BACKGROUND & AIMS: :Painful peripheral neuropathy is a dose-limiting side effect of cisplatin treatment. Using a murine model of cisplatin-induced hyperalgesia, we determined whether a PPARγ synthetic agonist, pioglitazone, attenuated the development of neuropathic pain and identified underlying mechanisms. Cisplatin produced mechanical and cold hyperalgesia and decreased electrical thresholds of Aδ and C fibers, which were attenuated by coadministration of pioglitazone (10 mg/kg, intraperitoneally [i.p.]) with cisplatin. Antihyperalgesic effects of pioglitazone were blocked by the PPARγ antagonist T0070907 (10 mg/kg, i.p.). We hypothesized that the ability of pioglitazone to reduce the accumulation of reactive oxygen species (ROS) in dorsal root ganglion (DRG) neurons contributed to its antihyperalgesic activity. Effects of cisplatin and pioglitazone on somatosensory neurons were studied on dissociated mouse DRG neurons after 24 hours in vitro. Incubation of DRG neurons with cisplatin (13 µM) for 24 hours increased the occurrence of depolarization-evoked calcium transients, and these were normalized by coincubation with pioglitazone (10 µM). Oxidative stress in DRG neurons was considered a significant contributor to cisplatin-evoked hyperalgesia because a ROS scavenger attenuated hyperalgesia and normalized the evoked calcium responses when cotreated with cisplatin. Pioglitazone increased the expression and activity of ROS-reducing enzymes in DRG and normalized cisplatin-evoked changes in oxidative stress and labeling of mitochondria with the dye MitoTracker Deep Red, indicating that the antihyperalgesic effects of pioglitazone were attributed to its antioxidant properties in DRG neurons. These data demonstrate clear benefits of broadening the use of the antidiabetic drug pioglitazone, or other PPARγ agonists, to minimize the development of cisplatin-induced painful neuropathy.

背景与目标： : 疼痛周围神经病变是顺铂治疗的剂量限制性副作用。使用顺铂诱导的痛觉过敏的鼠模型，我们确定了ppar γ 合成激动剂吡格列酮是否减轻了神经性疼痛的发展并确定了潜在的机制。顺铂产生机械和冷痛觉过敏，并降低了a δ 和C纤维的电阈值，这些阈值通过与顺铂共同施用吡格列酮 (10 mg/kg，腹膜内 [i.p.]) 而减弱。吡格列酮的抗痛觉过敏作用被ppar γ 拮抗剂T0070907 (10 mg/kg，ip) 阻断。我们假设吡格列酮减少背根神经节 (DRG) 神经元中活性氧 (ROS) 积累的能力有助于其抗痛觉过敏活性。体外24小时后，在离解的小鼠DRG神经元上研究了顺铂和吡格列酮对体感神经元的影响。将DRG神经元与顺铂 (13 µ m) 孵育24小时会增加去极化诱发的钙瞬变的发生，并通过与吡格列酮 (10 µ m) 共孵育将其标准化。DRG神经元中的氧化应激被认为是顺铂诱发的痛觉过敏的重要贡献者，因为ROS清除剂可减轻痛觉过敏，并在与顺铂共治疗时使诱发的钙反应正常化。吡格列酮增加了DRG中ROS降低酶的表达和活性，并使顺铂引起的氧化应激变化正常化，并用染料MitoTracker深红标记线粒体，表明吡格列酮的抗痛觉过敏作用归因于其在DRG神经元中的抗氧化特性。这些数据证明了扩大抗糖尿病药物吡格列酮或其他ppar γ 激动剂的使用以最大程度地减少顺铂引起的疼痛性神经病的发生的明显好处。

