过氧化物酶体增殖剂活化受体与心肌重塑

过氧化物酶体增殖剂活化受体是一类核转录因子 ,具有多种有益的生理作用 :参与心脏能量代谢 ,增加胰岛素敏感性 ,阻断过度激活的肾素 血管紧张素系统和胰岛素抵抗形成的恶性循环 ,抑制炎症反应 ,改善心功能 ,提高血管顺应性、降低后负荷 ,对抗心肌重塑。缺血 /再灌注时过氧化物酶体增殖剂活化受体激动剂抑制心肌组织炎症细胞浸润 ,减轻心肌缺血 /再灌注损伤而保护心脏。     

过氧化物酶增殖体激活受体-γ激动剂对急性肺损伤大鼠的保护作用及机制

目的 观察过氧化物酶增殖体激活受体-γ(PPAR-γ)激动剂对急性肺损伤大鼠的保护作用及其机制.方法 将72只Wistar大鼠按随机数字表法分为脂多糖组(32只)、曲格列酮干预组(32只)和对照组(8只).脂多糖组和曲格列酮干预组根据检测时间的不同再分为脂多糖及曲格列酮干预1、2、4、8 h组,每组各8只.脂多糖组静脉给予脂多糖(5 mg/kg),曲格列酮干预组在静脉注射脂多糖15 min后静脉给予曲格列酮(3 mg/kg).观察各组大鼠PaO2、肺组织髓过氧化物酶(MPO)活性、肺组织病理;采用RT-PCR法检测肺组织PPAR-γ、肿瘤坏死因子-γ(TNF-γ)mRNA表达;采用酶联免疫吸附法(ELISA)检测TNF-γ蛋白变化及用免疫组织化学观察肺组织PPAR-γ的改变;采用Western blot法测定肺组织核因子-γB(NF-γB)P65活性.采用SPSS 10.0软件进行统计学分析,各组间均数比较采用方差分析,均数两两比较采用q检验.结果 曲格列酮1、2、4、8 h组PaO2分别为(85±10)、(80±10)、(81±10)、(82±13)mm Hg(1 mm Hg=0.133 kPa),脂多糖组1、2.4、8 h组分别为(75±11)、(69±12)、(63±11)、(71±13)mm Hg,两组比较差异有统计学意义(F=4.32,P＜0.05);脂多糖2.4、8 h组MPO活性分别为(10.6±1.2)、(14.1±2.1)、(11.1±1.8)U/g,曲格列酮2、4、8 h组分别为(8.2±0.8)、(9.2±0.9)、(8.8±0.7)U/g,两组比较差异有统计学意义(F=14.99,P＜0.05);脂多糖1、2 h组肺组织TNF-γmRNA吸光度(A)值分别为0.68±0.07、0.92 ±0.05,曲格列酮1、2 h组分别为0.39±0.07、0.50±0.09,两组比较差异有统计学意义(q值分别为3.09、3.99,P＜0.05);脂多糖1、2 h组肺组织匀浆及血浆中TNF-?水平分别为(340±33)、(757±47)、(12.3±1.8)及(54.7±6.6)ng/L,曲格列酮1、2 h组为(306±30)、(685±47)、(10.0±1.7)及(46.8±5.9)ng/L,两组比较差异有统计学意义(q值分别为3.92、4.71、4.81、5.17,均P＜0.05);脂多糖1、2、4 h组肺组织PPAR-? mRNA表达(A值)分别为0.36±0.05、0.25±0.04、0.30±0.05,曲格列酮1、2.4 h干预组分别为0.39±0.02、0.44±0.05、0.46±0.04,两组比较差异有统计学意义(q值分别为6.13、5.69、3.72,均P＜0.05);脂多糖1、8 h组NF-?B P65由胞质向胞核移位(A值分别为0.81±0.14、1.91±0.16、0.33±0.06及2.01±0.18),曲格列酮1、8 h组分别为1.14±0.15、1.06±0.21、0.81±0.14、1.03±0.18,两组比较差异有统计学意义(q值分别为3.29、6.25、5.59、6.81,均P＜0.05).结论 在脂多糖诱发的大鼠急性肺损伤模型中,曲格列酮通过上调PPAR-γ表达来抑制NF-γB活性,使NF-γB调控的炎症介质表达下调,炎性细胞浸润和活化减少,从而保护肺组织.     

