排序方式: 共有31条查询结果,搜索用时 15 毫秒
1.
Carpentier A Taghibiglou C Leung N Szeto L Van Iderstine SC Uffelman KD Buckingham R Adeli K Lewis GF 《The Journal of biological chemistry》2002,277(32):28795-28802
To determine whether reduction of insulin resistance could ameliorate fructose-induced very low density lipoprotein (VLDL) oversecretion and to explore the mechanism of this effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted insulin-mediated suppression of the glucose production rate and to a approximately 2-fold increase in whole body insulin-mediated glucose disappearance rate (p < 0.001). Rosiglitazone ameliorated the defect in hepatocyte insulin-stimulated tyrosine phosphorylation of the insulin receptor, IRS-1, and IRS-2 and the reduced protein mass of IRS-1 and IRS-2 induced by fructose feeding. Protein-tyrosine phosphatase 1B levels were increased with fructose feeding and were markedly reduced by rosiglitazone. Rosiglitazone treatment led to a approximately 50% reduction of VLDL secretion rates (p < 0.05) in vivo and ex vivo. VLDL clearance assessed directly in vivo was not significantly different in the FR (fructose-fed + rosiglitazone-treated) versus F (fructose-fed + placebo-treated) hamsters, although there was a trend toward a lower clearance with rosiglitazone. Enhanced stability of nascent apolipoprotein B (apoB) in fructose-fed hepatocytes was evident, and rosiglitazone treatment resulted in a significant reduction in apoB stability. The increase in intracellular mass of microsomal triglyceride transfer protein seen with fructose feeding was reduced by treatment with rosiglitazone. In conclusion, improvement of hepatic insulin signaling with rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, is associated with reduced hepatic VLDL assembly and secretion due to reduced intracellular apoB stability. 相似文献
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Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease 总被引:1,自引:0,他引:1
El Khoury J Toft M Hickman SE Means TK Terada K Geula C Luster AD 《Nature medicine》2007,13(4):432-438
Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-beta (Abeta), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance. 相似文献
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LTP inhibits LTD in the hippocampus via regulation of GSK3beta 总被引:2,自引:0,他引:2
Peineau S Taghibiglou C Bradley C Wong TP Liu L Lu J Lo E Wu D Saule E Bouschet T Matthews P Isaac JT Bortolotto ZA Wang YT Collingridge GL 《Neuron》2007,53(5):703-717
Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information. 相似文献
4.
Mielke JG Taghibiglou C Liu L Zhang Y Jia Z Adeli K Wang YT 《Journal of neurochemistry》2005,93(6):1568-1578
While considerable research has examined diminished insulin responses within peripheral tissues, comparatively little has been done to examine the effects of this metabolic disruption upon the CNS. The present study employed biochemical and electrophysiological assays of acutely prepared brain slices to determine whether neural insulin resistance is a component of the metabolic syndrome observed within the fructose-fed (FF) hamster. The tyrosine phosphorylation levels of the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) in response to insulin were significantly reduced within FF hamsters. Also, insulin-mediated phosphorylation of both residues necessary for activation of the serine-threonine kinase Akt/PKB, a key effector of insulin signaling, was markedly decreased. Elevated levels of the protein tyrosine phosphatase 1B, which dephosphorylates the IR and IRS-1, were also observed within the cerebral cortex and hippocampus of FF hamsters. Examination of whether a nutritionally induced compromise of neural insulin signaling altered synaptic function revealed a significant attenuation of insulin-induced long-term depression, but no effect upon either paired-pulse facilitation or electrically induced long-term potentiation. Collectively, our results demonstrate, for the first time, that nutritionally induced insulin resistance significantly affects the neural insulin signaling pathway, and suggest that brain insulin resistance may contribute to cognitive impairment. 相似文献
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Changiz Geula Sara R. Dunlop Ivan Ayala Allegra S. Kawles Margaret E. Flanagan Tamar Gefen Marek-Marsel Mesulam 《Journal of neurochemistry》2021,158(6):1394-1411
7.
Sport-related mild traumatic brain injury (mTBI) or concussion is a significant health concern to athletes with potential long-term consequences. The diagnosis of sport concussion and return to sport decision making is one of the greatest challenges facing health care clinicians working in sports. Blood biomarkers have recently demonstrated their potential in assisting the detection of brain injury particularly, in those cases with no obvious physical injury. We have recently discovered plasma soluble cellular prion protein (PrPC) as a potential reliable biomarker for blast induced TBI (bTBI) in a rodent animal model. In order to explore the application of this novel TBI biomarker to sport-related concussion, we conducted a pilot study at the University of Saskatchewan (U of S) by recruiting athlete and non-athlete 18 to 30 year-old students. Using a modified quantitative ELISA method, we first established normal values for the plasma soluble PrPC in male and female students. The measured plasma soluble PrPC in confirmed concussion cases demonstrated a significant elevation of this analyte in post-concussion samples. Data collected from our pilot study indicates that the plasma soluble PrPC is a potential biomarker for sport-related concussion, which may be further developed into a clinical diagnostic tool to assist clinicians in the assessment of sport concussion and return-to-play decision making. 相似文献
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The purpose of this article is to introduce a novel model for discriminating correctly folded proteins from well designed decoy structures using mechanical interatomic forces. In our model, we consider a protein as a collection of springs and the force imposed to each atom is calculated. A potential function is obtained from statistical contact preferences within known protein structures. Combining this function with the spring equation, the interatomic forces are calculated. Finally, we consider a structure and define a score function on the 3D structure of a protein. We compare the force imposed to each atom of a protein with the corresponding atom in the other structures. We then assign larger scores to those atoms with lower forces. The total score is the sum of partial scores of atoms. The optimal structure is assumed to be the one with the highest score in the data set. To evaluate the performance of our model, we apply it on several decoy sets. Proteins 2009. © 2009 Wiley‐Liss, Inc. 相似文献
10.
Wang Y Ju W Liu L Fam S D'Souza S Taghibiglou C Salter M Wang YT 《The Journal of biological chemistry》2004,279(40):41267-41270
Excessive activation of the N-methyl-d-aspartate subtype glutamate receptor (NMDAR) is thought to be involved in mediating programmed cell death (apoptosis) in numerous central nervous diseases. However, the underlying mechanisms remain unknown. We report here that stimulation of NMDARs activates intracellular signaling cascades leading to apoptosis and facilitates clathrin-dependent endocytosis of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs). Both broad spectrum inhibitors of clathrin-dependent endocytotic processes and a specific inhibitor of AMPAR endocytosis selectively inhibit NMDA-induced apoptosis without affecting apoptosis produced by staurosporine. These results demonstrate that clathrin-dependent endocytosis of AMPARs is an essential step in NMDAR-mediated neuronal apoptosis. Our study not only identifies a previously unsuspected step in NMDA-induced apoptosis but also demonstrates that AMPAR endocytosis, in addition to attenuating synaptic strength as previously demonstrated in models of synaptic plasticity, may play a critical role in mediating other important intracellular pathways. 相似文献