BACKGROUND & AIMS: :Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1)). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1)  day(-1), per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity.

背景与目标： 过氧化物酶体增殖物激活受体-γ (PPAR-γ) 激动剂不仅可以改善糖尿病的代谢异常和随之而来的糖尿病肾病，而且还可以在实验模型中预防非糖尿病肾病。在这里，我们研究了PPAR-γ 激动剂吡格列酮对小鼠顺铂模型急性肾损伤的作用。单次腹腔注射顺铂 (10  mg  kg(-1)) 可引起肾毒性。吡格列酮连续6天，剂量为15或30  mg  kg(-1)  天 (-1)，每次os (p.o.)，从注射顺铂前3天开始。对小鼠进行顺铂治疗会导致明显的肾衰竭，其特征是血清尿素和肌酐水平显着增加以及肾组织结构的改变。暴露于顺铂引起的氧化应激，表现为非酶抗氧化防御 [谷胱甘肽 (GSH) 和抗坏血酸水平] 的降低和酶抗氧化防御 [超氧化物歧化酶 (SOD)，过氧化氢酶 (CAT) 谷胱甘肽过氧化物酶 (GPx)，肾组织中的谷胱甘肽还原酶 (GR) 和谷胱甘肽S-转移酶 (GST) 活性)]。吡格列酮的给药可显着防止顺铂治疗引起的尿素和肌酐水平的增加以及肾脏的组织学改变。吡格列酮的给药可改善小鼠中因顺铂暴露而降低的GSH和抗坏血酸水平。吡格列酮可防止顺铂在小鼠肾脏中抑制CAT，SOD，GPx，GR和GST活性。这些结果表明，吡格列酮对顺铂诱导的小鼠肾损伤具有保护作用。保护是通过防止抗氧化剂状态下降来介导的。该结果对PPAR-γ 激动剂在人类应用中用于预防药物引起的肾毒性具有重要意义。

BACKGROUND & AIMS: BACKGROUND:Many patients with type 2 diabetes mellitus receive several oral hypoglycemic agents, including sulfonylurea drugs. Intravenous glyburide (Glyb), a sulfonylurea agent, blocks the protective effects of "ischemic" and pharmacologic preconditioning in various animal models without affecting myocardial infarct size when administered alone. However, there are conflicting results when other sulfonylurea drugs are used. Pioglitazone (PIO) reduces infarct size in the rat. We asked whether oral Glyb and glimepiride (Glim) affect the infarct size-limiting effects of PIO. METHODS:Sprague-Dawley rats received 3-day oral treatment with: PIO (5 mg/kg/day); PIO + Glyb (10 mg/kg/day); PIO + Glim (4 mg/kg/day) or water alone (experiment 1) or PIO (5 mg/kg/day) with or without 5-hydroxydecanoate (5HD, 10 mg/kg), a specific mitochondrial ATP-sensitive K+ channels inhibitor, administered intravenously 30 min before coronary artery ligation. PIO, Glyb and Glim were administered by oral gavage. Sugar 5% was added to water to prevent hypoglycemia. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (n = 6 in each group). Ischemic area at risk was assessed by blue dye and infarct size by triphenyl-tetrazolium-chloride. RESULTS:Body weight and the size of the area at risk were comparable among groups. Infarct size (% of the area at risk) was significantly smaller in the PIO (14.3 +/- 1.1%; p < 0.001) and PIO + Glim (13.2 +/- 0.8%; p < 0.001) groups than in the control group (37.7 +/- 1.2%). Glyb completely blocked the effect of PIO (43.0 +/- 1.7%; p < 0.001). Glim did not affect the protective effect of PIO (p = 0.993). 5HD blocked the protective effect of PIO (infarct size 48.5 +/- 0.8% versus 14.8 +/- 0.6%, respectively; p < 0.0001). In conclusion, the infarct size limiting effects of PIO are dependent on activation of mitochondrial ATP-sensitive K+ channels. Oral Glyb, but not Glim, blocks the infarct size limiting effects of PIO. It is plausible that Glyb affects other pleiotropic effects of PIO and thus may attenuate favorable effects on cardiovascular outcomes. In contrast, Glim does not attenuate the protective effect of PIO.