大肠癌PPARγ和PPAR8基因的表达及其与临床病理的关系

目的研究大肠癌过氧化物酶体增殖物激活受体（Peroxisomeproliferator—activatedreceptor,PPAR）中PPARy和PPAR8基因mRNA的表达水平及其与患者临床病理参数的关系。方法采用SYBRGreenI实时定量RT—PCR技术检测38例手术切除的大肠癌及相应癌外正常大肠组织中PPARγ和PPAR8mRNA的表达。结果①表达阳性率PPARymRNA在癌组织低于相应癌外正常组织（52．6％VS86．8％,P=0．001）,PPARSmRNA在两者间无差异（50．0％VS44．7％,P=0．646）。大肠癌组织PPARγmRNA的表达水平低于癌外正常组织[0．0016（0,0．017）VS0．011（0,0．088）,P=0．036];PPARSmRNA则两者间表达无差异[0．086（0,0．24）VS0．052（0,0．19）,P=0．73]。②大肠癌浸润越深,PPARγmRNA相对表达水平越低,PPAR8mRNA的表达与临床病理参数间无明显关联。③PPARγ和PPARSmRNA表达无相关性（r=0．098,P=0．560）。结论大肠癌PPARγmRNA低表达,且与大肠癌浸润程度有关;PPARγmRNA表达无明显上调,两基因间表达水平无相关性。     

宫颈癌组织中PPARγ与HIF-1α的表达及相关性研究

目的研究宫颈癌组织中过氧化物酶体增殖物激活受体γ(PPARγ)与缺氧诱导因子-1α(HIF-1α)的表达及其相关性。方法采用免疫组织化学SABC法,检测40例宫颈癌组织、10例宫颈炎组织和10例非典型增生宫颈组织切片中的PPARγ与HIF-1α的表达。结果 PPARγ和HIF-1α在宫颈鳞癌组织、宫颈炎组织和宫颈非典型增生组织中均有表达,且3组间比较差异具统计学意义(P<0.05)。PPARγ和HIF-1α分别与宫颈癌的临床分期、放疗敏感性和骨、肺、肝等远处转移有关(P<0.05);40例宫颈癌组织PPARγ表达与HIF-1α表达进行相关性分析,相关系数为r=-0.345,P=0.029<0.05,呈明显负相关。结论宫颈癌组织中PPARγ和HIF-1α的表达均显著增高,对判断宫颈癌预后及指导临床治疗有重要的参考意义。     

Role of different types of potassium channels and peroxisome proliferator-activated receptors γ in the antidepressant-like activity of bis selenide in the mouse tail suspension test

In the present study we investigated the role of potassium (K(+)) channels and peroxisome proliferator-activated receptor gamma (PPARγ) in the antidepressant-like effect of bis selenide in the mouse tail suspension test (TST). Intracerebroventricular (i.c.v.) pretreatment with tetraethyl ammonium (TEA, a non-specific inhibitor of K(+) channels, 25 pg/site), glibenclamide (an ATP-sensitive K(+) channel inhibitor, 0.5 pg/site), charybdotoxin (a large and intermediate conductance calcium-activated K(+) channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K(+) channel inhibitor, 10 pg/site) produced a synergistic action with a sub effective dose of bis selenide (0.1 mg/kg, per oral--p.o.). Picrotoxin (1 mg/kg, intraperitoneally--i.p.) pretreatment did not prevent the reduction in immobility time elicited by bis selenide (1 mg/kg, p.o.) in the TST. The reduction in the immobility time elicited by an effective dose of bis selenide (1 mg/kg, p.o.) was prevented by the pretreatment of mice with cromakalim, minoxidil (K(+) channel openers, 10 μg/site, i.c.v.) and GW 9662 (a PPARγ antagonist, 10 μg/site, i.c.v.). The findings clearly suggest that an acute oral dose of bis selenide produced an antidepressant-like effect in the mouse TST by a mechanism that involves the K(+) channels and PPARγ receptors.     

Protective effects of asiaticoside on septic lung injury in mice

Asiaticoside (AS), a major triterpenoid saponin component isolated from Centella asiatica, has been described to exhibit antioxidant and anti-inflammatory activities. The present study aimed to determine the protective effects and the underlying mechanisms of AS on septic lung injury induced by cecal ligation and puncture (CLP). Mice were pretreated with the AS (45 mg/kg) or AS as well as GW9662 at 1 h before CLP, the survival, lung injury, inflammatory mediators and signaling molecules, and Peroxisome proliferator-activated receptor-γ (PPAR-γ) were determined 24 h after CLP. The results showed that AS significantly decreased CLP-induced the mortality, lung pathological damage, the infiltration of mononuclear, polymorphonuclear (PMN) leucocytes and total proteins. Moreover, AS inhibited CLP-induced the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein in lung tissues, and the production of serum tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). Interestingly, the expression of PPAR-γ protein in lung tissue was up-regulated by AS. Furthermore, GW9662 (the inhibitor of PPAR-γ) significantly reversed these beneficial effects of AS in septic mice. These findings suggest that AS could effectively protect from septic lung injury induced by CLP and the underlying mechanisms might be related to up-regulation of PPAR-γ expression to some extent, which inhibits MAPKs and NF-κB pathway.     

