心肌缺血再灌注损伤的分子修复机制及其抑制剂的研究进展

目前缺血性心脏病的发病率位于原发性心脏病之首,其中心肌缺血再灌注损伤约占50%以上。因此,开发治疗心肌缺血再灌注损伤的多靶点药物对防治心脏疾病具有重大价值和意义。研究MIRI的分子机制并开发针对各种靶点的MIRI抑制剂,以此调控多种信号通路,为进一步阐明MIRI分子机制及研发相关药物提供了新的思路。     

姜黄素对缺血再灌注损伤器官的保护作用

近年来姜黄素对局部缺血再灌注损伤（ I／R）的保护效应受到关注,姜黄素可通过抑制细胞凋亡、促新生神经细胞增殖、调控炎症因子表达、抑制脂质过氧化反应等多种机制减轻缺血再灌注器官的损伤,从而发挥对心、脑、肝、肺、肾等器官缺血再灌注损伤的保护作用。本文对姜黄素在缺血再灌注损伤的器官保护作用研究进行综述,为临床治疗局部缺血再灌注损伤提供理论依据,为研究寻找新的药物作用靶点提供新思路。     

中医药对心肌缺血-再灌注损伤的防治研究进展

心肌缺血-再灌注损伤（myocardial ischemia／reperfusion injury，MIRI）是指在心肌组织缺血恢复血流后，其细胞代谢功能障碍及结构破坏反而加重的现象。如何使心肌缺血一再灌注损伤程度降到最低已成为急性心肌梗死治疗的一个重要的研究课题。近年来，国内在MIRI治疗方面进行了大量的研究。现就心肌缺血．再灌注损伤机制及中医药治疗的进展综述如下。     

AMPK与心肌缺血再灌注损伤的研究进展

心肌缺血再灌注损伤(myocardial ischemiareperfusion injury,MIRI)是构成临床心内直视手术术后影响心功能恢复的主要原因.最新研究显示,急性心肌胰岛素抵抗(IR)很可能是MIRI的又一重要机制,心肌IR形成中,主要的两类心肌能量底物葡萄糖和脂肪酸代谢紊乱尤为突出;腺苷酸活化蛋白激酶(AMPK)作为心肌细胞能量感受器和效应器,在维持缺血缺氧及再灌注心肌细胞糖脂及能量代谢稳态中扮演关键的角色,有望为心肌IR及MI-RI的防治提供重要靶点.     

心肌缺血再灌注损伤的机制研究进展

冠心病严重危害人类的生命健康,主要临床表现为心绞痛或心肌梗死。心肌缺血后再获取血液供应,常会出现心律失常、梗死面积扩大、心功能低下等心肌细胞损伤现象,即心肌缺血再灌注损伤(MIRI)。国内外研究表明MIRI发生机制较为复杂,目前认为与再灌注后机体氧自由基攻击,炎症反应浸润,Ca2+超载,能量代谢障碍、细胞凋亡进程等有关。现对MIRI的机制及治疗的研究进展综述如下。本文通过归纳并总结有关MIRI研究进展的国内外文献,对MIRI的机制做出综述。     

基于疾病与活性化合物靶点网络研究牛舌草治疗大鼠脑缺血-再灌注损伤的作用

目的 基于脑缺血-再灌注损伤与牛舌草中活性化合物靶点网络,研究牛舌草治疗大鼠脑缺血-再灌注损伤的作用及机制。方法 采用线栓法制备脑缺血-再灌注损伤大鼠模型,缺血1.5 h再灌注24 h,对大鼠神经功能进行评分,2,3,5-三苯基氯化四氮唑(TTC)测定大鼠脑梗死体积。采用网络药理学的分子网络分析技术、蛋白质-蛋白质相互作用网络、基因本体(GO)生物过程富集分析、京都基因与基因组百科全书(KEGG)信号通路分析、分子对接等方法研究牛舌草治疗脑缺血-再灌注损伤作用机制。结果 牛舌草给药治疗能够显著改善脑缺血-再灌注损伤引起的神经行为功能障碍,减轻脑组织病理损伤。并且牛舌草能够通过143个缺血性脑卒中相关靶点,调控炎症反应、细胞凋亡等生物过程,干预肿瘤坏死因子信号通路、血管内皮生长因子信号通路和缺氧诱导因子-1信号通路等发挥作用。结论 网络药理学及动物实验表明,牛舌草通过多靶点、多机制整体联合治疗脑缺血-再灌注损伤,可有效降低脑损伤和保护神经功能。     

