过氧化物酶体增殖物激活受体γ与胃癌关系研究进展

过氧化物酶体增殖物激活受体γ（PPARγ）是一种核激素受体,受其配体激活后可调节体内的糖代谢.近年研究发现,它还可诱导多种肿瘤细胞分化,并抑制其恶性增殖,具有潜在的抗肿瘤作用.     

过氧化物酶体增殖物激活受体γ与动脉粥样硬化

过氧化物酶体增殖物激活受体γ（PPARγ）是配体激活的转录因子核受体超家族成员之一，它可通过调控脂肪细胞分化、改善糖、脂代谢紊乱，抑制炎症反应等，影响动脉粥样硬化（AS）的发生和发展。作者就PPA脚与AS关系的研究进展作一综述。     

过氧化物酶体增殖物激活受体γ在急性胰腺炎中的研究进展

过氧化物酶体增殖物激活受体(PPAR)属于核激素受体超家族.PPAR有3种亚型,即PPARα、PPARβ和PPARγ,其中PPARγ与急性胰腺炎的关系最为密切,成为最近研究的热点.本文就PPARγ的一般特性及其在急性胰腺炎中的研究进展作一综述,旨在为急性胰腺炎的治疗提供新的思路.     

过氧化物酶体增殖物激活受体γ在人垂肿瘤中的分布与表达

目的研究过氧化物酶体增殖物激活受体γ(PPAR-γ)在人垂体腺瘤组织中的分布和表达.方法免疫组织化学染色检测PPAR-γ在垂体腺瘤组织中的分布情况,Western blot方法分析PPAR-γ在正常垂体与垂体腺瘤中的表达水平.结果免疫组织化学染色显示,PPAR-γ主要分布于细胞核内.Western blot结果显示,PPAR-γ在垂体腺瘤中的表达水平显著高于正常垂体组织(P＜0.01),在促肾上腺皮质激素腺瘤中的表达水平显著高于其他内分泌类型垂体腺瘤(P＜0.05).结论PPAR-γ可能在肿瘤的发生、生长、侵袭中起重要作用,该受体有可能成为未来垂体腺瘤治疗的新靶点.     

过氧化物酶体增殖物激活受体γ在人垂体腺瘤中的分布和表达

目的研究过氧化物酶体增殖物激活受体γ(PPAR-γ)在人垂体腺瘤组织中的分布和表达。方法免疫组织化学染色检测PPAR-γ在垂体腺瘤组织中的分布情况,Western blot方法分析PPAR-γ在正常垂体与垂体腺瘤中的表达水平。结果免疫组织化学染色显示,PPAR-γ主要分布于细胞核内。Western blot结果显示,PPAR-γ在垂体腺瘤中的表达水平显著高于正常垂体组织(P<0·01),在促肾上腺皮质激素腺瘤中的表达水平显著高于其他内分泌类型垂体腺瘤(P<0·05)。结论PPAR-γ可能在肿瘤的发生、生长、侵袭中起重要作用,该受体有可能成为未来垂体腺瘤治疗的新靶点。     

过氧化物酶体增殖物激活受体γ与动脉粥样硬化

过氧化物酶体是胞浆内细胞器，在调节哺乳动物长链脂肪酸的代谢及胆固醇向胆汁盐转化过程中起重要作用。过氧化物酶体增殖物是一组包括纤维酸类调脂药，除草剂等在内的能促进实验动物肝细胞过氧化物酶体增殖的化学物质。其激活的受体称为过氧化物酶体增殖物激活受体(PPAR)。PPAR属于核内激素受体家族成员，也是一种转录因子。共有     

内脂素对THP-1源性泡沫细胞形成中过氧化物酶体增殖物激活受体γ表达的作用

目的:观察内脂素(visfatin)诱导人类单核细胞白血病细胞株THP-1源性泡沫细胞形成中过氧化物酶体增殖物激活受体γ(PPARγ)的表达作用。方法:给予不同浓度的visfatin处理THP-1源性巨噬细胞,并加入低密度脂蛋白(LDL)孵育24 h后,运用油红O染色观察细胞内脂滴的变化,运用逆转录聚合酶链反应和Western-blot检测PPARγ的mRNA和蛋白表达水平。结果:高浓度的visfatin刺激负荷LDL的THP-1源性巨噬细胞24 h后,细胞质内的脂滴明显增多。visfatin呈浓度依赖性的下调负荷LDL的THP-1源性巨噬细胞中PPARγmRNA和蛋白表达(P<0.05)。结论:visfatin对THP-1源性泡沫细胞形成中PPARγ表达水平的下调,这可能在动脉粥样硬化的发生发展起重要作用。     

