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排序方式: 共有3167条查询结果,搜索用时 15 毫秒
101.
Maxime Béland Mikaël BédardGuillaume Tremblay Pierre LavigneXavier Roucou 《Neurobiology of aging》2014
Plasma membrane cellular prion protein (PrPC) is a high-affinity receptor for toxic soluble amyloid-β (Aβ) oligomers that mediates synaptic dysfunction. Secreted forms of PrPC resulting from PrPC α-cleavage (PrPN1) or shedding (shed PrPC) display neuroprotective activity in neuronal cultures and in mouse models of Aβ-induced neuronal dysfunction. In vitro, recombinant PrPN1 and PrP inhibit Aβ fibrillization. However, the mechanism by which PrPN1 and shed PrPC neutralize Aβ oligomers is unclear, and evidence of such neuroprotective activity in Alzheimer's disease (AD) patients is lacking. Here, we show that PrPN1 association with Aβ causes a conformational change resulting in the formation of amorphous and insoluble aggregates that are not compatible with the assembly of Aβs. Using postmortem brain tissues of AD patients, we were able to coimmunoprecipitate Aβ with PrPC molecules and observed a coaggregation of Aβ and PrPN1 in the guanidine-extractable fraction presumably representing insoluble amyloid plaques. Furthermore, PrPC α-cleavage is increased in AD brains, and we noticed a significant positive correlation between the levels of α-cleavage and of guanidine-extractable Aβ. These data strongly support the hypothesis that PrPC α-cleavage is an endogenous neuroprotective mechanism in AD and support the development of PrPC-derived peptides as therapeutic molecules for AD. 相似文献
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Bissonnette EY Tremblay GM Turmel V Pirotte B Reboud-Ravaux M 《International immunopharmacology》2009,9(1):49-54
We have previously demonstrated the potency of coumarinic derivatives to inhibit human leukocyte elastase. Given the anti-inflammatory activities of some coumarins, we investigated the capacity of our coumarinic derivatives to inhibit inflammation and whether their anti-elastase activity was essential for their anti-inflammatory functions. All compounds studied were coumarinic derivatives displaying differential anti-proteinase activity. Coumarinic derivatives 1, 2, and 3 efficiently inhibited human leukocyte elastase in vitro, whereas the coumarinic derivative 4 did not show inhibitory activity. The anti-inflammatory effect of these compounds and a coumarin control, scopoletin, on interleukin-6 (IL-6), tumor necrosis factor (TNF), and macrophage chemotactic protein-1 (MCP-1) release was studied using lipopolysaccharide (LPS)-stimulated alveolar macrophages. The in vivo effect of compound 2, that inhibits elastase, and compound 4, that does not show proteinase inhibition, was investigated using a mouse model of LPS-induced lung inflammation and elastase-induced acute lung injury. All investigated coumarinic derivatives, regardless of their anti-proteinase activity, significantly inhibited IL-6 and TNF production by LPS-stimulated alveolar macrophages. However, only compounds 2, 3, and 4 significantly reduced MCP-1 release. Compound 2 attenuated LPS-induced leukocyte recruitment in bronchoalveolar lavage, whereas no inhibition was observed with compound 4 devoid of elastase inhibitory capacity. Interestingly, MCP-1 level was reduced in bronchoalveolar lavage of compound 4 treated mice, whereas TNF and IL-6 levels were not modulated by coumarins. Furthermore, compound 2, but not 4, reduced elastase induced lung injury. Our data suggest that although coumarinic derivatives have anti-inflammatory properties, their anti-elastase activity is essential to reduce lung inflammation in vivo. 相似文献
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Tremblay AJ Lamarche B Ruel I Hogue JC Bergeron J Gagné C Couture P 《Atherosclerosis》2004,172(2):367-373
Increasing evidence suggests that remnants of chylomicrons and very low density lipoprotein (VLDL) also known as triglyceride-rich lipoproteins (TRL) are directly related to the pathogenesis of atherosclerosis. While studies in animals suggest that low density lipoprotein (LDL) receptor deficiency delays clearance of chylomicron remnants, human data supporting this hypothesis are conflicting. The objective of this study was to compare the fractional catabolic rate (FCR) and production rate (PR) of TRL apolipoprotein B48, the principal structural protein of intestinally derived chylomicron remnants, between familial hypercholesterolemic (FH) heterozygotes and non-FH controls. This was achieved by examining the kinetics of TRL apo B48 labelled with a stable isotope (L-(5,5,5-D3)leucine) in five normolipidemic males (age: 24.7 +/- 1.3 years; body mass index (BMI): 23.9 +/- 1.4 kg/m2) and six genetically defined FH heterozygous males (age: 29.7 +/- 9.9 years; (BMI): 22.0 +/- 4.3 kg/m2) carrying the same null LDL receptor gene mutation. All participants were apo E3 homozygotes. During the kinetic study, the subjects consumed 1/30 of their daily food intake every 30 min over a 15 h period. No significant difference was observed between FH heterozygotes and controls for FCR of TRL apo B48 (7.9 +/- 2.1 versus 7.9 +/- 2.6 pools per day, P = 0.99) while the TRL apo B48 pool size (10.5 +/- 5.4 versus 5.7 +/- 2.4 mg, P = 0.03) and PR (1.1 +/- 0.3 versus 0.6 +/- 0.3 mg kg(-1) per day, P = 0.02) were significantly higher among FH than in controls. In conclusion, this study shows no evidence for reduced plasma apo B48 catabolism in patients with heterozygous FH carrying the same null LDL receptor gene mutation and suggests that the plasma levels of intestinally derived TRL are elevated in FH due to an increased production rate. 相似文献
107.
