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BACKGROUND: The effects of brain natriuretic peptide (BNP) on the risk of cardiovascular disease and atherosclerosis have been studied. However, little information is available regarding peripheral arterial disease (PAD), particularly among subjects with type-2 diabetes mellitus (T2DM). The aim of our study was to assess the potential relationship between BNP levels and PAD among T2DM patients. METHODS: The study cohort was 507 T2DM outpatients in which BNP levels were measured. Cross-sectional associations between BNP levels (in tertiles) and PAD were examined. RESULTS: Compared withT2DM patients without PAD, BNP levels were markedly higher in patients with PAD (p = 0.001). Correlation analyses showed that the BNP level was negatively correlated with the ankle-brachial index (r = -0.453, p = 0.033). At a cutoff value of 78.2 pg/ml, the BNP level showed a sensitivity of 71.9%, a specificity of 68.1%, and a positive predictive value of 84.3% for a diagnosis of PAD. The area under the receiver-operating characteristic curve increased significantly if BNP levels were incorporated into a predictive model of the potential risk factors for PAD (0.85 vs 0.81, p = 0.029). CONCLUSIONS: BNP is a potential and promising biomarker for PAD screening in T2DM patients.
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The identification of factors that promote ß cell proliferation could ultimately move type 1 diabetes treatment away from insulin injection therapy and toward a cure. We have performed high-throughput, cell-based screens using rodent ß cell lines to identify molecules that induce proliferation of ß cells. Herein we report the discovery and characterization of WS6, a novel small molecule that promotes ß cell proliferation in rodent and human primary islets. In the RIP-DTA mouse model of ß cell ablation, WS6 normalized blood glucose and induced concomitant increases in ß cell proliferation and ß cell number. Affinity pulldown and kinase profiling studies implicate Erb3 binding protein-1 and the IκB kinase pathway in the mechanism of action of WS6.
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Ensaios de Triagem em Larga Escala , Ilhotas Pancreáticas/efeitos dos fármacos , Ureia/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Ilhotas Pancreáticas/citologia , Camundongos , Estrutura Molecular , Peso Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
OBJECTIVE: To explore the relationship between sleep quality and glucose level, diabetic complications in elderly type 2 diabetes mellitus. METHODS: A total of 130 hospitalized elderly type 2 diabetes in our hospital were included in the study. Questionnaires and other related clinical data were collected within one week after admission. Patients were divided into two groups: poor-sleeper group and good-sleeper group according to Pittsburgh Sleep Quality Index (PSQI). RESULTS: Sixty percent (78/130) of these patients were poor sleepers. The following parameters differed in the two groups: the duration of diabetes [(7.9 ± 1.8) years vs (7.2 ± 1.5) years, t = 2.318], systolic blood pressure [(148 ± 30) mm Hg (1 mm Hg = 0.133 kPa) vs (138 ± 23) mm Hg, t = 2.037], fasting plasma glucose (FPG) [(10.7 ± 2.2) mmol/L vs (9.8 ± 1.9) mmol/L, t = 2.410], hemoglobin A1c (HbA1c) [(8.6 ± 2.2)% vs (7.8 ± 2.1)%, t = 2.068], high-sensitive C-reactive protein (hs-CRP) [(5.27 ± 2.34) mg/L vs (4.44 ± 1.76) mg/L, t = 2.179], ratio of diabetic complications (61% vs 32%, χ(2) = 4.257), percentage of depression (20% vs 8%, χ(2) = 3.722), score of life quality [(98 ± 19) scores vs (89 ± 13) scores, t = 2.980], and proportion of patients treated with insulin (32% vs 12%, χ(2) = 4.489). All the above parameters were significantly higher in poor-sleeper group than the good-sleeper group (all P value < 0.05). Multiple correlation analysis showed that the factors affecting sleep quality were FPG, HbA1c, duration of diabetes, diabetic complications, depression, life quality and insulin application (r = 0.213, 0.257, 0.223, 0.335, 0.422, 0.3451, 0.231, respectively; all P value < 0.05). By multivariate logistic regression analysis, the followings were found: FPG (ß = 1.29, P < 0.05) and PSQI (ß = 1.07, P < 0.05) were found to be correlated with HbA1c. With increasing of PSQI, FPG, HbA1c, diabetic complications and life quality were changed significantly (all P value < 0.05). The independent risk factors of diabetic complications were duration of diabetes (OR = 1.32, 95%CI 1.01 - 2.01), HbA1c (OR = 2.01, 95%CI 1.63 - 2.67), hs-CRP (OR = 1.12, 95%CI 1.08 - 1.21) and PSQI (OR = 1.71, 95%CI 1.58 - 2.02). CONCLUSIONS: Elderly type 2 diabetes mellitus are usually poor sleepers. Sleep quality probably affects blood glucose regulation, and is closely correlated with the occurrence of complications. In addition, poor sleep quality results in poor life quality.