过氧化物酶体增殖物激活受体α、γ激动剂与肿瘤

过氧化物酶体增殖物激活受体(PPAR)属于核激素受体超家族,现已知有3种亚型:PPARα、PPARβ/δ和PPARγ,其中PPARα和PPARγ分别是高血脂和糖尿病治疗药物的靶点,以PPARβ/δ为靶点的药物也已进入临床试验阶段。然而,近年来一些临床前及临床试验结果提示,PPARα/γ和PPARβ/δ激动剂可诱发小鼠多种肿瘤,PPARγ激动剂吡格列酮可能与人类膀胱癌发生有关。因此,PPAR与肿瘤的关系引起人们关注。本文综述了PPARα和PPARγ激动剂与肿瘤的关系,以期为PPAR激动剂的安全使用及进一步研发提供参考。     

过氧化物酶体增殖物激活受体γC161T基因多态性与慢性肾脏病的关系

目的 探讨过氧化物酶体增殖物激活受体γ(PPARγ)C161T基因多态性与慢性肾脏病(CKD)的关系.方法 选取91例CKD患者作为CKD组,经体格检查证实的149名健康者作为正常对照组.均检测血压、体质指数(BMI)、尿白蛋白/尿肌酐(ACR)、24 h尿蛋白定量、肾功能、空腹血糖、血脂、肾小球滤过率等临床指标,应用聚合酶链反应(PCR)技术检测PPARγC161T基因多态性,综合分析基因频率、等位基因频率分布以及不同基因型与临床资料、生化指标的关系.结果 ①CKD组与正常对照组间CC、TC+TT基因型分布频率以及C、T等位基因分布频率的差异均无统计学意义(P值均＞0.05).②CKD患者中,大量蛋白尿亚组的CC基因型、C等位基因分布频率均显著高于非大量蛋白尿亚组(P值均＜0.05),而TC+TT基因型、T等位基因分布频率均显著低于非大量蛋白尿亚组(P值均＜0.05),CKD 1期亚组与CKD 2～5期亚组问各基因型和等位基因分布频率的差异均无统计学意义(P值均＞0.05).③CKD患者中,CC基因型亚组与CT+TT基因型亚组患者的BMI、空腹血糖、收缩压、舒张压、24 h尿蛋白定量、三酰甘油、高密度脂蛋白胆固醇的差异均无统计学意义(P值均＞0.05),而CC基因型亚组的血肌酐、总胆固醇、低密度脂蛋白胆固醇均明显高于CT+TT基因型亚组(P值均＜0.05).结论 PPARTCγ161T基因多态性与CKD的致病危险因素及严重程度有关,C等位基因可能促进CKD的发展.     

过氧化物酶体增殖物激活受体γ辅激活剂-1αrs2946385基因多态性与帕金森病的相关性

目的 探讨过氧化物酶体增殖物激活受体γ辅激活剂-1α(PGC-1α)rs2946385基因多态性与帕金森病(PD)发病风险及患者焦虑、认知的关系.方法 选择2018年3月至2019年12月就诊于新乡医学院第一附属医院的86例PD患者(PD组)及86例健康体检人员(对照组)为研究对象.PD组患者根据运动症状分为强直少动型...     

过氧化脂质体增殖活受体—γ对系膜细胞炎症的调控作用

目的：了解过氧化脂质体增殖激活受体-γ(PPARγ)在核转录水对人系膜细胞（HMCL）炎症过程的调控作用。方法：培养人系膜细胞,利用IL-1β制备炎症性系膜细胞模型,酶联免疫吸附方法（ELISA）测定培养细胞上清液TNF-γ和IL-6水平;蛋白印迹方法测定HMCL中。加入不同浓度的罗格列酮（RGZ）、曲格列酮（TGZ）及15d-PGF2,PPARγ蛋白水平;逆转录聚合酶链反应（RT-PCR）方法检测培养细胞中PPARγ和炎症因子的mRNA表达。结果：IL-1β(10ng/ml)可使炎性细胞因子TNF-γ和IL-6蛋白、mRNA表达增加,正常人系膜细胞可低水平表达PPARγ,炎症刺激后PPARγ蛋白和mRNA表达显著增加,PPARγ特异性配基曲格列酮（TGZ）可下凡PPARγ表达。三种结构不同的PPARγ特异性配基TGZ、RGZ和15d-PGJ2可下调炎症刺激后IL-6和TNF-γ蛋白水平,且这种抗炎效应的作用环节在mRNA水平。结论：PPRAγ可能是系膜细胞炎症与抗炎反应过程中炎症自我限制的一个重要靶位,作用于这一靶位的特异性配基有望成为治疗肾小球肾炎的新药。     

