Vias de Sinalização da Insulina

Insulin is an anabolic hormone with powerful metabolic effects. The events after insulin binds to its receptor are highly regulated and specific. Defining the key steps that lead to the specificity in insulin signaling presents a major challenge to biochemical research, but the outcome should offer new therapeutic approaches for treatment of patients suffering from insulin-resistant states, including type 2 diabetes. The insulin receptor belongs to the large family of growth factor receptors with intrinsic tyrosine kinase activity. Following insulin binding, the receptor undergoes autophosphorylation on multiple tyrosine residues. This results in activation of the receptor kinase and tyrosine phosphorylation of a family of insulin receptor substrate (IRS) proteins. Like other growth factors, insulin uses phosphorylation and the resultant protein-protein interactions as essential tools to transmit and compartmentalize its signal. These intracellular protein-protein interactions are pivotal in transmitting the signal from the receptor to the final cellular effect, such as translocation of vesicles containing GLUT4 glucose transporters from the intracellular pool to the plasma membrane, activation of glycogen or protein synthesis, and initiation of specific gene transcription.A insulina é um hormônio anabólico com efeitos metabólicos potentes. Os eventos que ocorrem após a ligação da insulina são específicos e estritamente regulados. Definir as etapas que levam à especificidade deste sinal representa um desafio para as pesquisas bioquímicas, todavia podem resultar no desenvolvimento de novas abordagens terapêuticas para pacientes que sofrem de estados de resistência à insulina, inclusive o diabetes tipo 2. O receptor de insulina pertence a uma família de receptores de fatores de crescimento que têm atividade tirosina quinase intrínseca. Após a ligação da insulina o receptor sofre autofosforilação em múltiplos resíduos de tirosina. Isto resulta na ativação da quinase do receptor e conseqüente fosforilação em tirosina de um a família de substratos do receptor de insulina (IRS). De forma similar a outros fatores de crescimento, a insulina usa fosforilação e interações proteína-proteína como ferramentas essenciais para transmitir o sinal. Estas interações proteína-proteína são fundamentais para transmitir o sinal do receptor em direção ao efeito celular final, tais como translocação de vesículas contendo transportadores de glicose (GLUT4) do pool intracelular para a membrana plasmática, ativação da síntese de glicogênio e de proteínas, e transcrição de genes específicos.41942

An Eye for Possibilities in the Development of Children with Cerebral Palsy: Neurobiology and Neuropsychology in a Cultural-Historical Dynamic Understanding

Taking children with Cerebral Palsy (CP) as an example, the article seeks an understanding ofchildren with disabilities that connects neuropsychological theories of neural development withthe situated cognition perspective and the child as an active participant in its social practices. Theearly brain lesion of CP is reconceptualised as a neurobiological constraint that exists in therelations between the neural, cognitive and social levels. Through a multi-method study of twochildren with CP, it is analysed how neurobiological constraints arise, evolve and sometimes areresolved through local matches between the child and its social practices. The result is discussedas support of a developmental science approach that includes processes at the social practice levelalong with knowledge of biological processes

Defective Insulin And Acetylcholine Induction Of Endothelial Cell-nitric Oxide Synthase Through Insulin Receptor Substrate/akt Signaling Pathway In Aorta Of Obese Rats.

The actions of acetylcholine (ACh) on endothelium mainly are mediated through muscarinic receptors, which are members of the G protein-coupled receptor family. In the present study, we show that ACh induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS.561014-2

Rapid, low-cost MR imaging protocol to document central nervous system and sinus abnormalities prior to pediatric hematopoietic stem cell transplantation

Patients undergoing bone marrow transplant (BMT) are at risk for infectious complications, including those of the sinus. Central nervous system (CNS) abnormalities related to the chemotherapy or radiation that the patient received for the treatment of underlying malignancy or to transplant-related effects are also commonly seen. the only effective way to differentiate pre- and post-transplant causes is to have a baseline evaluation prior to the admission for transplant. the current method used to evaluate these patients is head CT. However, CT is not accurate to demonstrate CNS abnormalities and exposes the patient to radiation. MRI, despite better sensitivity for white matter abnormalities, has not been routinely used because of the higher cost and longer duration of the exam. Therefore, we designed a fast, low-cost and radiation-free MRI-based protocol to simultaneously evaluate sinus and brain abnormalities.Universidade Federal de São Paulo, Dept Diagnost Imaging, BR-04038002 São Paulo, BrazilUniversidade Federal de São Paulo, Div Pediat Oncol, Dept Pediat, BR-04038002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Diagnost Imaging, BR-04038002 São Paulo, BrazilUniversidade Federal de São Paulo, Div Pediat Oncol, Dept Pediat, BR-04038002 São Paulo, BrazilWeb of Scienc