PPARδ激动剂GW501516抑制ox-LDL或高糖诱导的人脐静脉内皮细胞凋亡

目的: 探讨过氧化物酶体增殖物激活受体δ(PPARδ)激动剂GW501516对氧化低密度脂蛋白(ox-LDL)和高糖诱导的人脐静脉内皮细胞(HUVECs)凋亡的抑制作用。方法: ox-LDL或高糖诱发HUVECs凋亡,给予不同浓度GW501516处理后,用流式细胞术检测细胞凋亡率的变化。采用MTT法检测ox-LDL或高糖对HUVECs生长活性的影响,用不同浓度GW501516干预后观察细胞生长活性的变化。结果: ox-LDL诱导的细胞凋亡率是21.30%,不同浓度GW501516处理组凋亡率分别为17.47%、9.72%和3.94%,高糖诱导的细胞凋亡率为22.65%,不同浓度GW501516处理组凋亡率分别为20.23%、17.01%和9.38%,结果显示GW501516可抑制ox-LDL或高糖诱导的细胞凋亡,且呈剂量依赖性;MTT结果显示,GW501516可使ox-LDL或高糖对HUVECs活性的抑制作用减弱。结论: GW501516可抑制ox-LDL或高糖诱导的HUVECs凋亡;并减弱ox-LDL或高糖对HUVECs活性的抑制作用。     

Adiponectin reduces connective tissue growth factor in human hepatocytes which is already induced in non-fibrotic non-alcoholic steatohepatitis

Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor β (TGFβ). Recently we have shown that the hepatoprotective adipokine adiponectin downregulates CTGF in primary human hepatocytes (PHH). In the current study, the mechanisms mediating suppression of CTGF by adiponectin and the well described downstream effector of adiponectin receptor 2 (AdipoR2), peroxisome proliferator activated receptor α (PPARα), were analyzed in more detail. Adiponectin downregulated CTGF mRNA and protein in primary human hepatocytes (PHH) and suppression was blocked by a PPARα antagonist indicating that AdipoR2 is involved. The PPARα agonists fenofibrate and WY14643 also reduced CTGF protein in these cells. Adiponectin further impaired TGFβ-mediated upregulation of CTGF. Phosphorylation of the TGFβ downstream effectors SMAD2 and –3 was reduced in PHH incubated with adiponectin or PPARα agonists suggesting that early steps in TGFβ signal transduction are impaired. CTGF and TGFβ mRNA levels were increased in human non-fibrotic non-alcoholic steatohepatitis (NASH), and here AdipoR2 expression was significantly reduced. Current data show that CTGF and TGFβ are already induced in non-fibrotic NASH and this may be partly explained by low adiponectin bioactivity which interferes with TGFβ signaling by reducing phosphorylation of SMAD2/3 and by downregulating CTGF.     

遗传性代谢疾病的研究进展

遗传性代谢疾病（IMD）是指由于基因突变引起酶缺陷、细胞膜功能异常或受体缺陷,致使体内相应的代谢产物不能正常代谢而出现相应的病理和临床症状的一组疾病。其临床表现复杂多样,体内任何器官系统均可受累,常导致早期夭折或终身残疾。产前诊断及新生儿筛查对其早期诊断具有重要意义;常规生化检测可为诊断提供重要线索;DNA芯片技术有望成为群体筛查的方法;过氧化物酶体增殖物激活受体（PPAR）的研究将为此类疾病的药物基因治疗另辟蹊径。     

罗格列酮通过下调环氧化酶-2、血管内皮生长因子的表达预防MNNG诱导大鼠胃癌发生

目的研究证实过氧化酶体增殖因子活化受体γ（PPAR-γ）配体罗格列酮（RSG）具有预防化学致癌剂N-甲基-N’-硝基-亚硝基胍（MNNG）诱导大鼠胃癌发生的作用,本研究拟探讨罗格列酮预防大鼠胃癌形成的可能机制。方法采用RT—PCR及免疫组化法检测罗格列酮处理后大鼠胃癌组织环氧化酶-2（COX-2）、血管内皮生长因子（VEGF）、基质金属蛋白酶-9（MMP-9）mRNA及蛋白的表达。结果MNNG诱癌组14例大鼠胃癌组织VEGF、COX-2mRNA的表达明显高于癌旁组织（P〈0．01）,而MMP-9的表达在大鼠胃癌及癌旁组织中差异无统计学意义（P〉0．05）,RSG处理组（15例）大鼠胃癌组织VEGF、COX-2mRNA的表达明显低于MNNG诱癌组大鼠胃癌组织,免疫组化显示MNNG诱癌组大鼠胃癌组织COX-2阳性物质主要分布在癌细胞胞浆或沿核膜周边,在间质的血管内皮细胞、成纤维细胞及单核细胞中亦可见阳性表达;VEGF阳性细胞主要位于癌细胞胞浆内,血管内皮细胞也有阳性表达。罗格列酮处理后大鼠胃癌组织的COX-2阳性细胞分布与MNNG诱癌组胃癌组织相似,而VEGF阳性细胞主要位于癌细胞胞浆内,血管内皮细胞未见明显VEGF表达。结论罗格列酮可下调大鼠胃癌组织COX-2及VEGF的表达,促进肿瘤细胞凋亡、减少肿瘤血管生成可能是罗格列酮预防大鼠胃癌发生的机制之一。