BACKGROUND & AIMS: BACKGROUND:The cholesterol gallstones diseases (CGD) is highly correlated with metabolic syndrome and type 2 diabetes. The present study aimed to investigate preventive effects of pioglitazone (PIO), an antidiabetic drug, on the CGD in guinea pigs fed with a lithogenic diet (LD). METHODS:The guinea pigs were fed with the LD for 8 weeks. All guinea pigs were grouped as follows: low fat diet; LD; LD plus PIO (4 mg/kg); LD plus PIO (8 mg/kg); LD plus ezetimibe (EZE) (2 mg/kg). Gallbladder stones were observed using microscopy. The profile of biliary composition, and blood glucose, insulin and lipid were analyzed. The liver or ileum was harvested for determinations of hydroxyl-methyl-glutaryl-CoA reductase (HMGCR), sterol regulatory element-binding proteins 2 (SREBP2), 7α-hydroxylase (CYP7A1), adenosine triphosphate-binding cassette (ABC) sterol transporters G5 and G8 (ABCG5, ABCG8), bile salt export pump (BSEP), Niemann-Pick C1-Like 1 (NPC1L1) and acetyl-coenzyme A cholesterol acyltransferase (ACAT2) by Western blot. The gallbladders were used for histological examination. RESULTS:The LD successfully induced gallstone. Both pioglitazone and ezetimibe prevented gallstone formation, as well as hepatic and cholecystic damages. Pioglitazone significantly decreased HMGCR and SREBP2, but increased CYP7A1, ABCG5, ABCG8, and BSEP in the liver. Pioglitazone also remarkably decreased NPC1L1 and ACAT2, while increased ABCG5/8 in the intestine. The beneficial alterations of cholesterol and bile acids in the bile, as well as profile of glucose, insulin and lipid in the blood were found in the guinea pigs treated with pioglitazone. CONCLUSION:Pioglitazone has a noticeable benefit towards the CGD, which is involved in changes of synthesis, transformation, absorption, and transportation of cholesterol.

背景与目标：

BACKGROUND & AIMS: :The agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma) ameliorate cardiovascular complications associated with diabetes mellitus. We tested the hypothesis that recovery from ailing to failing myocardium in diabetes by PPARgamma agonist is in part due to decreased matrix metalloproteinase-9 (MMP-9) activation and left ventricular (LV) tissue levels of homocysteine (Hcy). C57BL/6J mice were made diabetic (D) by feeding them a high-fat calorie diet. PPARgamma was activated by adding pioglitazone (Pi) to the diet. After 6 wk, mice were grouped into: normal calorie diet (N), D, N + Pi and D + Pi (n = 6 in each group). LV variables were measured by echocardiography, endothelial-myocyte (E-M) coupling was measured in cardiac rings, and MMP-9 activation was measured by zymography. Blood glucose levels were twofold higher in D mice compared with N mice. Pi decreased the levels of glucose in D mice to the levels in N mice. LV Hcy levels were 3.5 +/- 0.5 microM in N groups compared with 12.4 +/- 0.6 microM in D groups. Treatment with Pi normalized the LV levels of Hcy but had no effect on plasma levels of Hcy. In the D group, LV contraction was reduced compared with that of the N group and was ameliorated by treatment with Pi. LV wall thickness was reduced to 0.25 +/- 0.02 mm in the D group compared with 0.42 +/- 0.01 mm in the N group. LV diastolic diameter was 3.05 +/- 0.01 mm in the D group compared with 2.20 +/- 0.02 mm in the N group. LV systolic diameter was 1.19 +/- 0.02 mm in the D group and 0.59 +/- 0.01 mm in the N group. Pi normalized the LV variables in D mice. The responses to ACh and nitroprusside were attenuated in diabetic hearts, suggesting that there was E-M uncoupling in the D group compared with the N group, which was ameliorated by Pi. Plasma and LV levels of MMP-2 and -9 activities were higher in the D group than in the N group but normalized after Pi treatment. These results suggest that E-M uncoupling in the myocardium, in part, is due to increased MMP activities secondary to suppressing PPARgamma activity in high-fat, calorie-induced Type 2 diabetes mellitus.