Turnbull GB Arnold A Aronson L Hawke G LeBlanc K Parslow N Phillips D St-Cyr D Steeves C Tremblay L Wells C Zorzes SM 《Ostomy/wound management》2004,50(9):78-85
Financial and clinical resources (which include 260 enterostomal therapy nurses nationwide) to provide clinical and rehabilitative expertise to the estimated 50,000 to 60,000 Canadians living with an ostomy are limited. Hence, many persons with an ostomy fall through the cracks in the early pre- and postoperative period or are lost to follow-up afterdischarge. Problems and issues related to ostomy management continue to surface throughout their lives. As a result,the time required for rehabilitation is often lengthy, affecting the person's quality of life. The First Canadian Enterostomal Therapy Nurses' Advisory Council consisting of 10 Canadian enterostomal therapy nurses met in February 2004 to identify key issues and concerns for Canadians living the ostomy experience and to identify gaps in information and services available before surgery, during the immediate postoperative period, and as the time from surgery lengthened and patients moved through age-related life issues. The two most important gaps identified were the development of quality, pertinent resources and the dissemination of those resources. The Council also identified potential strategies to bridge these gaps, including utilizing the resources of manufacturer Customer Service departments to follow a communications protocol to provide information to patients, retailers, and providers. Finally, a process map from which individual ostomy manufacturers can build programs and processes for improving patient/provider/manufacturer communication was developed. 相似文献
108.
A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture 总被引:8,自引:7,他引:8
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110.
L-DOPA-induced dyskinesias are one of the main problems encountered in treating patients with Parkinson's disease (PD). They are induced by the antiparkinsonian medications and primarily related to the degree of dopaminergic depletion, as shown by the fact that they tend to appear several years after the onset of the disease. Do the initial therapeutic decisions taken in treating a PD patient influence the point at which dyskinesias first occur? This question is raised in view of the apparent priming phenomenon that occurs in first exposure to L-DOPA. L-DOPA administrated to an MPTP intoxicated monkey rapidly corrects the animals' motor symptoms but generate dyskinesias. In contrast, the administration of dopaminergic agonists with a long half-life has a similar therapeutic effect but without inducing dyskinesias. However, a parkinsonian monkey that had received L-DOPA and developed dyskinesias, which were subsequently abolished when the treatment was withdrawn for several months, proceeded to develop dyskinesias when treatment with dopaminergic agonists with long half-life was introduced. The monkeys' previous exposure to L-DOPA (i.e. priming) thus increased its susceptibility to develop dyskinesias after exposure to drugs which would not otherwise have had this effect. Pulsatile activation of type D2 dopamine receptors is reported to be the principal factor in the triggering of dyskinesias and may well be involved in the priming phenomenon. While the pathophysiological basis of priming is not yet known, the phenomenon would not appear to be related to a hyperexpression of dopamine receptors (types D1 and D2) in the sensorimotor striatum. The results of recent experiments have given rise to several different hypothesis for the mechanisms involved in priming: the role of internalization of dopamine receptors after administration of dopaminergic drugs; change in the distribution of D3 dopamine receptor; changes in the expression of peptides (substance P, enkephalin) in efferent neurons of the striatum; and reorganization of connections at the level of the dopaminergic neurons and their target tissue. While many questions remain unanswered, it may well be that the initial therapeutic decisions taken when treating de novo patient are crucial in trying to delay the onset of dyskinesias. 相似文献