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Allosteric inhibitors of plasma membrane Ca^(2+) pumps: Invention and applications of caloxins
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作者 Jyoti Pande M Szewczyk Ashok K Grover 《World Journal of Biological Chemistry》 CAS 2011年第3期39-47,共9页
Plasma membrane Ca2+pumps(PMCA)play a major role in Ca2+homeostasis and signaling by extruding cellular Ca2+with high affinity.PMCA isoforms are encoded by four genes which are expressed differentially in various cell... Plasma membrane Ca2+pumps(PMCA)play a major role in Ca2+homeostasis and signaling by extruding cellular Ca2+with high affinity.PMCA isoforms are encoded by four genes which are expressed differentially in various cell types in normal and disease states.Therefore, PMCA isoform selective inhibitors would aid in delineating their role in physiology and pathophysiology.We are testing the hypothesis that extracellular domains of PMCA can be used as allosteric targets to obtain a novel class of PMCA-specific inhibitors termed caloxins. This review presents the concepts behind the invention of caloxins and our progress in this area.A section is also devoted to the applications of caloxins in literature. We anticipate that isoform-selective caloxins will aid in understanding PMCA physiology in health and disease. With strategies to develop therapeutics from bioactive peptides,caloxins may become clinically useful in car diovascular diseases,neurological disorders,retinopathy,cancer and contraception. 展开更多
关键词 PHAGE display Calcium signaling Plasma membrane ca2+pumps Hypertension Neuronal disorders CONTRACEPTION Cancer Thrombosis Lipid RAFTS
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Plasma membrane calcium pump regulation by metabolic stress
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作者 Jason IE Bruce 《World Journal of Biological Chemistry》 CAS 2010年第7期221-228,共8页
The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic me... The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic metabolism,has the capacity to cause ATP depletion and thus inhibit PMCA activity.This has potentially fatal consequences,particularly for non-excitable cells in which the PMCA is the major Ca2+efflux pathway.This is because inhibition of the PMCA inevitably leads to cytosolic Ca2+ overload and the consequent cell death.However,the relationship between metabolic stress,ATP depletion and inhibition of the PMCA is not as simple as one would have originally predicted.There is increasing evidence that metabolic stress can lead to the inhibition of PMCA activity independent of ATP or prior to substantial ATP depletion.In particular,there is evidence that the PMCA has its own glycolytic ATP supply that can fuel the PMCA in the face of impaired mitochondrial function.Moreover, membrane phospholipids,mitochondrial membrane potential,caspase/calpain cleavage and oxidative stress have all been implicated in metabolic stress-induced inhibition of the PMCA.The major focus of this review is to challenge the conventional view of ATP-dependent regulation of the PMCA and bring together some of the alternative or additional mechanisms by which metabolic stress impairs PMCA activity resulting in cytosolic Ca2+ overload and cytotoxicity. 展开更多
