滇产回心草及回心康抗缺血心肌脂质过氧化作用及对前列环素／血栓素的影响

采用结扎大鼠冠脉造成急性心肌缺血模型,动态观测Ⅱ导联心电图ST段的变化,以S-T段上移为指标反映缺血程度,观察了滇产回心草及回心康对急性心肌缺血损伤的保护作用,同时检测血清SOD、MDA、PGI2和TXA2.结果表明,回心草及回心康均能显著减少S-T段上移,均以2 g/kg组为显著;其1 g/kg及2 g/kg均使心肌梗塞范围缩小(p＜0.05,p＜0.01);均使心肌缺血大鼠血清SOD显著提高(p＜0.05及p＜0.01);MDA显著降低(p＜0.05,p＜0.01).回心草及回心康还能提高大鼠血清PGI2水平,降低TXA2含量,以回心草2 g/kg及回心康2 g/kg为显著(p＜0.05),呈剂量依赖性.实验结果提示,回心草及回心康均具有抗心肌缺血及抗脂质过氧化作用,其提高PGI2/TXA2可能与其抗心肌缺血作用机制有关.     

基于Bcl-2/CytC探究槲皮素对肝硬化大鼠微循环及肝脏病变的影响

摘要 目的：基于Bcl-2/CytC调控网络探讨槲皮素对肝硬化大鼠微循环及肝脏病变的影响。方法：选取清洁级SD大鼠45 只,随机数字表法分为A组、LC组、QUE low group、QUE high group,ETV组,10 只/组,除10只健康大鼠外其余均建立肝硬化模型,QUE low group采用槲皮素50 mg/kg灌胃,QUE high group采用槲皮素100 mg/kg灌胃,ETV组采用恩替卡韦分散片0.5 mg/次灌胃,A组与LC组均用生理盐水灌胃,均1 次/d,共计14 d。采用ELISA检测大鼠血清中丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST)、总胆固醇（TC）、甘油三酯（TG）水平及血栓素A2（TXA2）、血管紧张素II（AngⅡ）、前列环素（PGI2）含量,HE染色比较各组肝组织形态,免疫印迹检测大鼠肝组织中Bcl-2、Bax、细胞色素C(CytC)蛋白表达。结果：与A group相比,LC group的ALT、AST、TC、TG、TXA2、AngII表达均较高,PGI2、CytC、Bax较低（P<0.05）;与LC组比较,QUE low group的ALT、AST、TC、TG、TXA2、AngII均降低,PGI2、CytC、Bax升高（P<0.05）;与QUE low group比较,ETV group的ALT、AST、TC、TG、TXA2、AngII均降低,PGI2、CytC、Bax升高（P<0.05）;与ETV group比较,QUE high group的ALT、AST、TC、TG、TXA2、AngII均降低,PGI2、CytC、Bax升高（P<0.05）。A组大鼠肝脏组织完好;LC group大鼠肝组织损伤严重;QUE low group大鼠肝间质仍有纤维组织增生及炎症浸润现象;ETV组仍有肝细胞变性及炎性因子;QUE high group大鼠肝组织变性反应及汇管区炎症降低。与A group比较,LC group有明显肝纤维化、肝细胞变性坏死及炎细胞浸润（P＜0.05）;与LC group比较,QUE low group大鼠肝脏纤维化等有所缓解（P＜0.05）;与QUE low group比较,ETV group大鼠肝脏纤维化、变性坏死及炎细胞浸润缓解（P＜0.05）;与ETV group比较,QUE high group大鼠肝脏纤维化、变性坏死及炎细胞浸润改善（P＜0.05）。结论：槲皮素对肝硬化大鼠的肝组织具有一定保护作用,改善肝功能和肝脏微循环、肝脏病变,其机制可能调节Bcl-2、Bax和CytC等相关蛋白有关。     