过氧化脂质体增殖激活受体-γ对系膜细胞炎症的调控作用

目的了解过氧化脂质体增殖激活受体-γ(PPARγ)在核转录水平对人系膜细胞(HMCL)炎症过程的调控作用.方法培养人系膜细胞,利用IL-1β制备炎症性系膜细胞模型,酶联免疫吸附方法(ELISA)测定培养细胞上清液TNF-γ和IL-6水平;蛋白印迹方法测定HMCL中.加入不同浓度的罗格列酮(RGZ)、曲格列酮(TGZ)及15d-PGF2,PPARγ蛋白水平;逆转录聚合酶链反应(RT-PCR)方法检测培养细胞中PPARγ和炎症因子的mRNA表达.结果 IL-1β(10 ng/ml)可使炎性细胞因子TNF-γ和IL-6蛋白、mRNA表达增加,正常人系膜细胞可低水平表达PPARγ,炎症刺激后PPARγ蛋白和mRNA表达显著增加,PPARγ特异性配基曲格列酮(TGZ)可下调PPARγ表达.三种结构不同的PPARγ特异性配基TGZ、RGZ和15d-PGJ2可下调炎症刺激后IL-6和TNF-γ蛋白水平,且这种抗炎效应的作用环节在mRNA水平.结论 PPARγ可能是系膜细胞炎症与抗炎反应过程中炎症自我限制的一个重要靶位,作用于这一靶位的特异性配基有望成为治疗肾小球肾炎的新药.     

Effects of curcumin on peroxisome proliferator-activated receptor γ expression and nuclear translocation/redistribution in culture-activated rat hepatic stellate cells

Background The function of peroxisome proliferator-activated receptor γ （PPARγ） in hepatic fibrogenesis remains largely unknown. Curcumin is a natural substance extracted form Curcuma Longa Linn and has a variety of pharmacological effects. In this study, the effects of curcumin on the proliferation, activation and apoptosis of rat hepatic stellate cells （HSCs） through PPARγ signaling were investigated. Methods HSCs were isolated from the normal Sprague Dawley rats through in situ peffusion of the liver with Pronase E and density-gradient centrifugation with Nycodenz. Cells were treated with curcumin, troglitazone, salvianolic acid B or GW9662. The effect on HSCs proliferation was determined by MTT colorimetry. Total RNA was extracted by TRizol reagent and gene levels were determined by semi-quantitative RT-PCR. Total cellular and nuclear protein were isolated and separated by 10% sodium dodecy Isulfate polyacrylamide gel electrophoresis. Protein levels were determined by Western blot. Cell apoptosis was detected by Hoechst 33258 staining. PPARγ subcellular distribution was detected by immunofluorescent staining. The activities of MMP-2 and 9 were measured by Gelatin zymograph assay. Results Curcumin suppressed HSCs proliferation in a dose-dependent manner. As HSCs underwent gradual activation with culture prolongation the PPARγ nuclear expression level decreased. Curcumin up-regulated PPARγ expression and significantly inhibited the production of a-SMA and collagen Ⅰ. PPARγ is expressed in the cytoplasm and nucleus and is evenly distributed in HSCs, but accumulated in the nucleus of HSCs and disappeared from cytoplasm after curcumin treatment. Hoechst 33258 staining showed that curcumin induced the apoptosis of culture-activated HSCs and significantly increased pro-apoptotic Bax expression and reduced anti-apoptotic Bcl-2 expression. Cyclin D1 gene, activated NFKB p65 protein and TGFβR-Ⅰ protein expression were down-regulated significantly by curcumin. The activities of MMP-2 and MMP-9 were enhanced significantly by curcumin. Conclusions Curcumin can inhibit the proliferation and activation of HSCs, induce the apoptosis of activated HSCs and enhance the activities of MMP-2 and MMP-9. The effects of curcumin are mediated through activating the PPARγ sianal transduction pathway and associated with PPARγ nuclear translocation/redistribution.     