关键词 Plasma membrane Ca 2+ -ATPase CALCIUM OVERLOAD METABOLIC stress CALCIUM pump MITOCHONDRIA
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高盐饮食对大鼠大脑皮质氧化应激及钠钙泵活性的影响 被引量:2
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作者 刘婵 陈涛 商黔惠 《中国老年学杂志》 CAS CSCD 北大核心 2015年第21期6027-6030,共4页
目的探讨长期高盐饮食对大鼠大脑皮质氧化应激和Na+-K+-ATPase、Ca2+-ATPase活性及其相关基因表达的影响。方法雄性Wistar大鼠随机分为正常盐对照组(NS组,n=13)、8%高盐组(HS组,n=24)和8%高盐+替米沙坦干预组(HS+Tel组,n=12),每2 w测量... 目的探讨长期高盐饮食对大鼠大脑皮质氧化应激和Na+-K+-ATPase、Ca2+-ATPase活性及其相关基因表达的影响。方法雄性Wistar大鼠随机分为正常盐对照组(NS组,n=13)、8%高盐组(HS组,n=24)和8%高盐+替米沙坦干预组(HS+Tel组,n=12),每2 w测量尾动脉压1次,喂养共24 w。比色法测定大鼠大脑皮质丙二醛(MDA)含量和超氧化物歧化酶(SOD)酶活性;用生化酶学法检测大脑皮质Na+-K+-ATPase、Ca2+-ATPase活性;通过实时荧光定量PCR法检测大脑皮质NAPDH、Na+-K+-ATPaseα1、细胞质膜钙泵(PMCA)1、钠钙交换蛋白(NCX)1和NADPH氧化酶亚单位P22phox mRNA表达。结果与NS组比较,HS组MDA含量增加、SOD活性减弱(P<0.05),Na+-K+-ATPase、Ca2+-ATPase活性均降低(P<0.05),NADPH氧化酶亚单位P22phox、Na+-K+-ATPaseα1、PMCA1 mRNA表达增加(P<0.05),NCX1mRNA表达无明显变化;与HS组比较,HS+Tel组Na+-K+-ATPase、Ca2+-ATPase活性升高(P<0.05),其他指标无明显改变。结论高盐饮食可引起大鼠大脑皮质氧化损伤及钠钙泵活性降低。 展开更多
关键词 高盐饮食 大脑皮质 氧化应激 钠钙泵
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高血压大鼠红细胞膜钙泵功能障碍机理的初步分析 被引量:1
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作者 文允镒 贾红鹏 +2 位作者 陈孟勤 张淑芳 周立平 《基础医学与临床》 CSCD 1990年第6期43-47,共5页
本工作比较自发性高血压大鼠(SHR)和肾性高血压大鼠(RHR)及对照大鼠红细胞膜Ca^(2+),Mg^(2+)-ATP酶(钙泵)活性及其对CaM、TFP、川芎嗪和硝苯吡啶(Nifedipine、Nif)等的反应,目的是分析高血压时钙泵功能障碍的机理,并寻找能有效提高钙泵... 本工作比较自发性高血压大鼠(SHR)和肾性高血压大鼠(RHR)及对照大鼠红细胞膜Ca^(2+),Mg^(2+)-ATP酶(钙泵)活性及其对CaM、TFP、川芎嗪和硝苯吡啶(Nifedipine、Nif)等的反应,目的是分析高血压时钙泵功能障碍的机理,并寻找能有效提高钙泵活性的药物,为高血压防治提供有效措施。 结果表明SHR及RHR基础钙泵活性明显低于相应对照大鼠钙泵活性;原因之一可能与高血压动物质膜钙泵对钙泵抑制剂TFP的敏感性增加有关,对RHR,川芎嗪作用很类似TFP。提示此药有CaM拮抗作用。Nif除了公认为钙通道阻断剂外,本实验表明对RHR它还有激活钙泵的作用。 展开更多
关键词 高血压 钙泵 钙调素 血管 平滑肌
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电针内关对缺血再灌注损伤大鼠心肌肌浆网钙泵活性及mRNA表达的影响 被引量:6
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作者 杨孝芳 王超 +4 位作者 严洁 易受乡 常小荣 林亚平 刁利红 《中华中医药杂志》 CAS CSCD 北大核心 2007年第6期345-348,共4页
目的:观察电针内关对缺血再灌注损伤大鼠心肌SERCA活性及其基因表达的影响,并以神门穴、合谷穴作对比研究。方法:实验分为假手术组、心肌缺血再灌注模型组(模型组)、电针内关组、电针神门组、电针合谷组,用无机磷比色法测定SERCA活性、R... 目的:观察电针内关对缺血再灌注损伤大鼠心肌SERCA活性及其基因表达的影响,并以神门穴、合谷穴作对比研究。方法:实验分为假手术组、心肌缺血再灌注模型组(模型组)、电针内关组、电针神门组、电针合谷组,用无机磷比色法测定SERCA活性、RT-PCR法分析SERCA基因表达。结果:与假手术组比,模型组SERCA活性及其基因表达均有非常显著性差异(P<0.01),电针内关组、电针神门组与模型组比较差异有显著性(P<0.05,P<0.01),电针内关组优于电针神门组(P<0.05,P<0.01)。结论:电针内关上调心肌SERCA基因表达,增强SERCA活性是实现对再灌注损伤心肌组织保护作用的途径之一。电针内关与电针神门两组疗效差异说明经穴对靶器官机制调节作用与经脉(穴)脏腑间的特异联系密不可分。 展开更多
关键词 内关 心肌缺血再灌注 肌浆网 钙泵/ca2+-ATPase SERCA 基因表达