背景与目标： 过氧化物酶体增殖物激活受体 γ (PPARgamma) 的激动剂可改善与糖尿病相关的心血管并发症。我们检验了以下假设: PPARgamma激动剂从糖尿病的病痛恢复到衰竭的心肌部分是由于基质metalloproteinase-9 (MMP-9) 激活降低和同型半胱氨酸 (Hcy) 的左心室 (LV) 组织水平降低。通过给C57BL/6J小鼠喂食高脂肪卡路里饮食，使它们成为糖尿病 (D)。通过在饮食中添加吡格列酮 (Pi) 来激活PPARgamma。6周后，将小鼠分为: 正常卡路里饮食 (N)，D，N Pi和D Pi (每组n = 6)。通过超声心动图测量LV变量，在心脏环中测量内皮-肌细胞 (E-M) 偶联，并通过酶谱测量MMP-9活化。D小鼠的血糖水平比N小鼠高两倍。Pi将D小鼠的葡萄糖水平降低至N小鼠的水平。N组LV Hcy水平为3.5 +/- 0.5 microM，D组为12.4 +/- 0.6 microM。Pi治疗使LV的Hcy水平正常化，但对血浆Hcy水平没有影响。在D组中，与N组相比，LV收缩减少，并通过Pi治疗得到改善。与N组的0.42 +/-0.01毫米相比，D组的LV壁厚减小至0.25 +/-0.02毫米。D组左室舒张直径为3.05 +/-0.01毫米，N组为2.20 +/-0.02毫米。左室收缩直径D组为1.19 +/-0.02毫米，N组为0.59 +/-0.01毫米。Pi对D小鼠的左室变量进行标准化。在糖尿病心脏中，对ACh和硝普钠的反应减弱，表明与N组相比，D组存在E-M解偶联，Pi对此有所改善。D组的血浆和LV MMP-2和-9活性水平高于N组，但在Pi处理后恢复正常。这些结果表明，心肌中的E-M解偶联部分是由于在高脂肪，卡路里诱导的2型糖尿病中抑制PPARgamma活性继发于MMP活性的增加。

BACKGROUND & AIMS: :Metabolic syndrome and type 2 diabetes mellitus are associated with an increased number of macrophage cells that infiltrate white adipose tissue (WAT). Previously, we demonstrated that the treatment of subjects with impaired glucose tolerance (IGT) with the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone resulted in a decrease in macrophage number in adipose tissue. Here, adipose tissue samples from IGT subjects treated with pioglitazone were examined for apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. TUNEL-positive cells were identified, and there was a significant 42% increase in TUNEL-positive cells following pioglitazone treatment. Overlay experiments with anti-CD68 antibody demonstrated that most of the TUNEL-positive cells were macrophages. To determine whether macrophage apoptosis was a direct or indirect effect of pioglitazone treatment, human THP1 cells were treated with pioglitazone in vitro, demonstrating increased TUNEL staining in a dose- and time-dependent manner. Furthermore, the appearance of the active proteolytic subunits of caspase-3 and caspase-9 were detected in cell lysate from THP1 cells and also increased in a dose- and time-dependent manner following pioglitazone treatment. Pretreatment with a PPARgamma inhibitor, GW9662, prevented pioglitazone induction of the apoptotic pathway in THP1 cells. Differentiated human adipocytes did not show any significant increase in apoptosis after treatment in vitro with piolgitazone. These findings indicate that PPARgamma has distinct functions in different cell types in WAT, such that pioglitazone reduces macrophage infiltration by inducing apoptotic cell death specifically in macrophages through PPARgamma activation.

背景与目标： 代谢综合征和2型糖尿病与浸润白色脂肪组织 (WAT) 的巨噬细胞数量增加有关。以前，我们证明用过氧化物酶体增殖物激活受体 γ (PPARgamma) 激动剂吡格列酮治疗葡萄糖耐量受损 (IGT) 的受试者会导致脂肪组织中巨噬细胞数量减少。在这里，用末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记 (TUNEL) 染色检查了用吡格列酮治疗的IGT受试者的脂肪组织样品的凋亡。鉴定出TUNEL阳性细胞，并且在吡格列酮处理后TUNEL阳性细胞有显著的42% 增加。用anti-CD68抗体进行的重叠实验表明，大多数TUNEL阳性细胞是巨噬细胞。为了确定巨噬细胞凋亡是吡格列酮治疗的直接还是间接影响，在体外用吡格列酮治疗人THP1细胞，证明TUNEL染色以剂量和时间依赖性方式增加。此外，在来自THP1细胞的细胞裂解物中检测到caspase-3和caspase-9的活性蛋白水解亚基的出现，并且在吡格列酮处理后以剂量和时间依赖性方式增加。用PPARgamma抑制剂GW9662进行预处理可防止吡格列酮诱导THP1细胞凋亡途径。用吡吉他酮体外处理后，分化的人脂肪细胞未显示出凋亡的任何显着增加。这些发现表明PPARgamma在WAT的不同细胞类型中具有不同的功能，因此吡格列酮通过PPARgamma激活在巨噬细胞中特异性诱导凋亡细胞死亡来减少巨噬细胞的浸润。