过氧化物酶体增殖物激活受体γ在胶质瘤中的表达

目的 探讨胶质瘤组织及细胞株中过氧化物酶体增殖物激活受体γ(PPARγ)的表达及其意义.方法 应用免疫组化检测40例胶质瘤中PPARγ蛋白的表达;Western blotting检测3株胶质瘤细胞SWO-38、U251和SHG-44中PPARγ及神经胶质酸性蛋白蛋白的表达;RT-PCR检测3株胶质瘤细胞PPARγ mRNA的表达.结果 PPARγ在胶质瘤组织中阳性表达率为37.5%,与肿瘤的分化程度无明显相关性(P=0.154);PPARγ蛋白及mRNA在SWO-38和U251中表达,而SHG-44不表达:神经胶质酸性蛋白则在SHG-44中高表达.结论 PPARγ可能与胶质瘤的发生相关,可为胶质瘤治疗提供新的靶点.     

过氧化物酶体增殖激活物受体γ在皮肤恶性黑色素瘤中的表达及意义

目的 研究过氧化物酶体增殖激活物受体γ(PPARγ)在皮肤恶性黑素瘤(MM)中的表达及其意义.方法 采用免疫组化方法(SP法)检测26例MM患者(MM组)及30例色素痣对照组(色素痣组)皮损部位PPARγ蛋白的表达水平.结果 MM组PPARγ的表达强度显著高于色素痣组(P<0.01);且有转移MM组显著高于无转移MM组(P<0.05).结论 MM患者皮损部位PPAR<的表达增高,在MM的发病机制中可能起一定的作用,有可能成为治疗MM的新靶点.     

Activation of peroxisome proliferator-activated receptor α in human endothelial cells increases plasminogen activator inhibitor type-1 expression

Objective To investigate the effect of peroxisome proliferator-activated receptors(PPARs) activators on plasminogen activator inhibitor 1(PAI-1) expression in human umbilical vein endothelial cells and elucidate a possible mechanism.Methods Human umbilical vein endothelial cells(HUVECs) were obtained from normal fetus,and cultured conventionally.Then the HUVEC were exposed to fatty acids and prostaglandin J2 in varying concentrations with fresh media.RT-PCR and ELISA were used to determine the expression of PPAR and PAI-1 in HUVECs.Transient co-transfection of PAI-1 promoter and PPARα gene or PPARγ gene to ECV304 was performed.Results PPARα,PPARγ and PPARγ mNRA in HUVECs were detected by RT-PCR.Treatment of HUVECs with PPARα and PPARγ activators-linolenic acid,linoleic acid,oleic acid and prostaglandin J2,but not with stearic acid could augment PAI-1 mRNA expression and protein secretion in a concentrationdependent manner.Proportional induction of PAI-1 promoter activity was observed through increasing amounts of PPARαDNA in HUVECs throgh a transient gene transfection assay,although the mRNA expression of the 3 subtypes of PPAR with their activators were not changes compared with controls.Conclusions HUVECs express PPARs,PPARs activators may increase PAI-1 expression in endothelial cells(EC).Although PPARs expresslon was not enhanced after being stimulated by their activators in EC,the functionally active PPARαis probably involved in regulating PAI-1 expression in EC.     

Association of β3 Adrenergic Receptor and Peroxisome Proliferator-activated Receptor Gamma 2 Polymorphisms With Insulin Sensitivity： A Twin Study

Objective To study the effect of β3 adrenergic receptor(β3AR) Trp64Arg and peroxisome proliferator activated receptor gamma 2(PPARγ2) Pro12Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment(HOMA). PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method,identity by state(IBS) was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg,Trp64Arg,and Arg64Arg were 72.3%,23.8%,and 3.9%,respectively,while the genotype frequencies of Pro12Pro,Pro12Ala,and Ala12Ala were 89.9%,9.6%,and 0.5%,respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio(WHR),blood glucose(GLU),and insulin(INS),homeostasis model assessment insulin resistance index(HOMA-IR) of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS,and HOMA-IR had statistic significance. For PPARγ2 Pro12Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index(BMI),WHR,percent of body fat(PBF) and GLU,but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Conclusions β3AR Trp64Arg and PPARγ2 Pro12Ala polymorphisms might be associated with insulin resistance and obesity,and there might be slight synergistic effects between this two gene loci,and further studies are necessary to confirm this finding.     