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卡维地洛与培哚普利联合干预心梗后心衰对心肌肌浆网Ca^(2+)泵活性和Ca^(2+)释放通道密度的影响
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作者 耿召华 刘春燕 +5 位作者 彭佑华 李隆贵 赵晓辉 王江 崔斌 于世勇 《南方医科大学学报》 CAS CSCD 北大核心 2009年第7期1461-1464,共4页
目的探讨β受体阻滞剂卡维地洛与血管紧张素转换酶抑制剂培哚普利联合干预心梗后慢性心衰对心肌肌浆网(SR)Ca2+泵活性和Ca2+释放通道(RyR2)密度的影响及意义。方法通过结扎大鼠左冠脉建立慢性心衰模型,术后1周开始分别给以卡维地洛(6mg&... 目的探讨β受体阻滞剂卡维地洛与血管紧张素转换酶抑制剂培哚普利联合干预心梗后慢性心衰对心肌肌浆网(SR)Ca2+泵活性和Ca2+释放通道(RyR2)密度的影响及意义。方法通过结扎大鼠左冠脉建立慢性心衰模型,术后1周开始分别给以卡维地洛(6mg·kg-1·d-1)、培哚普利(4mg·kg-1·d-1)、特拉唑嗪(2mg·kg-1·d-1)、卡维地洛(6mg·kg-1·d-1)+培哚普利(4mg·kg-1·d-1)联合干预9周,观察血流动力学、左室心肌SRCa2+泵活性和RyR2密度的变化。结果与假手术组相比,心衰组左室舒张末压(LVEDP)显著升高(P<0.01),+dp/dtmax、-dp/dtmax显著降低(P<0.01),左室心肌SRCa2+泵活性和RyR2密度显著降低(P<0.01)。卡维地洛、培哚普利单独及联合干预均降低LVEDP(P<0.01),升高+dp/dtmax、-dp/dtmax(P<0.01),并升高左室心肌SRCa2+泵活性和RyR2密度(P<0.01),联合干预变化更明显(P<0.01)。特拉唑嗪组对上述指标无明显影响(P>0.05)。左室心肌SRCa2+泵活性与+dp/dtmax、-dp/dtmax显著正相关(r=0.596,r=0.684,P<0.01)。结论β受体阻滞剂卡维地洛和血管紧张素转换酶抑制剂培哚普利长期联合干预心梗后慢性心衰,能够改善血流动力学和心肌SRCa2+泵活性,增加RyR2密度,优于任何单一药物干预。 展开更多
关键词 卡维地洛 培哚普利 心肌梗死 心力衰竭 心肌肌浆网 ca2+泵 ca2+释放通道
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心房颤动病人心房肌肌浆网Ca^(2+)泵和Ca^(2+)释放通道的变化
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作者 杨大春 杨永健 张鑫 《岭南心血管病杂志》 2007年第5期324-326,共3页
目的探讨心房颤动病人心房肌肌浆网Ca2+泵(sarcoplasmic reticulum Ca2 +ATPase,SERCA2a)及钙释放通道2型雷尼丁受体(type 2 ryanodine receptor,RYR2)mRNA表达的变化。方法39例风湿心脏病二尖瓣关闭不全接受外科手术者,分为3组,窦性心... 目的探讨心房颤动病人心房肌肌浆网Ca2+泵(sarcoplasmic reticulum Ca2 +ATPase,SERCA2a)及钙释放通道2型雷尼丁受体(type 2 ryanodine receptor,RYR2)mRNA表达的变化。方法39例风湿心脏病二尖瓣关闭不全接受外科手术者,分为3组,窦性心律组13例,心房颤动持续小于6个月组11例,心房颤动持续超过6个月组15例。手术时取右心房肌约100mg,用逆转录-聚合酶链反应检测心房肌SERCA2a和RYR2的mRNA表达。结果心房颤动者肌浆网SERCA2a、RYR2的mRNA较窦性心律者下调,而且下调随心房颤动持续时间延长而明显。结论心房颤动病人SERCA2a、RYR2的mRNA下调,提示肌浆网SERCA2a、RYR2与心房颤动的发生和维持有关。 展开更多
关键词 心房颤动 肌浆网 钙离子泵 2型雷尼丁受体
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The key target of neuroprotection after the onset of ischemic stroke: secretory pathway Ca^(2+)-ATPase 1 被引量:13
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作者 Li-hua Li Xiang-rong Tian Zhi-ping Hu 《Neural Regeneration Research》 SCIE CAS CSCD 2015年第8期1271-1278,共8页
The regulatory mechanisms of cytoplasmic Ca2+ after myocardial infarction-induced Ca2+ overload involve secretory pathway Ca2+-ATPase 1 and the Golgi apparatus and are well understood. However, the effect of Golgi ... The regulatory mechanisms of cytoplasmic Ca2+ after myocardial infarction-induced Ca2+ overload involve secretory pathway Ca2+-ATPase 1 and the Golgi apparatus and are well understood. However, the effect of Golgi apparatus on Ca2+ overload after cerebral ischemia and reperfusion remains unclear. Four-vessel occlusion rats were used as animal models of cerebral ischemia. The expression of secretory pathway Ca2+-ATPase 1 in the cortex and hippocampus was detected by immunoblotting, and Ca2+ concentrations in the cytoplasm and Golgi vesicles were