背景与目标：

BACKGROUND & AIMS: :Impaired intestinal mucosal integrity during colitis involves the peroxisome proliferator-activated receptor-γ (PPARγ), an important anti-inflammatory factor in intestinal mucosa homoeostasis, which is a potential target in colitis. Recurrent chronic pain is a vital pathogenetic feature of colitis. Nevertheless, potential functions of PPARγ in the colitis-associated hyperalgesia remain unclear. This study aimed to investigate biological roles of pioglitazone in relieving colitis-associated pain hypersensitivity by a PPARγ tight junction protein-dependent mechanism during the course of dextran sodium sulfate (DSS)-induced intestinal inflammation. The DSS-induced colitis model was generated in C57BL/6 mice. Changes in colitis induced the injury of intestinal mucosal barrier and hyperalgesia after a 6-day treatment of pioglitazone (25 mg/kg, IP injection) were assessed through immunofluorescent, hematoxylin and eosin (H&E) staining, western blot analysis, and determination of paw withdrawal mechanical threshold. A significant reduction of paw withdrawal mechanical threshold occurred after DSS treatment. Follow-up data showed that systematic administration of PPARγ agonist pioglitazone ameliorated the DSS-induced colitis and the development of colitis-associated hyperalgesia by repairing the intestinal mucosal barrier. The tight junction proteins ZO-1 and Claudin-5 were upregulated by PPARγ signaling, which in turn promoted the improvement of intestinal barrier function. Moreover, pioglitazone inhibited phosphorylation of ERK and NF-κB in the colon and decreased the levels of inflammatory cytokines in both colon spine tissues. Furthermore, systemically pioglitazone treatment inhibited the activation of microglia and astrocytes, as well as DSS-induced phosphorylation of NR2B subunit in spinal cord, which was correspondingly consistent with the pain behavior. Pioglitazone ameliorates DSS-induced colitis and attenuates colitis-associated mechanical hyperalgesia, with improving integrity of the intestinal mucosal barrier by directly upregulating tight junction proteins. The PPARγ-tight junction protein signaling might be a potential therapeutic target for the treatment of colitis-associated chronic pain.

背景与目标： : 结肠炎期间肠粘膜完整性受损涉及过氧化物酶体增殖物激活受体-γ (ppar γ)，这是肠粘膜稳态的重要抗炎因子，是结肠炎的潜在靶标。复发性慢性疼痛是结肠炎的重要发病特征。尽管如此，ppar γ 在结肠炎相关的痛觉过敏中的潜在功能仍不清楚。本研究旨在探讨吡格列酮在葡聚糖硫酸钠 (DSS) 诱导的肠道炎症过程中，通过ppar γ 紧密连接蛋白依赖性机制缓解结肠炎相关疼痛超敏反应的生物学作用。在C57BL/6小鼠中产生了DSS诱导的结肠炎模型。通过免疫荧光，苏木精和曙红 (H & E) 染色，western印迹分析和确定吡格列酮 (25 mg/kg，IP注射) 治疗6天后，对结肠炎引起的肠粘膜屏障损伤和痛觉过敏进行了评估。爪戒断机械阈值。DSS治疗后，paw撤爪机械阈值显着降低。随访数据显示，系统施用ppar γ 激动剂吡格列酮可通过修复肠粘膜屏障改善DSS诱导的结肠炎和与结肠炎相关的痛觉过敏的发展。Ppar γ 信号上调ZO-1和Claudin-5的紧密连接蛋白，进而促进肠屏障功能的改善。此外，吡格列酮抑制结肠中ERK和NF-κ b的磷酸化，并降低两个结肠脊柱组织中炎性细胞因子的水平。此外，吡格列酮治疗可抑制小胶质细胞和星形胶质细胞的活化，以及DSS诱导的脊髓NR2B亚基的磷酸化，这与疼痛行为相应地一致。吡格列酮可改善DSS诱导的结肠炎并减轻结肠炎相关的机械痛觉过敏，并通过直接上调紧密连接蛋白来改善肠粘膜屏障的完整性。Ppar γ 紧密连接蛋白信号可能是治疗结肠炎相关慢性疼痛的潜在治疗靶标。