BACKGROUND & AIMS: :Pioglitazone, peroxisome proliferator-activated receptor (PPAR-γ) agonist, is a therapeutic drug for diabetes. Present study investigated the interaction between PPAR-γ and alpha adrenoceptors in modulating vasopressor responses to Angiotensin II (Ang II) and adrenergic agonists, in diabetic & non-diabetic Spontaneously Hypertensive Rats (SHRs). Diabetes was induced with an i.p injection of streptozotocin (40 mg/kg) in two groups (STZ-CON, STZ-PIO), whereas two groups remained non diabetic (ND-CO, ND-PIO). One diabetic and non-diabetic group received Pioglitazone (10mg/kg) orally for 21 days. On day 28, the animals were anaesthetized with sodium pentobarbitone (60mg/kg) and prepared for measurement of systemic haemodynamics. Basal mean arterial pressure of STZ-CON was higher than ND-CON, whereas following pioglitazone treatment, MAP was lower compared to respective controls. MAP responses to i.v administration of NA, PE, ME and ANG II were significantly lower in diabetic SHRs: STZ-CON vs ND-CON (35%). Pioglitazone significantly decreased responses to NA, PE, ME and ANG II in ND-PIO versus ND-CON by 63%. Responses to NA and ANG II were significantly attenuated in STZ-PIO vs. ND-PIO (40%). PPAR-γ regulates systemic hemodynamic in diabetic model and cross-talk relationship exists between PPAR-γ and α1-adrenoceptors, ANG II in systemic vasculature of SHRs.

背景与目标： : 吡格列酮，过氧化物酶体增殖物激活受体 (PPAR-γ) 激动剂，是糖尿病的治疗药物。本研究调查了在糖尿病和非糖尿病自发性高血压大鼠 (shr) 中，PPAR-γ 和 α 肾上腺素受体之间的相互作用，以调节血管升压剂对血管紧张素II (Ang II) 和肾上腺素能激动剂的反应。两组 (STZ-CON，STZ-PIO) 通过静脉注射链脲佐菌素 (40 mg/kg) 诱发糖尿病，而两组仍为非糖尿病 (ND-CO，ND-PIO)。一个糖尿病和非糖尿病组口服吡格列酮 (10 mg/kg) 21天。在第28天，用戊巴比妥钠 (60 mg/kg) 麻醉动物，并准备用于测量全身血液动力学。STZ-CON的基础平均动脉压高于ND-CON，而在吡格列酮治疗后，MAP低于相应的对照组。在糖尿病shr: STZ-CON vs ND-CON (35%) 中，对NA，PE，ME和ANG II的iv给药的MAP响应显着降低。通过63%，吡格列酮显着降低了ND-PIO与ND-CON对NA，PE，ME和ANG II的反应。对NA和ANG II的反应在STZ-PIO与ND-PIO (40%) 中显著减弱。PPAR-γ 调节糖尿病模型中的全身血液动力学，并且在shr的全身脉管系统中，PPAR-γ 和 α1-肾上腺素受体ANG II之间存在串扰关系。

BACKGROUND & AIMS: PURPOSE:We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. METHODS AND MATERIALS:Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy gamma-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. RESULTS:Administration of Pio before, during, and for 4 or 54 weeks after WBI prevented the radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced the radiation-induced cognitive impairment. CONCLUSIONS:These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.

背景与目标：

BACKGROUND & AIMS: :Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist (fenofibrate) and a PPAR gamma agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment (p=0.001) and, in keeping with this, adiponectin increased by 85.2% (p<0.001). Pro-inflammatory cytokine levels (TNFalpha, IL-6 and IL-1 beta) fell with both treatments (p<0.01 for TNFalpha and IL-1 beta, p<0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments (p<0.001 for VCAM-1, p<0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment (p=0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment (p<0.001) and 16.3% with pioglitazone treatment (p<0.001). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.

