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1.
Chem Soc Rev ; 45(16): 4552-66, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-26808300

RESUMO

Since the first discovery of carbocupration of alkynes in the 1970s a tremendous amount of research has been carried out in this field. The exceptionally high selectivities obtained attribute to the great synthetic value of carbocupration reactions. This tutorial review will present the most important features of carbocupration of alkynes and highlight the most relevant reviews. Then a comprehensive review of copper mediated carbometalation of cyclopropenes will follow. The latter method has received much attention over the last decade as it allows the highly selective construction of poly-substituted cyclopropanes which can be transformed into acyclic derivatives bearing one or multiple tertiary or quaternary carbon stereocenters.

2.
Biochim Biophys Acta ; 1852(5): 962-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25638293

RESUMO

We recently reported that deletion of the stress-regulated nuclear protein 1 (Nupr1) protected against obesity-associated metabolic alterations due to increased beta cell mass, but complete Nupr1 ablation was not advantageous since it led to insulin resistance on a normal diet. The current study used Nupr1 haplodeficient mice to investigate whether a partial reduction in Nupr1 expression conferred beneficial effects on glucose homeostasis. Islet number, morphology and area, assessed by immunofluorescence and morphometric analyses, were not altered in Nupr1 haplodeficient mice under normal diet conditions and nor was beta cell BrdU incorporation. Glucose and insulin tolerance tests indicated that there were no significant changes in in vivo insulin secretion and glucose clearance in Nupr1 haplodeficient mice, and beta cell function in vitro was normal. However, reduced Nupr1 expression decreased visceral fat deposition and significantly increased insulin sensitivity in vivo. In contrast to wild type animals, high fat diet-fed Nupr1 haplodeficient mice were not hyperinsulinaemic or glucose intolerant, and their sustained insulin sensitivity was demonstrated by appropriate insulin-induced Akt phosphorylation, as determined by Western blotting. At the molecular level, measurements of gene expression levels and promoter activities identified Nupr1-dependent inhibition of heat shock factor-1-induced heat shock protein 70 (Hsp70) expression as a mechanism through which Nupr1 regulates insulin sensitivity. We have shown for the first time that Nupr1 plays a central role in inhibiting Hsp70 expression in tissues regulating glucose homeostasis, and reductions in Nupr1 expression could be used to protect against the metabolic defects associated with obesity-induced insulin resistance.


Assuntos
Proteínas de Ligação a DNA/genética , Intolerância à Glucose/genética , Proteínas de Choque Térmico HSP70/genética , Resistência à Insulina/genética , Proteínas de Neoplasias/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Imuno-Histoquímica , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias/metabolismo , Fosforilação , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Regulação para Cima
3.
Diabetologia ; 54(5): 1109-20, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21301804

RESUMO

AIMS/HYPOTHESIS: Irs2, which is upregulated by glucose, is important for beta cell plasticity. Cyclic AMP response element-binding protein (CREB) stimulates beta cell Irs2 expression and is a major calcium/calmodulin-dependent kinase (CaMK)(IV) target in neurons. We therefore hypothesised that CaMK(IV) mediates glucose-induced Irs2 expression in beta cells via CREB activation. METHODS: The functions of CaMK(IV) and CREB were investigated in MIN6 beta cells and mouse islets using the CaMK inhibitor KN62, the calcium chelator bapta-(AM) and the voltage-dependent calcium channel inhibitor nifedipine. Small interfering RNAs were used to silence endogenous CaMK(IV) production and expression vectors to overproduce constitutively active and dominant negative forms of CaMK(IV) and CREB. Irs1 and Irs2 expression were determined by quantitative PCR and Western blotting, and the role of CREB was also investigated by assessing its phosphorylation on serine 133. RESULTS: Increasing the glucose concentration from 2.5 to 25 mmol/l stimulated CREB phosphorylation on serine 133 and specifically stimulated Irs2 but not Irs1 expression. Similarly, overproduction of a constitutively active form of CaMK(IV) promoted sustained CREB phosphorylation and a significant increase in Irs2 but not Irs1 expression. In contrast, these stimulatory effects of glucose were all suppressed by overproducing an inactive CaMK(IV) mutant. Inhibition of glucose-induced calcium influx with nifedipine or chelation of intracellular calcium with bapta-(AM), as well as silencing of CaMK(IV) or inhibition of its activity with KN62 resulted in similar observations. Finally, overproduction of a dominant negative form of CREB completely suppressed glucose and CaMK(IV) stimulation of Irs2 expression. CONCLUSIONS/INTERPRETATION: Our results suggest that the Ca(2+)/CaMK(IV)/CREB cascade plays a critical role in the regulation of Irs2 expression in beta cells.


Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glucose/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Animais , Western Blotting , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Técnicas In Vitro , Proteínas Substratos do Receptor de Insulina/genética , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Diabetologia ; 49(2): 321-31, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16416272

RESUMO

AIMS/HYPOTHESIS: This study aimed to identify the expression of angiotensin II receptors in isolated human islets and beta cells and to examine the functional consequences of their activation. MATERIALS AND METHODS: Single-cell RT-PCR was used to identify whether human islet cells express mRNA for type 1 angiotensin II receptors (AT(1)), and western blotting was used to determine AT(1) protein expression by human islets and MIN6 beta cells. We measured changes in intracellular calcium by microfluorimetry using Fura 2-loaded MIN6 cells and human islet cells. Dynamic insulin secretory responses were determined by RIA following perifusion of human islets and MIN6 cells. RESULTS: Human islets expressed mRNAs for both the angiotensin precursor, angiotensinogen, and for angiotensin-converting enzyme. In addition, human and mouse beta cells expressed AT(1). These were functionally coupled to increases in intracellular calcium, which occurred at least in part through phospholipase-C-sensitive mechanisms and calcium influx through voltage-operated calcium channels. Short-term exposure of human islets and MIN6 cells to angiotensin II caused a rapid, short-lived initiation of insulin secretion at 2 mmol/l glucose and potentiation of insulin secretion induced by glucose (at 8 and 16.7 mmol/l). CONCLUSIONS/INTERPRETATION: These data demonstrate that the AT(1) is expressed by beta cells and that angiotensin II effects a short-lived and direct stimulation of human and mouse beta cells to promote insulin secretion, most probably through elevations in intracellular calcium. Locally produced angiotensin II may be important in regulating a coordinated insulin secretory response from beta cells.


Assuntos
Angiotensina II/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Receptores de Angiotensina/fisiologia , Angiotensina Amida/farmacologia , Angiotensina II/fisiologia , Angiotensinogênio/genética , Angiotensinogênio/fisiologia , Animais , Western Blotting , Cálcio/análise , Linhagem Celular , Células Cultivadas , Fluorometria , Regulação da Expressão Gênica , Glucose/farmacologia , Humanos , Imidazóis/farmacologia , Secreção de Insulina , Células Secretoras de Insulina/química , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Camundongos , Nifedipino/farmacologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/fisiologia , Piridinas/farmacologia , RNA Mensageiro/análise , RNA Mensageiro/genética , Receptores de Angiotensina/análise , Receptores de Angiotensina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saralasina/farmacologia
5.
Ann Emerg Med ; 19(8): 922-4, 1990 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2372177

RESUMO

Abdominal aortic injuries secondary to blunt trauma are uncommon, particularly without associated visceral injury or external signs of localized trauma. Blunt trauma-induced abdominal aortic injuries most frequently result in intimal tearing. The most common mechanism is localized impact over the lower abdomen from sudden deceleration against a fixed object. We present the case of a patient with atheromatous plaque rupture in the distal abdominal aorta associated with acute aortoiliac occlusion as the result of a fall. Atherosclerotic disease may be present in young asymptomatic individuals and may be a predisposing factor for aortic intimal tearing. A high degree of suspicion and periodic reassessment of peripheral circulation in trauma patients are required to ensure early diagnosis of this injury.


Assuntos
Aorta Abdominal/lesões , Arteriosclerose/complicações , Artéria Ilíaca/lesões , Adulto , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/cirurgia , Ruptura Aórtica , Emergências , Humanos , Artéria Ilíaca/diagnóstico por imagem , Artéria Ilíaca/cirurgia , Isquemia/etiologia , Perna (Membro)/irrigação sanguínea , Masculino , Radiografia
6.
Immunobiology ; 166(4-5): 494-9, 1984 May.
Artigo em Inglês | MEDLINE | ID: mdl-6434405

RESUMO

Mitogen-induced interferon production in peripheral blood lymphocytes from patients with colorectal tumors was not significantly different from that observed in patients with Crohn's disease and sex- and age-matched controls. In the group of patients with colorectal carcinomas, no correlation was obtained with regard to the interferon titer, the in vivo lymphocyte proliferation and the clinical stage of the disease or tumor staging and grading respectively. Most importantly, the data show that despite an obvious defect in T-lymphocyte proliferation, measurement of lymphokine production in mitogen-stimulated cell cultures was not impaired.


Assuntos
Neoplasias do Colo/imunologia , Interferon gama/biossíntese , Neoplasias Retais/imunologia , Humanos , Ativação Linfocitária , Pessoa de Meia-Idade , Mitógenos/farmacologia , Linfócitos T/imunologia
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