BACKGROUND & AIMS: :Immune activation and inflammation are closely associated with the development of depression. Pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has exhibited antidepressant-like effects in a couple of studies. However, the underlying mechanisms are far from being fully elucidated. The study aimed to investigate the effects of PIO on depression-like behaviors induced by lipopolysaccharide (LPS) and to explore the possible underlying mechanisms. The results showed that PIO pretreatment attenuated the depression-like behaviors in mice challenged with intracerebroventricular (i.c.v.) LPS administration. Moreover, Western blot analysis revealed the effects of PIO on inhibiting activation of the nuclear factor kappa B/interleukin 6/signal transducer and activator of transcription 3 (NF-κB/IL-6/STAT3) pathway, improving down-regulation of the cAMP response-element-binding protein/brain derived neurotrophic factor (CREB/BDNF) pathway, as well as regulating disturbed expression of proteins involved in central serotonergic neurotransmission following LPS administration. The beneficial effects of PIO, at both the behavioral and molecular level, were significantly inhibited by the PPAR-γ specific antagonist GW9662. In summary, our data reveals for the first time that the modulation of the NF-κB/IL-6/STAT3 and CREB/BDNF pathways, as well as the potential impact on central serotonergic neurotransmission, may be involved in the PPAR-γ-dependent effects of PIO on depression-like behaviors induced by LPS. Additionally, our findings may provide a novel therapeutic target for the treatment of depression-like behaviors in patients with inflammatory status.

背景与目标： : 免疫激活和炎症与抑郁症的发展密切相关。过氧化物酶体增殖物激活受体 γ (PPAR-γ) 激动剂吡格列酮 (PIO) 在几项研究中表现出抗抑郁样作用。然而，其潜在机制远未得到充分阐明。本研究旨在探讨PIO对脂多糖 (LPS) 诱导的抑郁样行为的影响，并探讨其可能的机制。结果表明，PIO预处理减轻了脑室内 (i.c.v.) 攻击的小鼠的抑郁样行为LPS管理。此外，蛋白质印迹分析揭示了PIO抑制核因子 κ B/白细胞介素6/信号转导子和转录激活因子3 (NF-κ B/IL-6/STAT3) 途径激活的作用。改善cAMP反应元件结合蛋白/脑源性神经营养因子 (CREB/BDNF) 途径的下调，并调节LPS给药后中枢5-羟色胺能神经传递中涉及的蛋白的表达。PPAR-γ 特异性拮抗剂gw9662显着抑制了PIO在行为和分子水平上的有益作用。总之，我们的数据首次揭示了NF-κ b/IL-6/STAT3和CREB/BDNF途径的调节，以及对中枢血清素能神经传递的潜在影响，可能与PIO对LPS诱导的抑郁样行为的PPAR-γ 依赖性作用有关。此外，我们的发现可能为炎症状态患者的抑郁样行为的治疗提供新的治疗靶点。

BACKGROUND & AIMS: :Antenatal steroids (ANS) accelerate fetal lung maturation and reduce the incidence of respiratory distress syndrome. However, sex specificity, i.e., being less effective in males, and potential long-term neurodevelopmental sequelae, particularly with repeated courses, remain significant limitations. The differential sex response to ANS is likely mediated via the inhibitory effect of fetal androgens on steroid's stimulatory effect on alveolar epithelial-mesenchymal interactions. Since peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists accelerate lung maturation by stimulating alveolar epithelial-mesenchymal interactions, independent of fetal sex, we hypothesized that the effect of PPAR-γ agonist pioglitazone (PGZ) would be sex-independent. Pregnant Sprague-Dawley rat dams were intraperitoneally administered dexamethasone (DEX) or PGZ on embryonic day (e) 18 and e19. At e20, pups were delivered by cesarean section, and fetal lungs and brains were examined for markers of lung maturation and apoptosis, respectively. Mixed epithelial-fibroblast cell cultures were examined to gain mechanistic insights. Antenatal PGZ increased alveolar epithelial and mesenchymal maturation markers equally in males and females; in contrast, antenatal DEX had sex-specific effects. Additionally, unlike DEX, antenatal PGZ did not increase hippocampal apoptosis. We conclude that PPAR-γ agonist administration is an effective, and probably even a superior, alternative to ANS for accelerating fetal lung maturity equally in both males and females.