背景与目标： 肥胖是一种与过早的心血管疾病发病率和死亡率相关的低度炎症状态。与传统的危险因素一起，内皮功能，胰岛素抵抗，炎症和动脉僵硬度的测量可能有助于评估心血管风险。我们进行了一项随机安慰剂对照试验，以评估PPAR α 激动剂 (非诺贝特) 和PPAR γ 激动剂 (吡格列酮) 治疗12周对肥胖葡萄糖耐量男性这些参数的影响。使用增强指数和脉搏波速度 (PWV) 测量动脉僵硬度。E-选择素、VCAM-1和ICAM-1被用作内皮功能的标志物。吡格列酮治疗改善了胰岛素敏感性 (p = 0.001)，与此一致，脂联素增加了85.2% (p<0.001)。促炎细胞因子水平 (TNFalpha，IL-6和IL-1 β) 在两种治疗中均下降 (TNFalpha和IL-1 β p<0.01，IL-6 p<0.001)。两种治疗均降低了VCAM-1和ICAM-1 (VCAM-1 p<0.001，ICAM-1 p<0.05)，吡格列酮治疗可改善E-选择素 (p = 0.05)。两种治疗都导致增强指数下降。非诺贝特治疗 (p<0.001) 和吡格列酮治疗 (p<0.001) 的PWV下降17.4%。吡格列酮和非诺贝特治疗肥胖，葡萄糖耐量的男性可减少炎症，改善内皮功能的标志物并降低动脉僵硬度。这些结果表明，使用PPAR激动剂治疗有可能降低与肥胖相关的过早心血管疾病的发生率。

BACKGROUND & AIMS: :Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.

背景与目标： : 噻唑烷二酮类 (TZDs) 如吡格列酮和罗格列酮被广泛用作胰岛素增敏剂治疗2型糖尿病。在患有多囊卵巢综合征的糖尿病女性中，吡格列酮或罗格列酮治疗可改善胰岛素抵抗和高雄激素血症，但TZDs下调雄激素产生的机制尚不清楚。雄激素是在人类性腺和肾上腺中合成的。我们通过分析吡格列酮和罗格列酮对人肾上腺NCI-H295R细胞类固醇生成的影响，研究了雄激素产生的调节，这是建立的人肾上腺皮质类固醇生成的体外模型。两种tzd都改变了NCI-H295R细胞的类固醇特征，并抑制了雄激素生物合成的关键酶P450c17和3betaHSDII的活性。吡格列酮但不抑制罗格列酮抑制CYP17和HSD3B2基因的表达。同样，吡格列酮抑制了NCI-H295R细胞中CYP17和HSD3B2启动子报告基因的基础和8-溴-camp刺激的活性。然而，吡格列酮没有改变cAMP反应性荧光素酶报告基因的活性，表明它不影响cAMP/蛋白激酶a/cAMP反应元件结合蛋白途径的信号传导。尽管过氧化物酶体增殖物激活受体 γ (PPARgamma) 是TZDs的核受体，但通过小干扰RNA技术抑制PPARgamma并没有改变吡格列酮对CYP17和HSD3B2表达的抑制作用，表明吡格列酮的作用是独立于PPARgamma。另一方面，用丝裂原激活的蛋白激酶激酶 (MEK)/细胞外信号调节激酶 (ERK) 抑制剂2-(2-氨基-3-甲氧基苯基)-4h-1-苯并吡喃-4-酮 (PD98059) 处理NCI-H295R细胞增强了cyp17的启动子活性和表达。通过吡格列酮处理逆转了这种作用，表明MEK/ERK信号通路在调节吡格列酮的雄激素生物合成中起作用。