PGI2-PPARδ信号传导途径与哺乳动物的胚胎着床

前列腺素 (PGs)在胚泡着床和子宫的蜕膜化过程中起着重要的调节作用 ,前列环素 (PGI2 )是着床位点表达量最高的PGs .前列环素受体 (IP)和过氧化物酶体增殖因子活化受体 (PPARs)分别是PGI2 的细胞表面G蛋白偶联的受体和细胞核内受体 ,IP在胚泡着床位点不表达或检测不到 ,而PPARδ表达丰富 ,RXRs (PPARs的异二聚体伴侣 )及相应的PPARδ RXRα复合物、PGI2 合成酶 (COX 2 /PGIS)也在着床位点表达丰富 ,因此推测PGI2 在胚泡着床中的作用可能是通过PPARδ受体介导的 .利用PGI2 类似物 (cPGI)和PPARδ特异性类似物能够恢复COX 2基因敲除小鼠的胚泡着床和蜕膜化 .总之 ,PGI2 通过PPARδ在胚泡着床和蜕膜化过程中起着重要的调节作用     

补肾活血汤对去卵巢大鼠心脏微血管内皮细胞形态及血清E_2、ET、NO、PGI_2、TXA_2含量的影响

目的:研究补肾活血汤对去卵巢大鼠冠脉微血管内皮细胞形态及功能的影响。方法:3月龄成年雌性大鼠随机分为8组,共计46只,分别为:正常组(NORM)、假手术组(SHAM),去卵巢组(OVX),补肾活血汤高、低剂量组(OVX/BHT-H、OVX/BHT-L)、17β-雌二醇干预组(OVX/ERT)。以透射电镜观察微血管内皮细胞细胞器变化;放射免疫法测定实验大鼠血清E2、ET、PGI2、TXA2的含量;采用硝酸还原酶法测定血浆NO含量。结果:与正常组相比,去卵巢组心肌及微血管内皮细胞细胞器破坏严重,中药组及17β-雌二醇干预组有所改善。与正常组相比,去卵巢组大鼠血浆中E2下降明显,有显著性差异;与去卵巢组相比,中药组大鼠E2明显上升,有显著性差异;与雌激素组相比无明显差异;与去卵巢组相比,中药组大鼠血浆ET-1值有所降低,其中以高剂量组最明显,中药组组大鼠的NO值稍有升高,但与正常组相比,没有显著性差异;中药组大鼠的TXA2值明显降低,其中以高剂量组最明显,中药组PGI2值升高,与正常组相比,有显著性差异,与17β-雌二醇干预组相比无显著性差异。结论:补肾活血汤能预防去卵巢后心肌微血管内皮细胞的形态和功能的破坏,其机制可能与其增加E2含量有关。     

血栓素A2与糖尿病心血管并发症

心血管疾病是现今导致病人发病和死亡的首要因素,很多因素在血管性疾病发病发展中起着重要作用,血栓形成是参与脑中风及急性冠状动脉综合症的首要因素。血栓素A2（TXA2）是一种强血小板活化因子,在糖尿病患者体内的合成显著增加,并通过作用于血栓素受体诱导血小板聚集,血管收缩,血栓形成参与糖尿病心血管并发症的发生发展。因此,以TXA2为靶点开发抗血栓类药物对心血管疾病起着预防及治疗作用。本文对TXA2介导的糖尿病血管并发症的发病机制,及以此为靶点开发的抗血栓药物进行综述,为糖尿病心血管并发症的治疗及新型低副作用抗血栓药物的研发提供新的靶点。     

缺血缺氧再灌注对胎鼠肾组织环氧化酶表达的影响

目的观察宫内缺血缺氧再灌注后,胎鼠肾组织COX蛋白表达及其AA代谢产物PGI2、PGE2和TXA2含量的变化,探讨COX在宫内窘迫胎鼠肾损伤发病机制中的作用.方法制备胎鼠子宫内缺血缺氧再灌注模型(缺血缺氧组：缺血缺氧30min;再灌注组：缺血缺氧30min后,分别再灌注30min,2h,6h,12h,24h,30h)缺血氧组：取胎鼠18只;再灌注组各时间点分别取胎鼠18只;对照组取胎鼠20只.将肾组织匀浆后采用Western免疫印迹和放免法检测COX蛋白表达及其PGI2、PGE2和TXA2含量的变化.同时HE染色观察肾组织病理学改变.结果子宫内缺血缺氧再灌注后胎肾组织COX-2蛋白表达上调,PGI2的稳定代谢产物6-Keta-PGF1α及PGE2均于再灌注2h开始增高(P<0.05).其中6-keta-PGF1α增加迅速,于再灌注12h达假手术组的6倍(P<0.01),PGE2于再灌注24h达假手术组的2倍(P<0.01),而TXB2增加幅度不大,无统计学意义.结论宫内缺血缺氧再灌注选择性地诱导胎肾COX-2蛋白表达增强,COX-2可能通过PGI2和PGE2对缺血性胎肾损伤具有保护作用,因此,在围产期肾损伤不宜应用COX-2抑制剂.     

