dysfunction.

Mol Med Rep ; 17(5): 6789-6795, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29488615


The present study aimed to investigate the association between insulin resistance (IR), nitric oxide (NO) production and myocardial apoptosis in a background of coexisting hypertension in a rodent animal model. A hypertensive rat model was established by feeding Wistar and spontaneously hypertensive rats (SHR) with a high sucrose/fat (HSF) diet for 12 weeks, in conjunction with isosorbide mononitrate (ISMN). Increased IR, NO content, apoptotic gene and protein expression, and morphological alterations within rat myocardium were evaluated. Following a total of 12 weeks of feeding with HSF and ISMN resulted in increased IR and NO content within the myocardial tissue of Wistar and SHR rats. HSF and ISMN activated myocardial apoptosis by downregulating the gene transcription and protein expression levels of the anti­apoptotic B­cell lymphoma 2 (Bcl­2), and increasing the pro­apoptotic Bcl­2 associated X protein. Apoptosis was demonstrated by DNA fragmentation in terminal deoxynucleotidyl­transferase­mediated dUTP nick end labelling assay. In all experiments, the combination of HSF and ISMN was associated with more pronounced effects, indicating the possible synergistic effects. In addition, the correlation analysis in the Wistar rats fed with HSF only, revealed a positive association between NO production and IR. The results of the present study indicated that HSF and ISMN simultaneously increased IR, NO production and myocardial apoptosis in the hypertensive rat model, and may therefore contribute to investigations into the long­term clinical use of ISMN in hypertensive patients.

Apoptose/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Hipertensão , Resistência à Insulina , Dinitrato de Isossorbida/análogos & derivados , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Sacarose/efeitos adversos , Animais , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/patologia , Dinitrato de Isossorbida/efeitos adversos , Dinitrato de Isossorbida/farmacologia , Masculino , Miocárdio/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sacarose/farmacologia
Endocr J ; 64(8): 787-796, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28674284


C1qTNF-related protein 1 (CTRP1) is independently associated with type 2 diabetes. However, the relationship between CTRP1 and insulin resistance is still not established. This study aimed to explore the role of CTRP1 under the situation of insulin resistance in adipose tissue. Plasma CTRP1 level was investigated in type 2 diabetic subjects (n = 35) and non-diabetic subjects (n = 35). The relationship between CTRP1 and phosphorylation of multi insulin receptor substrate 1 (IRS-1) serine (Ser) sites was further explored. Our data showed that Plasma CTRP1 was higher and negative correlation with insulin resistance in diabetic subjects (r = -0.283, p = 0.018). Glucose utilisation test revealed that the glucose utilisation rate of mature adipocytes was improved by CTRP1 in the presence of insulin. CTRP1 was not only related to IRS-1 protein, but also negatively correlated with IRS-1 Ser1101 phosphorylation (r = -0.398, p = 0.031). Furthermore, Phosphorylation levels of IRS-1 Ser1101 were significantly lower after incubation with 40 ng/mL CTRP1 in mature adipocytes than those with no intervention (p < 0.05). There was no significant correlation between CTRP1 and other IRS-1 serine sites (Ser302, Ser307, Ser612, Ser636/639, and Ser789). Collectively, our results suggested that CTRP1 might improve insulin resistance by reducing the phosphorylation of IRS-1 Ser1101, induced in the situation of insulin resistance as a feedback adipokine.

Diabetes Mellitus Tipo 2/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/fisiologia , Proteínas/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adulto , Idoso , Feminino , Humanos , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Proteínas/farmacologia , Transdução de Sinais/efeitos dos fármacos
Biochem Biophys Res Commun ; 488(1): 109-115, 2017 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-28479244


To investigate the effects of the PI3K inhibitors on the differentiation of insulin-producing cells derived from human embryonic stem cells. Here, we report that human embryonic stem cells induced by phosphatidylinositol-3-kinase (PI3K) p110ß inhibitors could produce more mature islet-like cells. Findings were validated by immunofluorescence analysis, quantitative real-time PCR, insulin secretion in vitro and cell transplantation for the diabetic SCID mice. Immunofluorescence analysis revealed that unihormonal insulin-positive cells were predominant in cultures with rare polyhormonal cells. Real-time PCR data showed that islet-like cells expressed key markers of pancreatic endocrine hormones and mature pancreatic ß cells including MAFA. Furthermore, this study showed that the expression of most pancreatic endocrine hormones was similar between groups treated with the LY294002 (nonselective PI3K inhibitor) and TGX-221 (PI3K isoform selective inhibitors of class 1ß) derivatives. However, the level of insulin mRNA in TGX-221-treated cells was significantly higher than that in LY294002-treated cells. In addition, islet-like cells displayed glucose-stimulated insulin secretion in vitro. After transplantation, islet-like cells improved glycaemic control and ameliorated the survival outcome in diabetic mice. This study demonstrated an important role for PI3K p110ß in regulating the differentiation and maturation of islet-like cells derived from human embryonic stem cells.