BACKGROUND & AIMS: OBJECTIVE:The aim of the study was to analyze the effect of pioglitazone (PIO) and simvastatin (SIMVA) on adiponectin and visfatin concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications in a prospective randomized clinical trial. RESEARCH DESIGN AND METHODS:One-hundred twenty-five nondiabetic patients with increased cardiovascular risk [78 females, 47 males, age (mean+/-STD:58.6+/-7.8years, BMI:30.8+/-4.2(kg/m2] were included after randomization to PIO+lacebo, SIMVA+placebo, or PIO+SIMVA treatment for 3 months. At baseline and endpoint, measurements of HbA1c, glucose, insulin, LDL cholesterol, adiponectin and visfatin were performed. Insulin resistance was assessed by means of the HOMAIR-score. RESULTS:Improvement in the HOMAIR-score was observed with PIO and the combination, but not with SIMVA alone, which was accompanied by an increase in adiponectin with PIO treatment groups, but a decrease with SIMVA alone (baseline/endpoint: PIO: 14.0+/-8.2 mg/l/ 27.6+/- 14.5 mg/l, p<0.05; PIO+SIMVA: 11.7+/-10.0 mg/l/26.7+/-15.7 mg/l, p<0.05; SIMVA: 15.5+/-12.7 mg/l/ 11.6+/-7.0 mg/l, p<0.05). No change could be observed in the visfatin concentrations (PIO: 47.6+/-14.5 ng/ml/48.0+/-11.6 ng/ml, PIO+SIMVA: 45.1+/-10.9 ng/ml/47.9+/-10.1 ng/ml, SIMVA: 49.2+/- 13.4 ng/ml/52.1+/-16.7 ng/ml, n. s. in all cases). CONCLUSIONS:Insulin resistance and/or cardiovascular risk indicators were not associated with visfatin levels. Regulation of visfatin secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin.

背景与目标：

BACKGROUND & AIMS: BACKGROUND & AIMS:Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease for which there is limited therapy available. Insulin sensitizing, anti-inflammatory, and antifibrotic properties of thiazolidinediones support their use in treating NASH. We have evaluated pioglitazone in the treatment of nondiabetic patients with NASH. METHODS:We randomized 74 nondiabetic patients (45 men; median age, 54 y) with histologically proven NASH to 12 months of standard diet, exercise, and either placebo or pioglitazone (30 mg/day). Sixty-one patients (30 placebo, 31 pioglitazone) had liver biopsies both at the beginning and the end of the study. RESULTS:Compared with placebo, pioglitazone therapy was associated with an increase in weight (mean change, -0.55 vs +2.77 kg; P = .04) and a reduction in glucose (+0.4 vs -0.1 mmol/L; P = .02), HbA1c (+0.16% vs -0.18%; P = .006), insulin C peptide level (+42 vs -78 pmol/L; P = .02), alanine aminotransferase level (-10.9 vs -36.2 u/L; P = .009), gamma-glutamyltransferase level (-9.4 vs -41.2 u/L; P = .002), and ferritin (-11.3 vs -90.5 microg/L; P = .01). Histologic features including hepatocellular injury (P = .005), Mallory-Denk bodies (P = .004), and fibrosis (P = .05) were reduced in patients treated with pioglitazone compared with those in the placebo group. CONCLUSIONS:Pioglitazone therapy over a 12-month period in nondiabetic subjects with NASH resulted in improvements in metabolic and histologic parameters, most notably liver injury and fibrosis. Larger extended trials are justified to assess the long-term efficacy of pioglitazone in this patient group.

背景与目标：

BACKGROUND & AIMS: :Adiponectin is a fat-derived cytokine with anti-diabetic and anti-atherogenic properties. In this study, effects of sulfonylureas (SUs) on adiponectin production and the action mechanism were evaluated using 3T3-L1 adipocytes. The cells were incubated with glimepiride, glibenclamide, gliclazide, pioglitazone, metformin and the medium only as the control. In the control, the adiponectin level evaluated as the production rate per 24 h was not changed, while pioglitazone significantly increased the adiponectin level. SUs also increased the adiponectin level, but metformin failed to show any increase in adiponectin production. SUs induced adiponectin gene expression as well as pioglitazone. Pioglitazone significantly increased adipogenesis, but glimepiride did not. The aP2 gene expression was increased by pioglitazone, but not by glimepiride. Forskolin, a protein kinase A stimulator, reduced the adiponectin production stimulated by glimepiride but not by pioglitazone. These observations strongly suggest that SUs stimulate the adiponectin production through a different mechanism from pioglitazone, namely an interaction with protein kinase A activity. The significance of the extrapancreatic action of SUs observed in this study should be further evaluated in the clinical field.