线粒体靶向抗氧化剂研究进展

线粒体是细胞呼吸的主要场所,在细胞的生命周期中扮演重要角色,三羧酸循环和氧化磷酸化都是在线粒体中进行。线粒体功能障碍可导致一系列疾病,如缺血-再灌注损伤、败血症和糖尿病等。线粒体是神经退行性病变的治疗靶点,也是药物转运策略研究的引人注目的靶位。虽然线粒体所介导的疾病进程的分子机制尚未完全阐明,但氧化应激是关键的环节。开发线粒体靶向的抗氧化应激保护药物具有诱人的前景。线粒体靶向抗氧化剂是指以线粒体为作用靶位的具有抗氧化作用的药物。该文介绍了现有的线粒体靶向抗氧化剂的概念、分类及其疾病治疗研究进展。     

骨骼肌缺血再灌注损伤的研究现状

骨骼肌缺血再灌注损伤是临床常见的病理过程。目前对骨骼肌缺血再灌损伤的病理机制尚不十分清楚,为此,不少学者就骨骼肌缺血再灌注损伤的发病机制及其防治方法进行了广泛深入的研究。本文就骨骼肌缺血再灌注损伤的研究现状综述如下。1　骨骼肌缺血再灌注损伤的病理机制骨骼肌代谢活跃,对缺血反应比较敏感。在缺血再灌注过程中,骨骼肌损伤不仅发生在缺血期间,而且还发生在再灌注时期。缺血再灌注损伤的程度与缺血时间有关。当骨骼肌缺血缺氧时,细胞代谢转化为无氧酵解。细胞能量大量消耗,代谢产物聚集,从而引起骨骼肌在代谢、结构和功能等方…     

黄芪甲苷抑制GSK-3β活性介导大鼠心肌缺血/再灌注损伤作用的线粒体机制研究

目的研究黄芪甲苷对心肌缺血/再灌注损伤(MIRI)的线粒体保护途径,并初步探讨其可能机制。方法建立离体心脏缺血/再灌注模型,结扎冠状动脉进行心肌缺血30min,再灌注120 min,♂Wistar大鼠随机分成对照组、黄芪甲苷组、mPTP开放剂苍术苷(atractyloside)组和抑制剂环孢素A(cyclosporin A,CsA)组;生物信号采集系统检测心功能指标;TTC法测定心肌梗死面积;电镜观察心肌线粒体超微结构变化;差速离心法分离线粒体及Ca2+诱导的线粒体肿胀实验;Western blot检测缺血/再灌注区磷酸化-GSK-3β的表达。结果黄芪甲苷能明显改善心功能,明显减少心肌梗死面积,明显抑制线粒体肿胀,再灌注期GSK-3β磷酸化表达明显增多,与对照组比较差异具有统计学意义(P<0.05)。结论黄芪甲苷对MIRI有保护作用,其机制可能与抑制GSK-3β活性,进而阻止mPTP开放有关。     

脑缺血再灌注损伤及脑保护药物研究进展

脑是一个对缺血缺氧最为敏感的器官,近年来,脑血管病的发病率逐年升高,在这一疾病发生发展过程中,缺血再灌注损伤（ischemia reperfusion injury）在脑血管病的发生发展中起着重要的作用。缺血再灌注致使神经元损伤的过程复杂,主要机制为线粒体受损、能量代谢异常、钙超载、兴奋性氨基酸（excitatory amino acids,EAAs）的神经毒性、自由基的积累、炎症相关介质产生等,致使细胞凋亡程序激活。通过对以上各机制的深入研究有助于明确各种脑保护药物的作用靶点。本文就脑缺血再灌注导致脑损伤的相关机制及最新治疗药物进展进行综述。     