背景与目标： : 产前类固醇 (ANS) 加速胎儿肺成熟，降低呼吸窘迫综合征的发生率。然而，性别特异性 (即在男性中效果较差) 和潜在的长期神经发育后遗症，尤其是在反复病程的情况下，仍然存在重大局限性。对ANS的性别差异反应可能是通过胎儿雄激素对类固醇对肺泡上皮-间质相互作用的刺激作用的抑制作用介导的。由于过氧化物酶体增殖物激活受体-γ (PPAR-γ) 激动剂通过刺激肺泡上皮-间充质相互作用 (与胎儿性别无关) 来加速肺成熟，因此我们假设PPAR-γ 激动剂吡格列酮 (PGZ) 的作用将与性别无关。怀孕的Sprague-Dawley大鼠在胚胎第18天 (e) 和e19腹膜内注射地塞米松 (DEX) 或PGZ。在e20时，通过剖宫产分娩幼崽，并分别检查胎儿肺和大脑的肺成熟和细胞凋亡标志物。检查了混合的上皮-成纤维细胞培养物以获得机理见解。产前PGZ增加了男性和女性的肺泡上皮和间充质成熟标记; 相反，产前DEX具有性别特异性作用。此外，与DEX不同，产前PGZ不会增加海马细胞凋亡。我们得出的结论是，PPAR-γ 激动剂的给药对于促进男性和女性的胎儿肺成熟度是一种有效的，甚至可能是更好的替代方案。

BACKGROUND & AIMS: :Endothelial progenitor cells (EPCs) have been implicated in vascular repair and found to be functionally impaired in patients with diabetes. We evaluated the effects of the anti-diabetic drug pioglitazone on human EPC function and the involvement of PPAR-gamma and TGF-beta1. EPCs in culture were characterized at day 7 by the development of colony-forming units (CFUs) and flow cytometry assessment of differentiation marker (DiI-ac-LDL/lectin, KDR and CD31). Adhesion on fibronectin and fibrinogen in flow was analyzed as functional parameter. Treatment with pioglitazone for 72 hours increased the number of EPC-CFUs, DiI-ac-LDL(+)/lectin(+), CD31(+) and KDR(+) EPCs at 1 microM but not at 10 microM. Since pioglitazone did not significantly alter proliferation and apoptosis in cultured EPCs, the increase in EPC number was most likely attributable to augmented adhesion and differentiation. Indeed, pioglitazone increased EPC adhesion in flow at 1 microM, an effect prevented by PPAR-gamma and beta2-integrin blockade. In contrast, pioglitazone did not promote EPC adhesion at 10 microM; however, increased adhesion became evident by co-incubation with a blocking TGF-beta1 antibody. As determined by ELISA, pioglitazone induced a persistent increase in TGF-beta1 secretion only at 10 microM when a significantly elevated expression of endoglin, the accessory receptor for TGF-beta1, was also observed. Taken together, pioglitazone exerts biphasic effects on the function of isolated EPCs, causing a PPAR-gamma-dependent stimulation at 1 microM and a TGF-beta1-mediated suppression at 10 microM. These results may help to define optimal therapeutic doses of pioglitazone for improving endothelial dysfunction.

背景与目标： : 内皮祖细胞 (epc) 与血管修复有关，并发现糖尿病患者的功能受损。我们评估了抗糖尿病药物吡格列酮对人EPC功能的影响以及PPAR-γ 和TGF-beta1的参与。培养物中的epc在第7天通过集落形成单位 (CFUs) 的发育和分化标记物 (DiI-ac-LDL/凝集素，KDR和CD31) 的流式细胞仪评估来表征。分析了血流中纤连蛋白和纤维蛋白原的粘附作为功能参数。吡格列酮治疗72小时可增加EPC-cfu，DiI-ac-LDL ()/凝集素 ()，CD31 () 和KDR () EPCs的数量，但在10微米时却没有。由于吡格列酮不会显着改变培养的EPC的增殖和凋亡，因此EPC数量的增加很可能归因于粘附和分化的增强。实际上，吡格列酮在1微米时增加了流动中的EPC粘附力，这是由PPAR-γ 和beta2-integrin阻断所阻止的。相反，吡格列酮在10微米时不促进EPC粘附; 然而，通过与阻断TGF-beta1抗体共孵育，增加的粘附变得明显。通过ELISA确定，当还观察到TGF-beta1的辅助受体endoglin的表达显着升高时，吡格列酮仅在10微米处诱导TGF-beta1分泌持续增加。合在一起，吡格列酮对分离的epc的功能发挥双相作用，在1微米处引起PPAR-γ 依赖性刺激，在10微米处引起TGF-beta1-mediated抑制。这些结果可能有助于确定吡格列酮改善内皮功能障碍的最佳治疗剂量。