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Glicemia , Diabetes Mellitus Tipo 2/complicações , Sono , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Qualidade de Vida , Fatores de RiscoRESUMO
Curcumin (CUR) is well known for its anti-inflammatory and antioxidant effects. However, the endothelial protective effect of CUR in diabetes and the underlying signaling pathway remains unclear. The goal of the current study was to provide evidence regarding the protective mechanism of CUR against the high glucose (HG)-induced damage to human umbilical vein endothelial cells (HUVECs). HG-induced HUVECs injury model was used to evaluate the protective effect and the underlying mechanism of CUR against endothelial injury. The cell viability was determined by the MTT method. The cell reactive oxygen species (ROS) were determined by using flow cytometry. The protein expression levels of Bcl-2, Bax, LC3-II/I, Beclin-1, p62, cleaved caspase-3, IκBα and NF-κB were measured by the western blotting. Results showed that CUR significantly decreased the cell apoptosis, the ROS generation and the inflammatory cytokine NF-κB activity in the HG-induced HUVECs versus the control, P<0.05. In addition, CUR significantly increased the expressions of LC3-II/I, Beclin-1, IκBα and Bax/Bcl-2 in the HG-induced HUVECs versus the control, P<0.05. Furthermore, the addition of autophagy inhibitor 3-MA impaired the autophagy, exacerbated the apoptotic death and increased the ROS and NF-κB levels in HUVECs under the high glucose condition, P<0.05. In brief, autophagy served a protective role in the HG-induced apoptosis in HUVECs and CUR alleviated apoptosis by promoting autophagy and inhibiting the ROS/NF-κB signaling pathway.
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OBJECTIVE: To explore the relationship between fasting plasma level of total homocysteine (tHcy) and mild cognitive impairment in senile patients with type 2 diabetes mellitus. METHODS: A total of 88 senile type 2 diabetics with mild cognitive impairment treated at our hospital from July 2008 to November 2010 were recruited into the MCI group while 52 senile type 2 diabetics into the DNC group. And the control group was composed of 36 healthy elders. The parameters of tHcy, total glyceride (TG), total cholesterol (TC), low density lipoprotein-C (LDL-C), high density lipoprotein-C (HDL-C), creatinine (Cr), hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), 2 h plasma glucose (2 hPG), fasting insulin (FINS), homeostasis model of insulin resistance (HOMA-IR), folic acid (FA) and vitamin B(12) (VitB(12)) were detected. RESULTS: The patients had a higher level of tHcy in the MCI group than those in the NCM and control groups [(11.3 ± 1.8) vs (9.8 ± 1.5) and (8.1 ± 1.1) µmol/L; P < 0.01]. ROC curve showed that tHcy level had some value of predicting the occurrence of mild cognitive impairment in senile patients with type 2 diabetes mellitus (AUC 0.825, 95%CI 0.758-0.893, P < 0.01). Logistic regression analysis showed that tHcy, SBP, HbA1c, 2 h PG, FINS, LDL-C, HOMA-IR, FA and VitB(12) [OR value: 3.64, 1.68, 1.10, 1.05, 0.81, 1.42, 0.83, 0.74, 0.86 (P < 0.05 or 0.01)] were independent risk factors of mild cognitive impairment in senile diabetic patients. CONCLUSION: Such factors as tHcy, SBP, HbA1c, FPG, 2 hPG, FINS, LDL-C, HOMA-IR, FA and VitB(12) induce senile patients with type 2 diabetes mellitus to suffer mild cognitive impairment. But tHcy level may play an important role in senile diabetic patients with mild cognitive impairment.
