Targeting the peroxisome proliferator-activated receptors (PPARs) in spinal cord injury

Introduction: Traumatic spinal cord injury (SCI) causes severe and permanent functional deficits, due to the primary mechanical insult, followed by secondary tissue degeneration. The direct damage is followed by a second phase of tissue degeneration, which may take place over a period of weeks or even months, causing neuronal and axonal destruction. A key mediator of this process is an acute and robust inflammatory response, which involves the synthesis and release of chemokines and cytokines, and a coordinated recruitment of circulating leucocytes, as well as microglia, from the CNS parenchyma. The search for a ‘cure’ for SCI has yet to produce a convincingly efficacious treatment that improves the outcome for patients.

Areas covered: This review explores the experimental studies describing the beneficial effects of PPAR receptor modulators in spinal cord trauma.

Expert opinion: Because of safety issues and limited data, PPAR agonists are not yet included in SCI-related treatment strategies. PPAR agonists for specific isoforms (α, β/δ and γ) have demonstrated both anti-inflammatory and immunomodulatory properties. Pharmacological activation of PPAR can be considered as a multi-faceted therapeutic target, due to its anti-inflammatory/antioxidant/anti-excitotoxic/pro-energetic profile, reported in some neurological and inflammatory-related diseases.     

PPARγ调节剂研究进展PPARγ调节剂研究进展

1　前言胰岛素增敏剂噻唑烷二酮类化合物(thiozolidiones,TZDs)在 2 0世纪 80年代就已被广泛研究。但开始并不清楚其分子作用机制 ,直到 1 0年后才有研究表明 ,TZDs的作用靶点是过氧化物酶体增殖因子活化受体 (peroxisomepoliferratoractivatedreceptors,PPARs) [1]。　　PPARs     

Cardioprotective mechanisms of PKC isozyme-selective activators and inhibitors in the treatment of ischemia-reperfusion injury

Current treatment for acute myocardial infarction (AMI) is aimed at limiting the duration of ischemia by either mechanical (balloon catheters) or enzymatic (thrombolytics) means to disrupt the occlusion. While these treatments are effective in limiting the duration of ischemia, no therapeutic treatment is currently available to prevent ischemic injury and to reduce reperfusion injury, which occurs after these interventions. The development of rationally designed PKC isozyme-selective regulator peptides has permitted investigation into the role of specific PKC isozymes in ischemia-reperfusion (IR) injury. Based on these studies, it is now evident that epsilon and deltaPKC have distinct temporal and opposing roles in regulating myocardial damage induced by IR. Activation of epsilonPKC before ischemia protects the heart by mimicking preconditioning, whereas inhibition of deltaPKC during reperfusion protects the heart from reperfusion-induced damage. These cardioprotective effects have been observed in isolated cardiomyocytes, isolated perfused hearts and in vivo in all species tested including mouse, rat and pig and may provide the basis for future therapeutic agents. Having established the efficacy of PKC isozyme-specific regulators in reducing IR injury, the next challenge is to outline the molecular mechanisms regulated by delta and epsilonPKC isozymes that result in enhanced tolerance to IR. In this review, we discuss progress that has been made in establishing cytoprotective mechanisms, which arise as a consequence of epsilonPKC activation or deltaPKC inhibition, and how they may lead to protection in the setting of myocardial ischemia reperfusion.     

肝移植相关的缺血再灌注损伤

随着新型免疫抑制剂的临床应用和血管吻合技术的提高,临床肝移植成功率大大提高,而严重肝脏缺血再灌注损伤所引起的移植肝功能受损始终未能解决,影响肝移植的效果。因此本文对肝脏缺血再灌注损伤的分类、机制、预防及治疗等方面予以综述。     

Peroxisome proliferator-activated receptor ligands in atherosclerosis

In this review, the effect of peroxisome proliferator-activated receptor (PPAR) ligands on atherosclerosis is examined. The PPAR-γ agonist thiazolidinediones are currently indicated for the management of Type 2 diabetes mellitus, and the PPAR-α agonist fibrates are used in dyslipidaemia. Here their mechanism of action and the pre-clinical and clinical evidence for the use of these medications for the prevention and treatment of atherosclerotic disease is explored. In addition, the role of PPAR-δ and the possibilities for the role of dual-binding agonists are examined.     