Diferenciação Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Células Cultivadas , Cromonas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos SCID , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/química , Pirimidinonas/farmacologia , Relação Estrutura-Atividade
Endocr J ; 61(9): 841-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24965225


Complement C1q tumor necrosis factor-related protein 1 (CTRP1), an adipose tissue-derived adipokine has been shown to decrease blood glucose levels and to improve metabolism of glucose in mice. In addition, CTRP1 has exhibited significant association with BMI, adiponectin and TNF-α in diabetic animal models. However, there are no published studies addressing CTRP1 levels in type 2 diabetic patients. Therefore, it was of interest to evaluate plasma CTRP1 levels and associated clinical parameters and biomarkers in patients with type 2 diabetes. 135 subjects were recruited to this study, including 62 type 2 diabetic patients (DM group) and 73 healthy subjects (control group). We measured biochemical parameters, CTRP1, TNF-α and adiponectin using enzyme-linked immunosorbent assay (ELISA). Plasma CTRP1 levels showed a significant difference between the DM group and the control group (646.3 ± 154.4 ng/mL vs. 442.6 ± 165.4 ng/mL, p < 0.01). In addition, CTRP1 was strongly positively associated with BMI, glucose levels, HbA1c, HOMA-IR and TNF-α in diabetic patients. CTRP1 showed negative correlation with adiponectin. In Multivariate regression analysis, CTRP1 was strongly independently associated with diabetes when CTRP1 levels were analyzed by both as a continuous variable and quartile (OR: 1.009, 95% CI: 1.004-1.015, p < 0.05; OR: 2.443, 95% CI: 1.379-4.182, p < 0.01, respectively). Increased plasma CTRP1 was independently associated with type 2 diabetes. Profiling of plasma adipokines such as CTRP1 is particularly important to obtain a greater understanding of their contribution to the type 2 diabetic state.

Diabetes Mellitus Tipo 2/sangue , Proteínas/metabolismo , Adipocinas , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Glicemia , Índice de Massa Corporal , Feminino , Hemoglobina A Glicada/metabolismo , Homeostase , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fator de Necrose Tumoral alfa/sangue
J Membr Biol ; 222(3): 115-25, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18458804


The aim of this work was to investigate interactions of the human ether-a-go-go channel heag2 with human brain proteins. For this, we used heag2-GST fusion proteins in pull-down assays with brain proteins and mass spectrometry, as well as coimmunoprecipitation. We identified tubulin and heat shock 70 proteins as binding to intracellular C-terminal regions of the channel. To study functional effects, heag2 channels were expressed in Xenopus laevis oocytes for two-electrode voltage clamping. Coexpression of alpha-tubulin or the application of colchicine significantly prolonged channel activation times. Application at different times of colchicine gave similar results. The data suggest that colchicine application and tubulin expression do not affect heag2 trafficking and that tubulin may associate with the channel to cause functional effects. Coexpression of heat shock 70 proteins had no functional effect on the channel. The role of tubulin in the cell cytoskeleton suggests a link for the heag2 channel in tubulin-dependent physiological functions, such as cellular proliferation.

Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Sequência de Aminoácidos , Animais , Química Encefálica/fisiologia , Proteínas de Transporte de Cátions , Linhagem Celular , Colchicina/farmacologia , Canais de Potássio Éter-A-Go-Go/fisiologia , Glutationa Transferase/química , Glutationa Transferase/genética , Humanos , Dados de Sequência Molecular , Oócitos/química , Oócitos/metabolismo , Técnicas de Patch-Clamp , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Mapeamento de Interação de Proteínas , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tubulina (Proteína)/fisiologia , Moduladores de Tubulina/farmacologia , Xenopus laevis