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Transtornos Cognitivos/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/psicologia , Homocisteína/sangue , Idoso , Feminino , Hemoglobinas Glicadas/análise , Humanos , Insulina/sangue , Resistência à Insulina , MasculinoRESUMO
The hepatocyte is a highly polarized cell with a heterogeneous distribution of plasma-membrane (PM) proteins. To reduce the complexity of the proteome of liver tissue and give a comprehensive profile of hepatocyte PM, two PM purification methods based on cell surface modification, named the biotin-avidin (BA) and cationic silica-polyanion (CSP) strategies were evaluated and compared with the traditional cell fractionation method to prepare highly enriched PM from freshly isolated C57 mouse hepatocytes. Employing different principles for PM modification, both methods were effective in the isolation of general and purified PM fraction. The CSP strategy showed better yield for the PM purification from freshly isolated hepatocytes. 189 non-redundant proteins were identified, including 49 from the BA method and 185 from CSP strategy. Many known and novel PM-associated proteins were also found. Our evaluation here should give implications for PM preparation from other freshly isolated tissue-derived cells. The hepatocyte PM proteins identified here should be taken as a references for the PM-related functional and diseases research.
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Fracionamento Celular/métodos , Membrana Celular/química , Hepatócitos/citologia , Proteoma/análise , Proteômica/métodos , Animais , Avidina/química , Membrana Celular/metabolismo , Eletroforese em Gel de Poliacrilamida , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Dióxido de Silício/químicaRESUMO
AIM: To explore the effect of neferine on angiotensin II (Ang II)-induced vascular smooth muscle cell (VSMC) proliferation. METHODS: Human umbilical vein smooth muscle cells (HUVSMCs) were used. Cell proliferation was determined by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis. Heme oxygenase (HO)-1 protein expression was tested by Western blot analysis. Extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation was determined by using immunoblotting. RESULTS: Pre-incubation of HUVSMCs with neferine (0.1, 0.5, 1.0, and 5.0 micromol/L) significantly inhibited Ang II-induced cell proliferation in a concentration-dependent manner and neferine 5.0 micromol/L increased HO-1 expression by 259% compared with control. The antiproliferative effect of neferine was significantly attenuated by coapplication of zinc protoporphyrin IX (ZnPP IX, an HO-1 inhibitor) with neferine. Ang II-enhanced ERK1/2 phosphorylation was markedly reversed by neferine. By inhibiting HO-1 activity with ZnPP IX, the inhibitive effect of neferine on ERK1/2 phosphorylation was significantly attenuated. Cobalt-protoporphyrin (CoPP), an HO-1 inducer, significantly decreased Ang II-induced ERK1/2 phosphorylation and inhibited Ang II-induced cell proliferation. The ERK1/2 pathway inhibitor PD98059 significantly blocked Ang II-enhanced ERK1/2 phosphorylation and inhibited cell proliferation. CONCLUSION: These findings suggest that neferine can inhibit Ang II-induced HUVSMC proliferation by upregulating HO-1, leading to the at least partial downregulation of ERK1/2 phosphorylation.
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Angiotensina II/farmacologia , Benzilisoquinolinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Western Blotting , Cardiotônicos/farmacologia , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologiaRESUMO
Myocardial infarction and following reperfusion therapy-induced myocardial ischemia/reperfusion (I/R) injury have been recognized as an important subject of cardiovascular disease with high mortality. As the antiarrhythmic agent, Wenxin Granule (WXG) is widely used to arrhythmia and heart failure. In our pilot study, we found the antioxidative potential of WXG in the treatment of myocardial I/R. This study is aimed at investigating whether WXG could treat cardiomyocyte hypoxia/reoxygenation (H/R) injury by inhibiting oxidative stress in mitochondria. The H9c2 cardiomyocyte cell line was subject to H/R stimuli to mimic I/R injury in vitro. WXG was added to the culture medium 24 h before H/R exposing as pretreatment. Protein kinase C-δ (PKC-δ) inhibitor rottlerin or PKC-δ lentivirus vectors were conducted on H9c2 cells to downregulate or overexpress PKC-δ protein. Then, the cell viability, oxidative stress levels, intracellular and mitochondrial ROS levels, mitochondrial function, and apoptosis index were analyzed. In addition, PKC-δ protein expression in each group was verified by western blot analysis. Compared with the control group, the PKC-δ protein level was significantly increased in the H/R group, which was remarkably improved by WXG or rottlerin. PKC-δ lentivirus vector-mediated PKC-δ overexpression was not reduced by WXG. WXG significantly improved H/R-induced cell injury, lower levels of SOD and GSH/GSSG ratio, higher levels of MDA, intracellular and mitochondrial ROS content, mitochondrial membrane potential and ATP loss, mitochondrial permeability transition pore opening, NOX2 activation, cytochrome C release, Bax/Bcl-2 ratio and cleaved caspase-3 increasing, and cell apoptosis. Similar findings were obtained from rottlerin treatment. However, the protective effects of WXG were abolished by PKC-δ overexpression, indicating that PKC-δ was a potential target of WXG treatment. Our findings demonstrated a novel mechanism by which WXG attenuated oxidative stress and mitochondrial dysfunction of H9c2 cells induced by H/R stimulation via inhibitory regulation of PKC-δ/NOX2/ROS signaling.