雌激素对兔脊髓缺血再灌注损伤的保护作用

目的：探讨雌激素对兔脊髓缺血再灌注损伤的神经保护效应。方法成年新西兰大白兔肾下腹主动脉钳夹20min恢复再灌注。实验分组如下：Control组（n=8）仅行肾下腹主动脉钳夹20min恢复再灌注;Sham组（n=8）行对照组操作除外肾下腹主动脉钳夹;雌激素处理组（n=8）分别在再灌注开始即刻经兔耳缘静脉给予雌激素200,400,800μg/kg。再灌注后48h进行下肢神经功能评分（Tarlov法）后处死受试动物,取脊髓行组织HE染色切片病理分析。结果Tarlov评分发现雌激素处理组神经功能评分明显高于control组（P＜0.05）。组织病理分析可见脊髓前角运动神经元凋亡,坏死较明显。雌激素处理组脊髓前角运动神经元计数明显多于Control组（P＜0.01）。结论兔脊髓缺血后静脉给予雌激素可明显改善下肢神经功能,增加脊髓前角正常运动神经元数量,减轻缺血再灌注损伤。     

PPAR及其激动剂与脂肪酸代谢及胰岛素抵抗

过氧化物酶体增殖物激活受体(PPAR)在脂肪细胞分化、脂肪酸代谢中起重要作用,PPAR及其所调控基因的激活可促进脂肪细胞分化、减少脂质产生、增加脂肪酸氧化,从而减少脂质的异位沉积,进一步改善损伤的胰岛素信号转导通路,逆转胰岛素抵抗。针对脂肪酸合成及氧化的关键调控点的药物可能是今后治疗胰岛素抵抗引发的一系列代谢异常的新的靶点。     

过氧化物酶体增殖物激活受体-γ与胰腺疾病的关系

过氧化物酶体增殖物激活受体γ（peroxisome proliferator activated receptor γ,PPARγ）是一类依赖配体活化的转录因子,属于Ⅱ型核激素受体超家族成员。PPAR-γ是近年来国内外研究的一个热点,现已明确其在细胞增殖分化、炎症反应、糖代谢及脂类代谢具有重要的调节作用。本文就PPARγ与胰腺疾病的关系作一综述。     

大鼠急性心肌缺血诱发肺损伤的信号机制

目的探寻大鼠急性心肌缺血再灌注后诱发肺损伤的信号机制。方法 12只健康雄性Wistar大鼠随机分为2组(n=6):心肌缺血再灌注组(C组)和假手术组(S组)。采用活结结扎冠状动脉左前降支(LAD)的方法制备心肌缺血再灌注模型。C组阻断LAD45min后再灌注3h;S组缝合针仅穿过LAD下方,不结扎。分别于实验结束时放血处死大鼠,提取肺组织、支气管肺泡灌洗(BAL)液和血清;进而测定血清肌酸激酶同工酶(CK-MB)、计算肺通透性指数(PPI)、蛋白印迹法检测肺组织转化生长因子(TGF)-β1和肿瘤坏死因子(TNF)-α蛋白的含量。结果与S组相比,C组CK-MB和PPI明显升高;同时TGF-β1和TNF-α蛋白含量增加。结论大鼠心肌缺血再灌注后肺组织TGF-β1和TNF-α蛋白含量明显增加。     

心肌缺血再灌注损伤发生机制的研究进展

随着社会的发展,物质水平的不断提高,不健康的饮食习惯、运动的缺乏、大量吸烟饮酒、精神压力过大等因素导致心血管疾病的发病率呈逐年增高趋势,严重威胁着人类的身体健康,而在心血管疾病的治疗过程中,心肌缺血再灌注损伤可加重原有的损伤,引起心肌细胞的结构及功能发生不可逆性改变,进而加重原有的心血管疾病,最终导致患者病情恶化甚至死亡,因此探讨缺血再灌注损伤的发生机制具有十分重要的意义.该文从氧自由基爆发、Ca2+超载、线粒体功能障碍、炎症、能量代谢障碍几个方面对心肌缺血再灌注损伤的发生机制作一综述,为临床上减轻缺血再灌注损伤提供一定的理论依据.     

高脂饮食对非酒精性脂肪肝大鼠肝脏过氧化物酶体增殖物活化受体γ表达的影响

目的探讨过氧化物酶体增殖物活化受体(PPARγ)在高脂饮食所致非酒精性脂肪肝(NAFLD)大鼠肝脏的表达及其意义。方法模型组Wistar大鼠给予高脂饮食饲养,分批于实验第4、8、12周处死,设普通饮食饲养大鼠作对照。测定空腹血糖(FBG)、空腹胰岛素(FINS),计算胰岛素敏感指数(ISI);测定血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总胆固醇(TC)、甘油三酯(TG);苏木素-伊红(HE)染色观察肝组织病理变化;反转录聚合酶链反应(RT-PCR)分别检测大鼠肝脏PPARγmRNA的表达。结果模型组大鼠第4周呈现单纯性脂肪肝,第8~12周从单纯性脂肪肝进展为脂肪性肝炎,个别出现肝纤维化;RT-PCR显示,随着造模时间延长,肝脏PPARγmRNA的表达逐渐减弱,于第12周达到最低。结论持续12周的高脂饮食可以成功复制大鼠NAFLD模型;模型大鼠肝脏PPARγmRNA表达随造模时间的延长而逐渐减弱,PPARγ可以通过对胰岛素抵抗的调控参与NAFLD的发生发展。     