左旋卡尼汀对大鼠心脏缺血-再灌注损伤能量代谢的影响

目的：观察左旋卡尼汀对离体大鼠心脏缺血-再灌注损伤的作用及对心肌细胞能量代谢的影响。方法：将制备成功的Langendorff离体心脏模型随机分成3组（各8只）。正常对照组（CON组）：K—H液灌注65min；左旋卡尼汀组（L—CAR组）：离体心脏用K—H液平衡15min后，K—H液中加入5mmol／L左旋卡尼汀继续灌注20min．然后全心停灌20min，再用相同的液体复灌30min；心肌缺血-再灌注组（MIRI组）：整个实验过程同L—CAR组．但灌注液中不含左旋卡尼汀。比色法测定冠脉流出液中乳酸脱氢酶（LDH）含量，高效液相色谱法测定再灌注末心肌组织中腺苷酸的含量。结果：缺血前各组LDH活性差异无统计学意义（P〉0．05），再灌注末L—CAR组LDH含量明显低于MIRI组（P〈0．01），而心肌组织ATP、ADP、总腺苷酸水平及能荷则高于该组（P〈0．05，P〈0．01）。结论：左旋卡尼汀对缺血-再灌注心肌有保护作用，其保护机制与改善心肌能量代谢有关。     

心肌缺血再灌注损伤的机制研究进展及相关药物的研发

心肌缺血再灌注损伤是在心肌缺血基础上恢复血流后组织损伤加重、甚至发生不可逆性损伤的现象,近年来已成为研究人员普遍关注的临床问题。对心肌缺血再灌注损伤病理机制的研究进展作一综述,并对相关治疗药物进行了简介,旨在为心肌缺血再灌注损伤机制的进一步阐明及有关药物的研发提供参考和思路。     

Mitochondrial-targeted drug and DNA delivery

The field of mitochondrial research is currently among the fastest growing disciplines in biomedicine. Approximately 12,000 articles on mitochondria have been published since the beginning of the new millennium. What brings mitochondria into the limelight of the scientific community? Since the end of the 1980s, a series of key discoveries has been made that have rekindled the scientific interest in this long-known cell organelle. It has become increasingly evident that mitochondrial dysfunction contributes to a variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Moreover, since the middle of the 1990s, mitochondria, the "power houses" of the cell, have also become accepted as the cells' "arsenal," reflecting their increasingly acknowledged key role during apoptosis. Based on these recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of mitochondrial medicine" as a new field of biomedical research. Targeting of biologically active molecules to mitochondria in living cells will open avenues for manipulating mitochondrial functions, which may result in the selective protection, repair, or eradication of cells. This review gives a comprehensive overview of current strategies of mitochondrial targeting and their possible therapeutic applications.     

心肌缺血再灌注损伤的主要机制与相关药物治疗的研究进展

缺血性心肌病在治疗后可能发生缺血再灌注损伤,受损心肌的损伤程度加重,梗死面积扩大,这种现象的发生与多种机制有关,包括：钙超载、氧自由基增多、炎症反应等.随着心肌缺血的治疗技术的提高,缺血再灌注时期的治疗已成为缺血性心肌病的治疗重点,因此,针对防治该时期的药物研发也已成为重点.常见药物作用机制包括：减轻钙超载、抗炎症反应、抗氧自由基和改善能量代谢等.本文旨在对MIRI不同病理机制和相关药物的研究进展进行阐述.     

线粒体在脓毒症肝损伤发病机制及治疗中的作用

线粒体功能障碍所致的细胞能量衰竭与脓毒症期间器官功能损害密切相关。肝脏细胞中存在丰富的线粒体,肝脏是脓毒症相关器官损伤的重要靶点。本文概述了线粒体在脓毒症肝损伤发病机制中的作用,以及线粒体修复过程的动态平衡对于维持线粒体稳态和减轻肝脏损伤的重要意义,以期为脓毒症治疗提供参考。     