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Medicamentos de Ervas Chinesas/farmacologia , Mitocôndrias/metabolismo , NADPH Oxidase 2/metabolismo , Estresse Oxidativo , Oxigênio/metabolismo , Proteína Quinase C-delta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Loss of ß-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase ß-cell mass are less developed. Promoting ß-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring ß-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3ß (GSK3ß) was previously reported to induce primary human ß-cell proliferation inâ vitro and inâ vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring ß-cell proliferation.
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Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Células Secretoras de Insulina/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Relação Estrutura-Atividade , Quinases DyrkRESUMO
Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).
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Compostos Aza/química , Compostos Aza/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Indóis/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Compostos Aza/farmacocinética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Indóis/farmacocinética , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Quinases DyrkRESUMO
To investigate the heterogeneous protein composition of highly polarized hepatocyte plasma membrane (PM), three PM-associated subfractions were obtained from freshly isolated rat hepatocytes using density gradient centrifugation. The origins of the three subfractions were determined by morphological analysis and western blotting. The proteins were subjected to either one-dimensional (1-D) SDS-PAGE or two-dimensional (2-D) benzyldimethyl-n-hexadecylammonium chloride (BAC)/SDS-PAGE before nano-Liquid Chromatography-Electrospray Ionization--tandem mass spectrometry analysis (LC-ESI-MS/MS). A total of 613 non-redundant proteins were identified, among which 371 (60.5%) proteins were classified as PM or membrane-associated proteins according to GO annotations and the literatures and 32.4% had transmembrane domains. PM proteins from microsomal portion possessed the highest percentage of transmembrane domain, about 46.5% of them containing at least one transmembrane domain. In addition to proteins known to be located at polarized liver PM regions, such as asialoglycoprotein receptor 2, desmoplakin and bile salt export pump, several proteins which had the potential to become novel subfraction-specific proteins were also identified, such as annexin a6, pannexin and radixin. Our analysis also evaluated the application of 1-D SDS-PAGE and 2-D 16-BAC/SDS-PAGE on the separation of integral membrane proteins.
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Membrana Celular/metabolismo , Hepatócitos/citologia , Proteínas de Membrana/metabolismo , Proteômica/métodos , Animais , Carbonatos/farmacologia , Cromatografia Líquida/métodos , Biologia Computacional/métodos , Eletroforese em Gel de Poliacrilamida , Hepatócitos/metabolismo , Espectrometria de Massas/métodos , Estrutura Terciária de Proteína , Ratos , Espectrometria de Massas por Ionização por Electrospray , Frações Subcelulares/metabolismoRESUMO
Our research groups recently described a series of small-molecule inducers of ß-cell proliferation that could be used to increase ß-cell mass. To mitigate the risk of nonspecific proliferation of other cell types, we devised a delivery strategy built on the tissue specificity observed in the experimental ß-cell imaging agent (+)-dihydrotetrabenazine (DTBZ). The ß-cell proliferator agent aminopyrazine (AP) was covalently linked with (+)-DTBZ to afford conjugates that retain both the proliferation activity and binding affinity for vesicular monoamine transporter-2 (VMAT2). Inâ vivo mouse tissue distribution studies of a prototypical AP-DTBZ conjugate showed 15-fold pancreas exposure over plasma. Tissue-to-plasma ratios in liver and kidneys were two- and five-fold, respectively. This work is the first demonstration of enhanced delivery of ß-cell-proliferating molecules to the pancreas by leveraging the intrinsic tissue specificity of a ß-cell imaging agent.
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Pâncreas/metabolismo , Tetrabenazina/análogos & derivados , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos/química , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Rim/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Piridazinas/química , Coelhos , Espectrometria de Massas em Tandem , Tetrabenazina/sangue , Tetrabenazina/química , Tetrabenazina/metabolismo , Tetrabenazina/farmacologia , Distribuição Tecidual , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
[reaction: see text] Dirhodium tetrakis((S)-N-dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4) catalyzed reaction of 1,2-dihydronaphthalenes with an excess of methyl vinyldiazoacetates results in a formal double C-H activation, generating four new stereogenic centers with very high stereoselectivity. The mechanism of the C-H activation is complex, involving a combined C-H activation/Cope rearrangement followed by a retro-Cope rearrangement.
