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排序方式: 共有292条查询结果,搜索用时 15 毫秒
1.
目的:探讨Egr-1基因剔除对实验性胰腺炎小鼠胰腺组织中炎性相关因子表达的影响。 〖HTH〗方法:利用Egr-1基因剔除小鼠,采用大剂量雨蛙素诱导的实验性胰腺炎模型,观察Egr-1基因剔除后,胰腺组织水肿、MPO水平、血清淀粉酶水平、肺组织MPO水平的改变。并利用定量PCR的方法,检测胰腺组织中炎症相关因子组织因子(TF)、纤维蛋白溶酶原激活因子抑制因子(PAI-1)、单核细胞趋化吸引蛋白1(MCP-1)、Gro-1、IL-6和细胞间黏附分子-1(ICAM-1) mRNA的表达。 〖HTH〗结果:Egr-1基因剔除小鼠胰腺组织水肿明显轻于野生型,但组织MPO水平与血清淀粉酶与野生型组间相比无明显差异;肺组织MPO水平明显低于野生型。定量PCR检测结果表明, Egr-1基因剔除组,胰腺组织中TF、PAI-1,以及MCP-1、ICAM-1和IL-6 mRNA的表达,明显少于野生型组。 〖HTH〗结论:Egr-1基因剔除可明显减轻急性胰腺炎的严重程度,其作用可能通过减少胰腺组织中TF、PAI-1,以及MCP-1、ICAM-1和IL-6的表达而实现。 相似文献
2.
Objective and design:The roles of histamine formed by the macrophage – T lymphocyte system were evaluated in the regulation of lymphocyte proliferation using mice lacking histamine receptors.
Methods:Mice deficient in histamine type 1 (H1R), type 2 (H2R) or both receptors were employed to estimate possible intervention of the receptors in the histamine-dependent lymphocyte proliferation.
Results:Histamine was produced de novo by spleen cells. Con A-dependent T cell proliferation decreased when histamine produced in the culture was degraded by the addition of histaminase. The H2R-deficient mice also showed a significant decrease in the Con A-dependent T cell proliferation, whereas it was not modulated in the H1R-deleted mice. Consistent with the reduction in T cell proliferation, there was a significant down-regulation of the production of IL-2, a T cell growth factor, in the H2R-deficient mice. Con A-dependent IL-2 synthesis was abrogated by the addition of histaminase.
Conclusions:Con A-dependent T cell proliferation is (up)regulated by histamine produced de novo through the H2R, suggesting that histamine is a newly found regulator of T cell proliferation.Received 18 October 2003; returned for revision 17 December 2003; accepted by M. J. Parnham 6 February 2004 相似文献
3.
《Annals of medicine》2013,45(1):22-27
Type 2 diabetes is caused by genetic and environmental factors that affect the ability of the organism to respond to insulin. This impairment results from decreased insulin action in target tissues and insulin production in (3 cells. Genetic factors play a key role in the development of type 2 diabetes. However, the inheritance of diabetes is non-Mendelian in nature because of genetic heterogeneity, polygenic pathogenesis, and incomplete Perretrance. Novel insight into this complex process has been obtained from ‘designer’ mice bearing targeted mutations in genes of the insulin action and insulin secretion pathways. These mutant mice are beginning to challenge established paradigms in the pathogenesis of type 2 diabetes and to shed light on the genetic interactions underlying its complex inheritance. Here we review recent progress in the field and assess its relevance to the pathogenesis of diabetes in humans. 相似文献
4.
目的探讨青蒿素对ApoE-/-基因敲除小鼠动脉粥样硬化以及炎症因子的影响。方法将20只ApoE-/-基因敲除小鼠分为青蒿素组和PBS处理组,每组10只,经高脂喂养8周,与对照组小鼠(C57BL/6J标准饮食小鼠,10只)比较,通过血管大体油红O染色评价斑块面积;HE染色观察病变形态及血浆中炎症因子的变化。结果与对照组比较,PBS处理组及青蒿素组均可见动脉硬化斑块,炎症因子水平升高。青蒿素组的动脉硬化程度及炎症因子水平均明显低于PBS处理组。结论青蒿素可以改善ApoE-/-基因敲除小鼠动脉粥样硬化进展。 相似文献
5.
Inclusion of homologous DNA in nuclease‐mediated gene targeting facilitates a higher incidence of bi‐allelically modified cells
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6.
Sabine Zollner Elmar Raquet Philipp Claar Jochen Müller-Cohrs Hubert J. Metzner Thomas Weimer Ingo Pragst Gerhard Dickneite Stefan Schulte 《Thrombosis research》2014
Introduction
rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII.Materials and Methods
Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate®) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl3-induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200–250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice.Results
rVIII-SingleChain displayed a high affinity for von Willebrand factor (KD = 44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl3-induced arterial occlusion model.Conclusions
rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models. 相似文献7.
Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two ‘classical’ estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1−/−); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism. 相似文献
8.