大鼠心肌缺血再灌注损伤组织中MMP-2、9/TIMP-1、2mRNA表达比值的变化及意义

目的探讨心肌缺血再灌注损伤(MIRI)组织中基质金属蛋白酶-2、9(MMP-2、9)和组织金属蛋白酶抑制因子-1、2(TIMP-1、2)基因mRNA表达的变化规律及其临床意义。方法建立大鼠MIRI模型,采用HE、RTPCR、免疫组化、酶谱分析等方法,检测MIRI不同时相中MMP-2、9和TIMP-1、2 mRNA表达变化。结果在MIRI过程中MMP-2、9的mRNA和蛋白相对表达量呈升高趋势,二者在MIRI 8 h时表达量达高峰,与对照组(sham组)相比具有非常显著性差异(P<0.01)。TIMP-1、2的mRNA相对表达量在整个再灌注过程中增高,与sham组相比有显著性差异(P<0.05),而蛋白水平的相对表达量与sham组相比无统计学差异(P>0.05)。MMP-2、9/TIMP-1、2 mRNA表达比值趋于失衡。酶活性MMP-2在MIRI 4 h达高峰(16832.67±727.40),MMP-9在MIRI 12 h达高峰(6534.85±421.50),与sham组和MIRI 30 min组相比,二者均有非常显著性差异(P<0.01)。结论 MMP-2、9/TIMP-1、2mRNA表达比值失衡是MIRI的重要指标之一。     

Mitochondria: a target for neuroprotective interventions in cerebral ischemia-reperfusion

Evidence obtained over the past two decades shows that reactive oxygen species (ROS) are involved in brain lesions, including those due to cerebral ischemia-reperfusion. The mitochondria are the primary intracellular source of ROS, as they generate huge numbers of oxidative-reduction reactions and use massive amounts of oxygen. When anoxia is followed promptly by reperfusion, the resulting increase in oxygen supply leads to overproduction of ROS. In ischemic tissues, numerous studies have established a direct role for ROS in oxidative damage to lipids, proteins, and nucleic acids. Thus, mitochondria are both the initiator and the first target of oxidative stress. Mitochondrial damage can lead to cell death, given the role for mitochondria in energy metabolism and calcium homeostasis, as well as the ability of mitochondria to release pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor (AIF). This review discusses possible mitochondrion-targeted strategies for preventing ROS-induced injury during reperfusion. The sequence of events that follow oxidative damage provides the outline for the review: thus, we will discuss protection of oxidative phosphorylation, mitochondrial membrane integrity and fluidity, and antioxidant or mild-uncoupling strategies for diminishing ROS production. Among mechanisms of action, we will describe the modulation of mitochondrial permeability transition pore (MPTP) opening, which may not only operate as a physiological Ca(2+) release mechanism, but also contribute to mitochondrial deenergization, release of pro-apoptotic proteins, and protection by ischemic preconditioning (IPC). Finally, we will review genetic strategies for controlling apoptotic protein expression, stimulating mitochondrial oxidative defences, and increasing mitochondrial proliferation.     

Protective effect of PNU-120596, a selective Alpha7 nicotinic acetylcholine receptor-positive allosteric modulator, on myocardial ischemia-reperfusion injury in rats

The cholinergic anti-inflammatory pathway has been found to exert a protective role in myocardial ischemia-reperfusion injury (MIRI). Alpha7 nicotinic acetylcholine receptor (α7nAChR) is a regulator of cholinergic anti-inflammatory pathway; however, little information is available on the effect of α7nAChR on MIRI. In the present study, we hypothesized that 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596), a potent positive allosteric modulator of α7nAChR, could play a protective role on MIRI. Fifty-five rats were randomly assigned into 4 groups: Sham group, ischemia-reperfusion group, PNU-120596 group, α-bungarotoxin group. Compared with ischemia-reperfusion group, PNU-120596 treatment markedly decreased infarct size, ultrastructural damage, serum creatine kinase, and lactate dehydrogenase. Serum proinflammatory cytokine production, myocardium endothelial activation and neutrophil infiltration, myocardium malondialdehyde were also significantly decreased, accompanied by increased myocardium superoxide dismutase production, in the PNU-120596 group compared with the ischemia-reperfusion group. Meanwhile, we observed a significant inhibition of nuclear factor kappa B activation in PNU-120596 group compared with ischemia-reperfusion group. Pretreatment of α7nAChR-selective antagonist, α-bungarotoxin, abolished all the protective effects of PNU-120596 on MIRI. In conclusion, PNU might have a protective effect against MIRI. Its action mechanisms might be involved in the inhibition of inflammatory responses, attenuation of lipid peroxidation, and suppression of nuclear factor kappa B activity.