HCG诱导排卵期间黄鳝血浆6-酮-前列腺素F1α含量的变化

在已研究过的鱼类中,用放射免疫分析法(RIA)所检测的PGS仅限于前列腺素E(PGE)和前列腺素F(PGF),而其他前列腺素类化合物例如前列环素(PGI2)等与鱼类排卵的关系,则未见报道。本文探讨PGI2在排卵中的作用,为鱼类排卵机制的研究积累资料。       

GLIPR-2的生物学特性及与疾病的关系

神经胶质瘤致病相关蛋白2(glioma pathogenesis-related protein 2,GLIPR-2)是CAP蛋白质超家族中的一种高尔基体膜蛋白,具有CAP保守结构域,在体内的分布具有一定的组织和细胞特异性,在免疫器官和肺脏中表达较高。GLIPR-2与细胞膜系统具有高度的亲和力,可能与十四酰基化有关。GLIPR-2在HSAB和紫外光作用下形成二聚体,且能与Caveolin-1相互作用。GLIPR-2与疾病也很相关,目前发现GLIPR-2能诱导肾脏上皮细胞发生上皮细胞间质转化(epithelial to mesenchymal transition,EMT)而参与肾脏纤维化。CAP家族的SCRIP-3和GLIPR-1与肿瘤关系密切,GLIPR-2与上述两个蛋白具有相似的保守结构域,因此GLIPR-2可能也与肿瘤有关。     

低氧,山莨菪碱对肺内小动脉平滑肌细胞产生血栓素A2和前列环素的影响

本工作观察了急性重度低氧及山莨菪碱（anisodamine,Am）对分离培养家兔肺内小动脉平滑肌细胞（PASMCS）培养液中TXB2和6-酮-PGF1a含量及它们的比值的影响。结果是：重度低氧明显增加PASMCS培养液中TXB2和6-酮-PGF1a含量及它们的比值。常氧和低氧条件下,终浓度为2.5×10－5×mol／L的山莨菪碱显著降低TXB2的含量,但6-酮-PGF1a的含量无变化。这提示：急性重度低氧可能通过增加PASMCS产生和释放TXA2和PGI2及它们的比值而致肺血管收缩,山莨菪碱可能通过抑制PASMCs产生ThA2和降低ThB2与PGI2的比值逆转低氧所致的肺血管收缩效应。     

针刺对胰岛素抵抗模型血管内皮功能的影响

目的:探讨针刺对实验性胰岛素抵抗模型大鼠血管内皮功能的影响.方法:将50只大鼠随机分成空白对照组、模型1组、模型2组、针刺1组、针刺2组,每组10只.采用高脂高糖高盐饲料喂养方法复制胰岛素抵抗模型.造模成功后,空白对照组继续以普通饲料喂养;模型1组继续以高脂高糖高盐饲料饲养;模型2组改为普通饲料喂养;针刺1组继续以高脂高糖高盐饲料喂养2周,同时给予针刺治疗,1次/d;针刺2组给予普通饲料喂养2周,同时给予针刺治疗,1次/d.治疗结束后继续取血观察各组大鼠的FPG、FINS、ISI、PGI2、TXA2、ET、NO的变化.结果:模型1组大鼠的FPG、FINS、ISI、TXA2、ET均较空白对照组升高(P＜0.01),而PGI2、NO低于空白对照组(P＜0.01).FPG、FINS、ISI、TXA2、ET在饮食及针刺联合干预的针刺2组中得到显著的改善,与针刺1组、模型1组及模型2组相比P＜0.01或P＜0.05;针刺1组与模型1组、模型2组相比,P＜0.05,模型2组与模型1组相比,P＜0.05.结论:胰岛素抵抗可造成血管内皮功能的损伤,针刺对胰岛素抵抗血管内皮功能的损伤具有一定的逆转效应,合理饮食可以促进这种效应.     