Maike Hartlage-Rübsamen Alexander WaniekSteffen Roßner 《International journal of developmental neuroscience》2013
The amyloid precursor protein (APP) can be proteolytically degraded via non-amyloidogenic α-secretase and amyloidogenic β-secretase pathways. Previously, we have identified the presynaptic protein Munc13-1 as a diacylglycerol/phorbolester (DAG/PE) receptor that contributes to secretory, non-amyloidogenic APP processing after PE stimulation. Here, we used organotypic brain slice cultures from wild-type mice and from Munc13-1 knock-out (KO), Munc13-2 KO and Munc13-1/2 double KO (DKO) mice for pharmacological stimulation experiments. First, we demonstrate that neuronal populations and synaptic components important for secretory APP processing develop normally in organotypic brain slice cultures of all genotypes analyzed. Blockade of voltage-gated Na+ channels by tetrodotoxin reduced the PE-stimulated secretory APP processing, whereas depolarization by high extracellular K+ concentration evoked APP secretion. Additionally, the PE-stimulated APP secretion from Munc13-1 KO brain slices was significantly lower than that from wild-type brain slices. This effect was not observed in brain slices from Munc13-2 KO mice, which is consistent with the lower abundance and subpopulation-specific distribution of Munc13-2 in presynaptic elements. In Munc13-1/2 DKO brain slices, the deficiency of Munc13-1 dominated the effect of APP processing. The Munc13-1 KO effect on APP processing could be rescued by the stimulation of postsynaptic glutamatergic receptors. This indicates that lack of postsynaptic glutamate receptor stimulation in Munc13-1 KO brain slice cultures but not presynaptic mechanisms account for compromised APP processing. We conclude that organotypic brain slices cultures are a valuable tool for studying APP processing pathways in intact neuronal circuits and that neuronal activity is important for maintenance of the non-amyloidogenic APP processing. 相似文献
9.
Matos JE Sorensen MV Geyti CS Robaye B Boeynaems JM Leipziger J 《Pflügers Archiv : European journal of physiology》2007,454(6):977-987
Luminal P2 receptors are ubiquitously expressed in transporting epithelia. In steroid-sensitive epithelia (e.g., lung, distal
nephron) epithelial Na+ channel (ENaC)-mediated Na+ absorption is inhibited via luminal P2 receptors. In distal mouse colon, we have identified that both, a luminal P2Y2 and a luminal P2Y4 receptor, stimulate K+ secretion. In this study, we investigate the effect of luminal adenosine triphosphate/uridine triphosphate (ATP/UTP) on electrogenic
Na+ absorption in distal colonic mucosa of mice treated on a low Na+ diet for more than 2 weeks. Transepithelial electrical parameters were recorded in an Ussing chamber. Baseline parameters:
transepithelial voltage (V
te): −13.7 ± 1.9 mV (lumen negative), transepithelial resistance (R
te): 24.1 ± 1.8 Ω cm2, equivalent short circuit current (I
sc): −563.9 ± 63.8 μA/cm2 (n = 21). Amiloride completely inhibited I
sc to −0.5 ± 8.5 μA/cm2. Luminal ATP induced a slowly on-setting and persistent inhibition of the amiloride-sensitive I
sc by 160.7 ± 29.7 μA/cm2 (n = 12, NMRI mice). Luminal ATP and UTP were almost equipotent with IC50 values of 10 μM and 3 μM respectively. In P2Y2 knock-out (KO) mice, the effect of luminal UTP on amiloride-sensitve Na+ absorption was absent. In contrast, in P2Y4 KO mice the inhibitory effect of luminal UTP on Na+ absorption remained present. Semiquantitative polymerase chain reaction did not indicate regulation of the P2Y receptors
under low Na+ diet, but it revealed a pronounced axial expression of both receptors with highest abundance in surface epithelia. Thus,
luminal P2Y2 and P2Y4 receptors and ENaC channels co-localize in surface epithelium. Intriguingly, only the stimulation of the P2Y2 receptor mediates inhibition of electrogenic Na+ absorption. 相似文献
10.
Min Yang Anup Ramachandran Hui-Min Yan Benjamin L. Woolbright Bryan L. Copple Peter Fickert Michael Trauner Hartmut Jaeschke 《Toxicology letters》2014
Osteopontin (OPN) is a chemotactic factor which can be cleaved to the pro-inflammatory form by matrix metalloproteinases (MMPs). To test the hypothesis that OPN can modulate inflammatory liver injury during cholestasis, wild-type (WT) C57BL/6 and OPN knockout (OPN-KO) mice underwent bile duct ligation (BDL). OPN-KO mice showed significant reduction in liver injury (plasma ALT and necrosis) and neutrophil recruitment compared with WT animals at 24 h but not 72 h after BDL. In WT mice, a 4-fold increase in hepatic MMP-3 mRNA and elevated MMP activities and cleaved OPN levels were observed in bile. WT mice subjected to BDL in the presence of the MMP inhibitor BB-94 showed reduced liver injury, less neutrophil extravasation and diminished levels of cleaved OPN in bile. Thus, during obstructive cholestasis, OPN released from biliary epithelial cells could be cleaved by MMPs in bile. When the biliary system leaks, cleaved OPN enters the parenchyma and attracts neutrophils. In the absence of OPN, other chemoattractants, e.g. chemokines, mediate a delayed inflammatory response and injury. Taken together, our data suggest that OPN is the pro-inflammatory mediator that initiates the early neutrophil-mediated injury phase during obstructive cholestasis in mice. 相似文献