determined. Results showed an overload of cytoplasmic Ca2+ during ischemia and reperfusion that reached a peak after reperfusion. Levels of Golgi Ca2+ showed an opposite effect. The expression of Golgi-specific secretory pathway Ca2+-ATPase 1 in the cortex and hippocampus decreased before ischemia and reperfusion, and increased after reperfusion for 6 hours. This variation was similar to the alteration of calcium in separated Golgi vesicles. These results indicate that the Golgi apparatus participates in the formation and alleviation of calcium overload, and that secretory pathway Ca2+-ATPase 1 tightly responds to ischemia and reperfusion in nerve cells. Thus, we concluded that secretory pathway Ca2+-ATPase 1 plays an essential role in cytosolic calcium regulation and its expression can be used as a marker of Golgi stress, responding to cerebral ischemia and reperfusion. The secretory pathway Ca2+-ATPase 1 can be an important neuroprotective target of ischemic stroke. 展开更多
关键词 nerve regeneration brain injury global cerebral ischemia Golgi apparatus Golgi stress cytoplasmic ca2 homeostasis Golgi ca2 ca2 pump secretory pathway ca2+-ATPase 1 neural protection NSFC grant neural regeneration
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Study of the Pathogenesis of Hypertension Associated with Non-Insulin Dependent Diabetes Mellitus 被引量:1
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作者 丁国宪 陈家伟 何戎华 《The Journal of Biomedical Research》 CAS 1997年第2期36-41,共6页
In order to study the pathogenesis of hypertension associated with noninsulin dependent diabetes mellitus (NIDDM), Plasma glucose, insulin levels at fasting and following an oral glucose load were measured. Na +K +pum... In order to study the pathogenesis of hypertension associated with noninsulin dependent diabetes mellitus (NIDDM), Plasma glucose, insulin levels at fasting and following an oral glucose load were measured. Na +K +pump and Ca 2+ pump activities of red blood cell membrane were also assessed. Hypertensive patients with normal or impaired glucose tolerance (NGT, or IGT) had hyperinsulinemia. Obese hypertensive patients also had hyperinsulinemia, while nonobese hypertensive patients had no hyperinsulinemia, but exhibited a delay in insulin response to oral glucose tolerance test (OGTT). In multivariate analysis, considering the factors of age, BMI and plasma glucose level, DBP were still positively related to both 30 min insulin level and IAUC, but negatively correlated to activities of Na +K +pump and Ca 2+ pump. These results demonstrated that a link between obesity, hpertension and NIDDM is the insulin resistance and/or hyperinsulinemia. 展开更多
关键词 Noninsulin dependent diabetes mellitus HYPERTENSION Insulin resistance HYPERINSULINEMIA Na +K +pump Ca 2+ pump
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Age-Dependent Comparative Study of 4 Hz and 8 Hz EMF Exposure on Heart Muscle Tissue Hydration of Rats