氟吡洛芬酯减轻大鼠脑缺血损伤通过激活脑PPAR-γ起作用

我们以前的研究证实氟吡洛芬酯(FA),COX抑制剂,在大鼠局灶性脑缺血模型有较广的治疗时间窗,然而其机制是否通过激活或者部分激活PPAR-γ还未被证实。48只SD大鼠被随机分为六组（每组8只）,缺血再灌注组(I/R)仅进行120分钟大脑中动脉阻塞(MCAO);I/R+FA组大脑中动脉阻塞120分钟后经尾静脉给予FA10mg.kg-1;I/R +FA+GW9662组在MCAO前30分钟经腹腔给予GW9662(a PPAR-γ 抑制剂) 4mg.kg-1,MCAO120分钟后经尾静脉给予FA10mg.kg-1; I/R +GW9662组在MCAO前30分钟经腹腔给予GW9662 4mg.kg-1,而后进行120分钟MCAO; I/R +DMSO组在MCAO前30分钟经腹腔给予3% DMSO (GW9662的溶媒)1ml.kg-1; 假手术组（Sham）仅进行除大脑中动脉栓塞的MCAO操作。再灌注72小时神经缺陷评分（NDS）后深麻醉下处死大鼠取脑TTC染色计算脑梗死容积百分比。与I/R组相比,I/R+FA组[12.0(10-15)], I/R+FA+GW9662组[10.0(8-12)]以及I/R+FA+DMSO组[12.0(9-14)]72小时NDS明显提高;I/R+FA组[12.0(10-15)]与I/R+FA+GW9662组[10.0(8-12)]相比,NDS有明显差异.与I/R +FA 组(23.52±9.90)%, I/R+FA+GW9662组(33.17±7.15)%相比,I/R组(45.82±8.83)% 脑梗死容积百分比（MBIVP）明显增大; I/R +FA组(23.52±9.90)% MBIVP也明显小于I/R +FA+GW9662组(33.17±7.15)%. 氟吡洛芬酯在大鼠局灶性脑缺血模型有明显的神经保护作用且PPAR-γ拮抗剂GW9662可减弱此保护作用,这些数据表明氟吡洛芬酯在大鼠局灶性脑缺血模型中的神经保护作用是通过激活至少是部分激活PAR-γ.     

Flurbiprofen axetil promotes neuroprotection by activation of cerebral peroxisome proliferator-activated receptor gamma after focal cerebral ischemia in rats

Background  Our previous papers indicate that flurbiprofen axetil (FA), a cyclooxygenase inhibitor, is a promising therapeutic strategy for cerebral ischemia in rats. This study aimed to investigate whether FA could promote a neuroprotective effect by activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) after focal cerebral ischemia in rats.

Methods  Totally 48 male Sprague-Dawley (SD) rats were randomly assigned into six groups (n=8 in each group): animals in group ischemia/reperfusion (I/R) only received 120-minute transient middle cerebral artery occlusion (tMCAO); animals in group I/R +FA were administered FA (10 mg/kg) by caudal vein just after 120-minute tMCAO; animals in group I/R +FA+GW9662 were administered GW9662 (a PPAR-γ inhibitor, 1 mg/kg) intraperitoneally 30 minutes before cerebral ischemia onset and FA (10 mg/kg) by caudal vein just after 120-minute tMCAO; animals in group I/R +GW9662 were administered GW9662 (1 mg/kg) intraperitoneally 30 minutes before cerebral ischemia onset; animals in group I/R +DMSO were administered 3% DMSO (vehicle of GW9662, 1 ml/kg) intraperitoneally 30 minutes before cerebral ischemia onset; animals in sham group experienced the identical surgery apart from the insertion of the nylon filament. The neurologic deficit score (NDS) were performed at 72 hours after reperfusion, and then mean brain infarct volume percentage (MBIVP) was determined with 2,3,5-triphenyltetrazolium chloride (TTC) 10 g/L staining.

Results  NDS was significantly increased in group I/R+FA (12.0 (10.0–15.0)), group I/R+FA+GW9662 (10.0 (8.0–12.0)), and in group I/R+FA+DMSO (12.0 (9.0–14.0)) at 72 hours after reperfusion compared with those in group I/R (7.5 (6.0–10.0)). NDS was conspicuously different between group I/R+FA (12.0 (10.0–15.0)) and group I/R+FA+GW9662 (10.0 (8.0–12.0)). MBIVP in group I/R ((45.82±8.83)%) was significantly greater than that in group I/R+FA ((23.52±9.90)%), group I/R+FA+GW9662 ((33.17±7.15)%); MBIVP in group I/R+FA ((23.52±9.90)%) was significantly smaller than that in group I/R+FA+GW9662 ((33.17±7.15)%).

Conclusions  FA confers the neuroprotective effect on tMCAO in rats and the selective PPAR-γ antagonist GW9662 attenuates the effect of FA. FA could promote a neuroprotective effect by, or in part, activation of PPAR-γ after focal cerebral ischemia in rats.