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Naftalenos/química , Compostos Organometálicos/química , Prolina/análogos & derivados , Catálise , Compostos de Diazônio/química , Estrutura Molecular , Prolina/química , EstereoisomerismoRESUMO
Insufficient pancreatic ß-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from ß-cells in diabetic patients, no pharmacological agents have been described that increase ß-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust ß-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces ß-cell proliferation, increases ß-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore ß-cell mass, and highlights a tractable pathway for future drug discovery efforts.
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Proliferação de Células , Quinase 3 da Glicogênio Sintase/genética , Células Secretoras de Insulina/citologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Regulação para Baixo/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/enzimologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Piridazinas/farmacologia , Quinases DyrkRESUMO
Rh(2)(S-DOSP)(4)-catalyzed C-H activation to N,N-dimethylanilines is described. A double C-H activation was possible by using an excess of methyl aryldiazoacetate, and this provided a very direct approach to C(2)-symmetric anilines. [reaction--see text]
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BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are thought to be associated with increased mortality in elderly patients. Low retinol-binding protein-4 (RBP4) is associated with a high risk of respiratory infections in the general population. Therefore, we hypothesized that low RBP4 levels are associated with an increased risk of AECOPD and can be used as a biomarker for AECOPD in elderly patients. METHODS: Enzyme-linked immunosorbent assays were used to assess RBP4 levels in elderly with AECOPD within the first 24 hours after intensive care unit admission. Forty-six elderly patients with stable COPD in outpatient clinics and 50 healthy elderly persons who had physical examinations as outpatients were controls. RESULTS: In AECOPD patients, RBP4 levels were lower than those in stable COPD patients and healthy controls (59.7 vs 91.2 and 113.6 mg/L, p < 0.001). RBP4 levels were decreased by 30.6% in non-survivors compared with survivors (51.5 vs 74.2 mg/L, p < 0.001). A higher Acute Physiology and Chronic Health Enquiry II (APACHE II) score and Simplified Acute Physiology score (SAPS II) were associated with lower RBP4 levels (r = -0.692, p = 0.024 and r = -0.670, p = 0.015, respectively). RBP4 was positively correlated with creatinine and body mass index, and negatively correlated with C-reactive protein and Global Initiative for Chronic Obstructive Lung Disease stage. Multivariate logistic regression showed that RBP4 was an independent mortality predictor of AECOPD (odds ratio: 0.926, p = 0.007). Analysis of the area under the receiver operating characteristic (AUC) curve showed that RBP4 showed good discrimination (AUC: 0.88; 95% confidence interval: 0.78-0.94; p = 0.008) in predicting mortality. RBP4 improved the prognostic accuracy of mortality for the APACHE II and SAPS II scores. CONCLUSIONS: Serum RBP4 levels are significantly reduced in elderly AECOPD patients. RBP4 might be a good predictive biomarker for mortality in elderly AECOPD patients in the intensive care unit.
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BACKGROUND: Diabetes mellitus is associated with many kinds of complications. Recent studies have shown that oxidative stress and inflammatory reactions have critical roles in the pathogenesis of diabetic gastroparesis. Curcumin is known to have antioxidant and anti-inflammatory properties. In the present study, we investigated the effect of curcumin on diabetic gastric motility in a Sprague Dawley rat model of type 1 diabetes mellitus. METHODS: Male SD rats were divided into a control group, a control group receiving curcumin, a diabetic group, and a diabetic group receiving curcumin. Diabetes was induced by intraperitoneal injection of streptozotocin. Curcumin (150 mg/kg) was given intragastrically for 6 weeks, and blood glucose levels and body weights were measured. Stomachs were excised for analysis of gastric emptying rates, and levels of oxidative stress. NF-κB, I-κB, and stem cell factor (SCF)/c-kit protein levels were assessed by western blot analysis, while the apoptosis of interstitial cells of Cajal (ICCs) was assessed by TUNEL staining. RESULTS: Curcumin-treated diabetic rats showed significantly improved gastric emptying rates [(59.4 ± 7.5)%] compared with diabetic rats [(44.3 ± 5.7)%], as well as decreased levels of MDA [21.4 ± 1.8 (nmol/mg) vs 27.9 ± 2.1 (nmol/mg)], and increased SOD activity [126.2 ± 8.8 (units/mg) vs 107.9 ± 7.5 (units/mg)]. On the other hand, the gastric emptying level in the control group was not significantly different from that in the control group receiving curcumin treatment. In addition, curcumin-treated diabetic rats showed significantly increased levels of SCF/c-kit protein in stomach tissues, inhibited I-κB degradation and NF-κB activation, and reduced ICC apoptosis index [(26.2 ± 4.1)% vs (47.5 ± 6.2)%], compared with the diabetic group. CONCLUSION: Curcumin treatment improved gastric emptying by blocking the production of oxidative stress, abolishing NF-κB signal transduction and enhancing expression of SCF/c-kit in rats with diabetic gastroparesis.