清栓酶治疗脑梗塞疗效与血浆血栓素A2及前列环素之间的关系

应用清栓酶治疗不同病期脑梗塞３８例,总有效率８６．７％,发病后治疗时间越早,疗效越好。治疗前病人均有不同程度的ＴＸＡ２升高,ＰＧＩ２下降,急性期更为明显,治疗后ＴＸＡ２下降,ＰＧＩ２上升,使失调的ＰＧＩ２－ＴＸＡ２平衡得以恢复     

A possible role of thromboxane A2 (TXA2) and prostacyclin (PGI2) in circulation.

Recently two local hormones, thromboxane A2 (TXA2) and prostacyclin (PGI2) have been discovered. These hormones are labile metabolites of arachidonic acid. TXA2 is generated by blood platelets, while PGI2 is produced by vascular endothelium. TXA2 is a potent vasoconstrictor. It also initiates the release reaction, followed by platelet aggregation. PGI2 is a vasodilator, especially potent in coronary circulation. It also inhibits platelet aggregation by virtue of stimulation of platelet adenyl cyclase. Common precursors for both hormones are cyclic endoperoxides PGG2 and PGH2, being formed by cyclooxygenation of arachidonic acid. This last enzymic reaction is more efficient in platelets than in vascular endothelium, and therefore the generation of PGI2 by vasuclar wall is accelerated by an interaction between platelets and endothelial cells. During this interaction platelets supply the endothelial PGI2 synthetase with their cyclic endoperoxides. The newly formed PGI2 repels the platelets from the intima. When PGI2 synthetase is irreversibly inactivated by low concentration of lipid peroxides, then the platelets are not rejected but stick to the endothelium, generate TXA2 and mature thrombi are formed. A balance between formation and release of PGI2, TXA2 and/or cyclic endoperoxides in circulation is of utmost importance for the control of intra-arterial thrombi formation and possibly plays a role in the pathogenesis of atherosclerosis.     

Comparative effects of some 3-amino 4,6-diarylpyridazines on the biosynthesis in vitro of TXA2 and PGI2- and on the TXA2- and PGI2-synthesizing activities of cardiac tissue

Some 3-amino 4,6-diarylpyridazine derivatives were tested for their effects on TXA2 and PGI2 biosyntheses in vitro and on the TXA2- and PGI2-synthesizing activities of cardiac tissue. Horse platelet and aorta microsomes were used as sources of thromboxane and prostacyclin synthetases respectively. The TXA2- and PGI2-synthesizing activities of cardiac tissue were studied on isolated perfused rabbit hearts (the heart microsomes being used both as TXA2 synthetase and PGI2 synthetase sources). TXB2 and 6-keto PGF1 alpha were determined by RIA. Among the compounds under study, 3-morpholino 4,6-diphenylpyridazine (III) was shown to inhibit specifically the TXA2 synthetase. Substitution of the morpholino group by a dimethylamino one (I) reinforced the inhibiting effects on TXA2 synthetase but it also revealed a slight anti-prostacyclin synthetase action of the molecule. Replacement of 3-morpholino moieties by either a 3-hydrazino (IV), or a 2-dimethylaminoethylamino (V), or a 2-morpholinoethylamino group (VI) abolished completely the effects of the molecule on TXA2 and PGI2 synthetases. Likewise the addition of chlorine on the para-position on the phenyl ring of I neutralized all its inhibitory effects both on TXA2 and PGI2 synthetases in vitro. None of the 3-amino 4,6-diarylpyridazine derivatives was active on either the TXA2- or PGI2-synthesizing activities of cardiac tissue.     