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作者 Lilia Narinyan Sinerik Ayrapetyan 《Open Journal of Biophysics》 2019年第1期70-82,共13页
Previously we have shown that 4 Hz and 8 Hz EMF exposures have depressing effect on the thermodynamic activity of water, which decreases peroxide formation. It has also been shown that 4 Hz EMF-treated physiological s... Previously we have shown that 4 Hz and 8 Hz EMF exposures have depressing effect on the thermodynamic activity of water, which decreases peroxide formation. It has also been shown that 4 Hz EMF-treated physiological solution modulates the growth and development of microbes and heart muscle contractility, but 8 Hz EMF has pronounced inhibitory effect on bacterial growth and development. Therefore, in order to elucidate the possible mechanism of 4 Hz and 8 Hz EMF effects on heart muscle function, in the present work the effects of 4 Hz and 8 Hz EMF exposures on heart muscle tissue hydration, the sensitivity of 4 Hz and 8 Hz EMF-induced tissue hydration to 10&minus;4 M ouabain (Na+/K+ pump inhibition) and 10&minus;9 M ouabain (activation of intracellular signaling system) as well as the effects of 4 Hz and 8 Hz EMF exposures on the number of Na+/K+ pump units in the membrane of both young and old rats have been studied. The obtained data allow us to suggest that 8 Hz EMF exposure has more pronounced age-dependent modulation effect on tissue hydration of heart muscle than 4 Hz EMF and this effect is sensitive to Na+/K+ pump activity and intracellular signaling system. 展开更多
关键词 EMF TISSUE HYDRATION HEART Na+/K+ pump Na+/ca2+ Exchange
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依那普利、厄贝沙坦单用和联用对高血压大鼠主动脉重塑与中膜钠泵及钙泵的影响 被引量:7
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作者 胡威 商黔惠 +2 位作者 姜黔峰 吴芹 袁萍 《中华高血压杂志》 CAS CSCD 北大核心 2010年第6期528-533,共6页
目的观察依那普利、厄贝沙坦单用及联用改善肾血管性高血压大鼠(RHR)主动脉重塑的疗效,观察RHR主动脉平滑肌细胞膜钠泵、钙泵活性及钠泵α1亚单位、细胞质膜钙泵亚型1(PMCA1)mRNA表达水平变化,探讨依那普利及厄贝沙坦改善动脉重塑的可... 目的观察依那普利、厄贝沙坦单用及联用改善肾血管性高血压大鼠(RHR)主动脉重塑的疗效,观察RHR主动脉平滑肌细胞膜钠泵、钙泵活性及钠泵α1亚单位、细胞质膜钙泵亚型1(PMCA1)mRNA表达水平变化,探讨依那普利及厄贝沙坦改善动脉重塑的可能机制。方法建立"两肾一夹"RHR模型,设立假手术组(n=6)、模型组(n=6)、依那普利组[10mg/(kg.d),n=6]、厄贝沙坦组[50mg/(kg.d),n=6]、依那普利+厄贝沙坦组[5mg/(kg.d)+25mg/(kg.d),n=6)],药物连续干预6周。采用HE染色、免疫组化染色、Masson染色观察主动脉中膜形态和结构变化,放射免疫法检测血管紧张素Ⅱ(AngⅡ)含量,酶学比色法检测细胞膜钠泵及钙泵活性,realtime PCR法检测细胞膜钠泵及钙泵mRNA表达水平。结果 RHR血压显著升高,主动脉中膜面积及厚度明显增加,组织局部钠泵、钙泵活性及钠泵α1亚单位、PMCA1 mRNA表达水平明显降低(P<0.01)。依那普利及厄贝沙坦均能减小RHR主动脉中膜面积及厚度,改善平滑肌肥大和胶原纤维含量增加,且均能升高RHR主动脉中膜钠泵、钙泵活性(P<0.01或P<0.05)。依那普利降低主动脉中膜AngⅡ含量,上调钠泵α1亚单位、PMCA1 mRNA表达水平(P<0.01),而厄贝沙坦升高动脉中膜AngⅡ含量(P<0.01),对钠泵α1亚单位、PMCA1 mRNA表达水平无显著影响。两药联合降压及减小动脉中膜面积、厚度和升高钠泵、钙泵活性存在协同作用(P<0.01)。结论依那普利、厄贝沙坦联用改善主动脉重塑优于两药单用,其机制可能与它们升高主动脉中膜钠泵和钙泵活性有关。依那普利可能通过上调钠泵及钙泵mRNA表达水平改善钠泵及钙泵活性受抑。 展开更多
关键词 高血压 肾血管性 钠泵 钙泵 平滑肌 动脉重塑 依那普利 厄贝沙坦
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