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Excessive caloric intake is a contributing risk factor for human metabolic disorders. Caloric restriction may prolong a person's life by lowering the incidence of deadly diseases. Reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMC) have been associated with the biochemical basis of the relationship between caloric intake and pathophysiologic processes. Polymorphisms associated with ROS generation genes are being increasingly implicated in inter-individual responses to daily caloric intake alterations. In the current study, a single nucleotide polymorphism, rs1836882, in the nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) gene's promoter region was found to modulate associations between dietary caloric intake and ROS levels in PBMC. Based on rs1836882, 656 Chinese Han participants were classified into CC, CT and TT genotypes. ROS levels in PBMC were significantly higher in the CC or CT genotypes compared with the TT genotype with the same increases in daily caloric intake. Using an electrophoretic mobility shift assay, NOX4 promoter region with rs1836882 (T) was observed to have a higher affinity for hepatocyte nuclear factor gamma (HNF3γ) protein than rs1836882 (C). HNF3γ protein over-expression decreased NOX4 gene transcriptional activity in the TT genotype more than in the CC genotype (5.68% vs. 2.12%, P<0.05) in a dual luciferase reporter assay. By silencing the NOX4 gene using small interfering RNA or over-expressing HNF3γ using an expression plasmid, serum from high dietary caloric intake participants decreased ROS levels in PBMC of the TT genotype more than in the CC or CT genotype via HNF3γ down-regulating the NOX4 gene expression signaling pathway. This is the first study to report on the functions of phenotypes of rs1836882 in the NOX4 gene, and it suggests rs1836882 as a candidate gene for interpreting inter-individual ROS levels differences in PBMC induced by alterations in daily caloric intake.
Assuntos
Dieta , Ingestão de Energia/genética , Leucócitos Mononucleares/metabolismo , NADPH Oxidases/genética , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio/sangue , Adulto , Regulação para Baixo/genética , Feminino , Fator 3-gama Nuclear de Hepatócito/genética , Humanos , Masculino , Pessoa de Meia-Idade , NADPH Oxidase 4 , Regiões Promotoras Genéticas/genética , Transcrição Gênica/genéticaRESUMO
BACKGROUND: Plasma galectin-3, a mediator of fibrogenesis and inflammation, its potential to associate with type 2 diabetes (T2DM) is poorly investigated. Here, we explored its interaction with the serum galectin-3 and vascular complications. METHODS: We conducted a population-based cross-sectional survey in Zhejiang, China involving 165 men and 119 women (age range, 43 - 84 years), investigating the relationship between serum galectin-3 and vascular disease in patients with T2DM. RESULTS: Serum galectin-3 was higher in subjects with T2DM than that in control participants (27.4 vs. 17.6 ng/ml, P < 0.001). Compared with subjects with galectin-3 values in the lowest quartile, those with values in the highest quartile had an increased likelihood of vascular complications (4th quartile odds ratio (OR) 2.52, 95% confidence interval (CI), 1.25 - 4.07). Increased risk of micro- or macrovascular complications correlated with serum galectin-3 concentration (ORs 11.4 and 8.5, respectively). An increased number of vascular complications was associated with high serum galectin-3 levels (P < 0.05). Patients with serum galectin-3 levels > 25 ng/ml had an elevated risk of diabetes relative to patients with levels < 10 ng/ml (OR for any vascular complication 2.64, for heart failure 3.97, for nephropathy 4.09, for peripheral arterial disease (PAD) 4.18; all P < 0.05). Complication risk was higher in patients with neurogenic, stroke, or retinopathy complications, but this difference was not significant after risk factor adjustment. Serum galectin-3 levels correlated with diabetes duration, C-reactive protein (CRP) levels, and albuminuria. CONCLUSION: High galectin-3 values were associated with increased odds of developing heart failure, nephropathy, and peripheral arterial disease in patients with T2DM.