The prostacyclin/thromboxane balance is favourably shifted in Greenland Eskimos

The rare incidence of cardiovascular disease in Eskimos has been ascribed to their diet rich in eicosapentaenoic acid (EPA, C20:5n-3) and hence a possible formation of trienoic prostanoids. In this study we compare endogenous formation of prostacyclin (PGI), which is formed by the endothelial cell, and thromboxane (TXA), which is formed by platelets in 20 Eskimos and 20 age and sex matched Danish controls by measurement of the main urinary metabolites. Considerable formation of bioactive PGI3 from dietary EPA was shown in Eskimos, which was barely detectable in the controls. Furthermore synthesis of PGI2 was significantly higher in Eskimos in spite of a markedly lower arachidonate content in membrane lipids. In contrast formation of TXA2,3 was lower in Eskimos as compared to the Danish controls. We conclude, that the balance between PGI and TXA, which may regulate the interaction of platelet and vessel wall, is favourably shifted in Greenland Eskimos to an antithrombotic state.     

Myocardial prostacyclin and thromboxane A2 synthetase activities during ischemia and reperfusion in isolated rabbit heart

The aim of the study was to determine the prostacyclin (PGI2) and thromboxane A2 (TXA2) synthetase activities of myocardial tissue and their variation during ischemia and reperfusion. Regional ischemia was induced by 10 min occlusion of the left anterior descending coronary artery in isolated Langendorff rabbit hearts. Biosynthesis of PGI2 and TXA2 were carried out by using arachidonic acid as substrate and left ventricle microsomes (LVM) from ischemic and non-ischemic areas as sources of PGI2 and TXA2 synthetase. 6-keto-PGF1 alpha and TXB2, stable metabolites of PGI2 and TXA2 respectively, were determined by radioimmunoassay. Experiments carried out under the adopted conditions showed that LVM were able to synthetise PGI2 as well as TXA2 from arachidonic acid. On the other hand, ischemia depressed both PGI2 and TXA2 synthetase activities of cardiac tissue: the depression was more pronounced on TXA2 synthetase than on PGI2 synthetase with no significant difference between ischemic and non-ischemic regions. Moreover, ischemia increased the ratio 6-keto-PGF1 alpha/TXB2 indicating therefore that it can facilitate the formation of PGI2. The post ischemic reperfusion of the heart counteracted the decrease in PGI2 synthetase induced by ischemia which returned to the normal level: reperfusion also slightly reversed the decrease in TXA2 the decrease in TXA2 synthetase. However, the diminution in TXA2 synthetase of non-ischemic myocardium was attenuated but it remained lower than the normal level. These results suggested that the whole left ventricle is affected by regional ischemia. Furthermore it appears that myocardial TXA2 synthetase is more vulnerable than PGI2 synthetase to a lack of oxygen and nutrients.     

Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2

The two cyclooxygenase (COX) isoforms, COX-1 and COX-2, both metabolize arachidonic acid to PGH(2), the common substrate for thromboxane A(2) (TXA(2)), prostacyclin (PGI(2)), and PGE(2) synthesis. We characterized the synthesis of these prostanoids in HUVECs in relation to COX-1 and COX-2 activity. Untreated HUVEC expressed only COX-1, whereas addition of IL-1beta caused induction of COX-2. TXA(2) was the predominant COX-1-derived product, and TXA(2) synthesis changed little with up-regulation of COX-2 by IL-1beta (2-fold increase). By contrast, COX-2 up-regulation was associated with large increases in the synthesis of PGI(2) and PGE(2) (54- and 84-fold increases, respectively). Addition of the selective COX-2 inhibitor, NS-398, almost completely abolished PGI(2) and PGE(2) synthesis, but had little effect on TXA(2) synthesis. The up-regulation of COX-2 by IL-1beta was accompanied by specific up-regulation of PGI synthase and PGE synthase, but not TX synthase. An examination of the substrate concentration dependencies showed that the pathway of TXA(2) synthesis was saturated at a 20-fold lower arachidonic acid concentration than that for PGI(2) and PGE(2) synthesis. In conclusion, endothelial prostanoid synthesis appears to be differentially regulated by the induction of COX-2. The apparent PGI(2) and PGE(2) linkage with COX-2 activity may be explained by a temporal increase in total COX activity, together with selective up-regulation of PGI synthase and PGE synthase, and different kinetic characteristics of the terminal synthases. These findings have particular importance with regard to the potential for cardiovascular consequences of COX-2 inhibition.