背景与目标： : 脂联素是一种具有抗糖尿病和抗动脉粥样硬化特性的脂肪衍生细胞因子。在这项研究中，使用3T3-L1脂肪细胞评估了磺脲类 (SUs) 对脂联素产生的影响及其作用机制。将细胞与格列美脲，格列本脲，格列齐特，吡格列酮，二甲双胍和仅作为对照的培养基孵育。在对照中，评估为每24小时产生速率的脂联素水平没有改变，而吡格列酮显着增加了脂联素水平。SUs也增加了脂联素水平，但二甲双胍未能显示出脂联素产生的任何增加。SUs诱导脂联素基因表达以及吡格列酮。吡格列酮显着增加脂肪生成，但格列美脲没有。吡格列酮增加了aP2基因的表达，但格列美脲没有增加。Forskolin是一种蛋白激酶a刺激剂，可减少格列美脲但吡格列酮刺激的脂联素产生。这些观察结果强烈表明，SUs通过与吡格列酮不同的机制刺激脂联素的产生，即与蛋白激酶a活性的相互作用。在本研究中观察到的SUs胰腺外作用的重要性应在临床领域进一步评估。

BACKGROUND & AIMS: BACKGROUND:Composite end points of major adverse cardiovascular events (MACEs) are standard measures for comparing treatment in large cardiovascular outcome studies. This analysis from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes. METHODS:PROactive was a cardiovascular outcome study that randomized patients with type 2 diabetes to pioglitazone (n = 2605) or placebo (n = 2633), in addition to existing glucose-lowering and cardiovascular medications. Pioglitazone was titrated from 15 to 45 mg/d based upon tolerability. Mean follow-up was 34.5 months. RESULTS:At final visit, 257 (9.9%) pioglitazone-treated and 313 (11.9%) placebo-treated patients had a first event that contributed to the MACE1 end point (hazard ratio 0.82, 95% CI 0.70-0.97, P = .0201). There were statistically significant differences in favor of pioglitazone in 5 of the other MACE end points (P < .05) and a trend to benefit in the sixth (P = .052), with hazard ratios of 0.79 to 0.83. CONCLUSIONS:In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.

背景与目标：

BACKGROUND & AIMS: AIMS:Unfortunately, growing number of type 2 diabetic hemodialysis (HD) patients with insulin resistance are now being diagnosed in Japan. Worse still, PPARgammaagonists such as pioglitazone are now contraindicated in diabetic HD patients in Japan. In this study we evaluated the efficacy of pioglitazone in diabetics on HD. METHODS:Following a 12-week baseline period, we enrolled a study population of poorly controlled diabetic HD patients who had mean hemoglobin A1c (HbA1c) levels greater than 6.5% at baseline and who were not receiving insulin injection therapy. The patients were administered pioglitazone 15mg daily with their morning meal for the first 4 weeks. Subsequently, the doses were titrated by dose-doubling to a maximum of 30mg/day if no adverse effects appeared. The efficacy was determined by monitoring glycemic control (plasma glucose and HbA1c), and insulin resistance (plasma immunoreactive insulin (IRI) and homeostasis model assessment for insulin resistance (HOMA-R)). Safety and tolerance were determined by monitoring clinical and laboratory parameters. RESULTS:Pioglitazone was effective in reducing plasma glucose and HbA1c from the baseline levels from week 4 after the commencement of treatment. The agent was also effective in reducing triglycerides. Plasma IRI and HOMA-R, two parameters of insulin resistance, decreased significantly at 4 weeks, and the decreases continued for 24 weeks. Systolic and diastolic blood pressures were statistically lower at 8 weeks. No serious adverse effects such as hypoglycemia, liver impairment, or rhabdomyolysis were observed in any of the patients. CONCLUSIONS:Pioglitazone was effective in the treatment of diabetics on dialysis therapy. Pioglitazone might have the potential to reduce the number of type 2 diabetics on HD who ultimately require insulin injection therapy.

