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The effect of nebivolol on atherogenesis in apoE - knockout mice

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Nebivolol is a novel beta1-blocker with a nitric oxide (NO) - potentiating, vasodilatory effect that is unique among beta-blockers. It was already shown that nebivolol ameliorates atherosclerosis in cholesterol-fed rabbits. We, therefore, wanted to investigate whether this is the case in the fine experimental model of atherosclerosis: apolipoprotein E (apoE)- knockout mice. Nebivolol attenuated atherogenesis, measured both by "en face" method (9.23±1.8% vs. 14.6±2.1%) and "cross-section" method (63125±8455 µm2 vs. 91416±8357 m2). This is the first report showing the effect of nebivolol on atherogenesis in gene-targeted mice.
Objective: It was reported that some effects of pentoxifylline (PTX) are mediated by heme oxygenase-1 (HO-1) induction. We investigated the role of HO-1 in anti-inflammatory activity of PTX. Methods: Experiments were performed in human and murine monocytes and endothelial cells and in HO-1 deficient mice. Results: PTX dose-dependently decreased expression of HO-1 in cell lines studied. As expected, PTX reduced also production of TNF. This effect was independent of HO-1 activity, as demonstrated in cells treated with HO-1 activators and inhibitors or in cells overexpressing HO-1. Moreover, inhibition of TNF was the same in human endothelial cells of different HO-1 genotypes, showing that PTX is similarly efficient in carriers of more and less active HO-1 promoter variants. In mice, PTX did not influence HO-1 expression, as measured in liver, kidney, spleen, heart, and skin. Accordingly, the response of PTX treated animals to LPS was the same in wild type and HO-1 deficient mice. PTX to a similar extent increased influx of leukocyte into peritoneal cavity, decreased production of TNF and reduced expression of VCAM-1 in vascular intima. Conclusion: PTX inhibits production of TNF and may decrease inflammatory reaction both in vitro and in vivo, but these effects are independent of HO-1.
This study explores the quantitative patterns of immunolabeled Fos protein incidence in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) oxytocinergic (OXY) neurons in response to immobilization (IMO) stress in corticotrophin releasing hormone deficient (CRH-KO) mice. Adult male mice, taken directly from cages or 120 min after a single IMO, were sacrificed by intracardial perfusion with fixative. Coronal brain sections of 30 µm thickness were processed for dual Fos/OXY immunohistochemistry. In control wild type (WT) and CRH-KO mice, scattered Fos immunoreactivity was observed in hypothalamus, including the PVN where scanty Fos signal occurred in both parvocellular and magnocellular PVN subdivisions. Dual Fos/OXY immunostainings revealed higher basal Fos expression in the PVN of control CRH-KO mice. IMO evoked a marked rise in Fos expression in OXY neurons of the PVN and SON in both WT and CRH-KO groups of mice. The present data demonstrate that 1/ CRH deficiency upregulates the basal activity of hypothalamic PVN OXY cells in CRH-KO mice and 2/ IMO stress in both WT and CRH-KO mice affects distinctly the activity of OXY cells in both SON and PVN. Our data indicate that CRH deficiency does not alter the responsiveness of PVN and SON OXY cells to IMO stress.
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The effect of montelukast on atherogenesis in APOE-LDLR-double knockout mice

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We have shown that inhibitors of five lipoxygenase activating protein (FLAP) - MK-886 and BAYx1005 inhibit atherosclerosis in apolipoprotein E / LDL receptor - double knockout mice. We, therefore, investigated whether cysteinyl leukotrienes receptor inhibitor - montelukast, given at a dose of 0.125 µg per 100 mg of body weight per day during 16 weeks, could also attenuate atherogenesis. In apoE/LDLR - DKO mouse model montelukast significantly decreased atherogenesis, measured both by "en face" method (25.5±2.% vs. 17.23 ± 1.8%) and "cross-section" method (455 494 ± 26 477 µm2 vs. 299 201 ± 20 373 µm2). The results were, however, less pronounced, comparing to FLAP inhibitors. This is the first report showing the effect of montelukast on atherogenesis in gene-targeted mice.
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Mouse models of experimental atherosclerosis

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Since 1992 the mouse has become an excellent model for experimental atherosclerosis research. Until 1992, the diet - induced atherosclerosis mouse model has been used effectively, but the lesions tended to be small and were limited to early fatty-streak stage. This model was also criticized because of the toxicity and inflammatory responses due to the diet. In 1992 the first line of gene targeted animal models, namely apolipoprotein E - knockout mice was developed. Of the genetically engineered models, the apoE - deficient model is the only one that develops extensive atherosclerotic lesions on a chow diet. It is also the model in which the lesions have been characterized most thoroughly. The lesions develop into fibrous plaques; however, there is no evidence that plaque rupture occurs in this model. The LDL receptor - deficient model has elevated LDL levels, but no lesions, or only very small lesions, form on the chow diet, however, robust lesions do form on the western-type diet. The creation of apoE - knockout mice has changed the face of atherosclerosis research.
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