下肢缺血预处理对大鼠肺缺血-再灌注损伤的保护作用

目的 研究下肢缺血预处理在大鼠肺组织缺血-再灌注(I-R)损伤中的作用及机制.方法 18只SD大鼠随机均分为假手术(A组)、I-R(B组)和下肢缺血预处理十I-R(C组)三组.实验结束时,取肺组织测定湿/干重比(W/D)、超氧化物歧化酶(SOD)、髓过氧化物酶(MPO)活性和丙二醛(MDA)含量,观察肺组织病理学变化;ELISA法检测血清肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)和IL-6含量.结果 与B组比较,C组肺组织W/D、MPO活性和MDA、TNF-α、IL-1β、IL-6的含量均明显降低(P＜0.05),SOD活性升高(P＜0.05).光镜下C组肺组织病理学改变较B组明显减轻.结论 下肢缺血预处理可以通过抑制大鼠肺组织I-R后炎症细胞的聚集、氧自由基的产生和促炎细胞因子TNF-α、IL-1β、IL-6的释放而减轻肺I-R损伤.     

乌司他丁对肝脏缺血再灌注损伤中线粒体的作用

目的探讨乌司他丁在肝脏缺血再灌注损伤中对线粒体的作用及其机制。方法采用健康杂交狗全肝缺血再灌注模型,检测肝功能、线粒体H+-ATP酶活性及电镜观察线粒体形态的变化。结果肝功能指标的测定:对照组、实验组较假手术组丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)均增高,差异有统计学意义(P<0.05),肝脏缺血再灌注损伤实验模型制作成功。实验组较对照组ALT、AST均降低,差异有统计学意义(P<0.05)。线粒体结构及功能检测:阻断组较假手术组H+-ATP酶活性均降低,差异有统计学意义(P<0.05)。实验组较对照组H+-ATP酶活性均增高,差异有统计学意义(P<0.05)。手术组线粒体分级为0级;对照组:缺血15min线粒体分级为2￣3级;再灌注损伤1h线粒体分级为4级;实验组:缺血15min,分级为1￣2级;再灌注损伤1h线粒体分级为2￣3级。结论乌司他丁对线粒体损伤有保护作用,其作用机制为稳定线粒体脂质双分子膜,增高线粒体H+-ATP酶活性,保护线粒体结构及其功能,从而保护肝细胞,减轻肝脏缺血再灌注损伤。     

参麦及缺血预处理对大鼠肝缺血再灌注损伤的保护作用

目的:研究参麦注射液及缺血预处理对肝缺血再灌注损伤的保护作用.方法:64只Wistar大鼠随机分成4组:假手术组(sham-operation,SO);缺血再灌注组(ischemia reperfusion,IR);缺血预处理组(ischemic preconditioning,IPC);参麦组(Shengmai injection,SM).建立肝脏缺血再灌注损伤模型.SO组行剖腹假手术;IR、IPC、SM组于再灌注60 min 、90 min时分别随机取8只大鼠检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、乳酸脱氢酶(LDH)和白细胞介素6(IL-6),同时取肝组织制成匀浆检测金属硫蛋白(MT),SO组于相应时点取样检测相同指标.分析比较各组计量资料.结果:SM组及IPC组在再灌注60 min、90 min时ALT、AST、LDH、IL-6水平均低于IR组(P＜0.01),而金属硫蛋白水平均高于IR组.结论:参麦及缺血预处理对肝缺血再灌注损伤具有保护作用.     

川芎嗪对大鼠局灶性脑缺血再灌注损伤的保护作用及机制研究

目的探讨川芎嗪对大鼠局灶性脑缺血再灌注损伤的保护作用及机制。方法将64只健康雄性SD大鼠随机分为四组：（1）假手术组;（2）缺血再灌注组;（3）川芎嗪20 mg/kg处理组;（4）川芎嗪40 mg/kg处理组。每组各16只,8只用于脑梗死体积测定,8只用于mRNA和蛋白的测定。采用线栓法制备大鼠局灶性大脑中动脉栓塞模型,缺血2 h再灌注24 h。术后对大鼠神经功能进行评分;2,3,5-氯化三苯四氮唑染色观察脑梗死体积;酶联免疫吸附法测定脑组织中肿瘤坏死因子-α（TNF-α）、白介素-1β（IL-1β）和核因子-κBp65（NF-κBp65）水平;实时定量聚合酶链反应和蛋白质印迹法分别检测Toll样受体4（TLR4）mRNA和蛋白的表达。结果与假手术组比较,缺血再灌注组大鼠的神经功能缺陷评分和脑梗死体积明显增加;脑组织中TNF-α、IL-1β和NF-κBp65水平以及TLR4的表达也显著升高,差异均有统计学意义（P〈0.05）。川芎嗪处理组上述指标,与缺血再灌注组比较,差异有统计学意义（P〈0.05）;不同剂量川芎嗪处理组间比较,差异无统计学意义（P〉0.05）。结论川芎嗪可抑制脑缺血再灌注诱导的损伤,其机制与抑制TLR4/NF-κB信号通路,进而减少炎症因子的产生有关。