背景与目标：

BACKGROUND & AIMS: :Peroxizome proliferator-activated receptor gamma (PPARγ) is highly expressed in the central nervous system where it modulates numerous gene transcriptions. Nitric oxide synthase (NOS) expression could be modified by simulation of PPARγ which in turn activates nitric oxide (NO)/soluble guanylyl-cyclase (sGC)/cyclic guanosine mono phosphate (cGMP) pathway. It is well known that NO/cGMP pathway possesses pivotal role in the development of opioid dependence and this study is aimed to investigate the effect of PPARγ stimulation on opioid dependence in mice as well as human glioblastoma cell line. Pioglitazone potentiated naloxone-induced withdrawal syndrome in morphine dependent mice in vivo. While selective inhibition of PPARγ, neuronal NOS or GC could reverse the pioglitazone-induced potentiation of morphine withdrawal signs; sildenafil, a phosphodiesterase-5 inhibitor amplified its effect. We also showed that nitrite levels in the hippocampus were significantly elevated in pioglitazone-treated morphine dependent mice. In the human glioblastoma (U87) cell line, rendered dependent to morphine, cAMP levels did not show any alteration after chronic pioglitazone administration while cGMP measurement revealed a significant rise. We were unable to show a significant alteration in neuronal NOS mRNA expressions by pioglitazone in mice hippocampus or U87 cells. Our results suggest that pioglitazone has the ability to enhance morphine-dependence and to augment morphine withdrawal signs. The possible pathway underlying this effect is through activation of NO/GC/cGMP pathway.

背景与目标： : 过氧化物酶体增殖物激活受体 γ (ppar γ) 在中枢神经系统中高度表达，它调节许多基因转录。可以通过模拟ppar γ 来修饰一氧化氮合酶 (NOS) 的表达，从而激活一氧化氮 (NO)/可溶性鸟苷酸环化酶 (sGC)/环鸟苷单磷酸 (cGMP) 途径。众所周知，NO/cGMP途径在阿片样物质依赖的发展中起着关键作用，本研究旨在研究ppar γ 刺激对小鼠以及人胶质母细胞瘤细胞系阿片样物质依赖的影响。吡格列酮在体内增强了纳洛酮诱导的吗啡依赖小鼠戒断综合征。虽然选择性抑制ppar γ，神经元NOS或GC可以逆转吡格列酮诱导的吗啡戒断迹象的增强; phosphodiesterase-5抑制剂西地那非增强了其作用。我们还显示，在吡格列酮治疗的吗啡依赖性小鼠中，海马中的亚硝酸盐水平显着升高。在依赖于吗啡的人类胶质母细胞瘤 (U87) 细胞系中，慢性吡格列酮给药后，cAMP水平未显示出任何改变，而cGMP测量显示显着升高。我们无法显示吡格列酮在小鼠海马或U87细胞中神经元NOS mRNA表达的显着改变。我们的结果表明，吡格列酮具有增强吗啡依赖性和增强吗啡戒断症状的能力。这种作用的潜在途径是通过激活NO/GC/cGMP途径。

BACKGROUND & AIMS: OBJECTIVE:To determine whether peroxisome proliferator-activated receptor (PPAR) gamma ligands improve survival of patients with septic shock we treated a mouse model of sepsis [apolipoprotein (Apo) E) knockout mice] with pioglitazone, a PPAR-gamma ligand. ApoE knockout mice have a high mortality rate due to sepsis because the endotoxin is not cleared. DESIGN AND SETTING:Prospective study in a university laboratory. SUBJECTS:We assorted 87 male ApoE knockout mice and 60 wild-type C57/B6 mice randomly into three groups (sepsis, pretreatment, posttreatment). INTERVENTIONS:Cecal ligation and puncture (CLP) was carried out in the sepsis and treatment groups. Mice were injected with pioglitazone (5 mg/kg per day) on the day before CLP or 6 h after surgery. MEASUREMENTS AND RESULTS:Both pre- and post-CLP treatment with pioglitazone improved survival of ApoE knockout and wild-type mice. Serum levels of cytokines and chemokines and myeloperoxidase activity in lung and liver were suppressed in the pioglitazone-treated group. Pioglitazone also suppressed monocyte adhesion to vascular endothelium under flow conditions. CONCLUSIONS:Pioglitazone improved survival of ApoE knockout mice after onset of septic shock through suppression of inflammatory responses.

背景与目标：