BACKGROUND & AIMS: :Clinical studies have suggested that pioglitazone, an insulin sensitizer, has a stronger effect in women than in men. To determine the sex difference in the pharmacokinetics of pioglitazone, we examined the plasma and white adipose tissue levels of pioglitazone and its active metabolites (M-II, M-III and M-IV) in male and female rats treated with a single or repeated oral administration of pioglitazone (10 mg/kg). The AUCs of pioglitazone (149.6+/-22.6 vs. 103.3+/-14.0 microg.h/ml; P<0.01), M-III (31.4+/-8.1 vs. 20.2+/-4.7 microg.h/ml; P<0.05) and M-IV (41.9+/-15.5 vs. 14.1+/-1.6 microg.h/ml; P<0.01) were larger in female rats than in male rats, but the levels of M-II were similar. Any of the compounds did not accumulate in plasma after repeated administration. According to kinetic model analysis, the apparent elimination rate of pioglitazone and the formation rate of M-II were faster in male rats than in female rats. No significant sex difference was found in the tissue-to-plasma concentration ratios of pioglitazone or its active metabolites in white adipose tissue. These results suggest that there are sex differences in the plasma levels of pioglitazone and some of its active metabolites and that those differences are reflected in differences in white adipose tissue levels.

背景与目标： 临床研究表明，胰岛素增敏剂吡格列酮对女性的作用强于男性。为了确定吡格列酮的药代动力学的性别差异，我们检查了吡格列酮及其活性代谢物 (m-ii，M-III和M-IV) 在单次或重复口服吡格列酮 (10 mg/kg) 治疗的雄性和雌性大鼠中。吡格列酮的auc (149.6 +/-22.6对103.3 +/-14.0微g.h/ml; P<0.01)，M-III (31.4 +/-8.1对20.2 +/-4.7微g.h/ml; P<0.05) 和M-IV (41.9 +/-15.5 vs. 14.1 +/-1.6 microg.h/ml; P<0.01) 在雌性大鼠中大于雄性大鼠，但M-II的水平相似。重复给药后，任何化合物均未在血浆中积累。根据动力学模型分析，雄性大鼠吡格列酮的表观消除率和M-II的形成速率均快于雌性大鼠。在白色脂肪组织中吡格列酮或其活性代谢物的组织与血浆浓度比中未发现明显的性别差异。这些结果表明，吡格列酮及其某些活性代谢物的血浆水平存在性别差异，这些差异反映在白色脂肪组织水平的差异上。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: AIMS:To compare the efficacy of sitagliptin versus pioglitazone as add-on drugs in patients with poorly controlled diabetes with metformin and sulfonylureas. METHODS:This is a randomized, open-label, parallel assignment clinical trial. Patients who had inadequate glycemic control [7% (53 mmol/mol) ≤ A1C < 11% (97 mmol/mol)] despite a minimum 6-month period of active treatment with metformin 2000 mg/day plus gliclazide 240 mg/day were enrolled in the study. HbA1C, fasting blood glucose (FBG), fasting plasma lipid parameters [total cholesterol (TC0, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C)], systolic and diastolic blood pressure (SBP, DBP), weight, waist circumference, and body mass index were measured at baseline and after 17, 34, and 52 weeks of treatment. Generalized estimating equation analysis was done to compare treatment groups for continuous efficacy parameters. RESULTS:No significant difference in HbA1C reduction was observed between the treatment groups during the study course. (P = 0.149, adjusted P = 0.434; coefficient - 0.11 ± 0.08). The FBG (P = 0.032; coefficient 7.44 ± 3.48), HDL-C (P = 0.001; coefficient - 2.69 ± 0.83), TG (P = 0.027; coefficient 12.63 ± 5.71) and SBP (P < 0.001; coefficient 5.43 ± 1.26) changes from baseline, and weight gain were greater in the pioglitazone group. The mean changes in LDL-C and TC from baseline to week 52 were greater in the sitagliptin group (P = 0.034; coefficient - 7.40 ± 3.50, P = 0.013; coefficient - 7.16 ± 2.88, respectively). CONCLUSION:Sitagliptin and pioglitazone were equally effective in improvement of HbA1C. There were some differences in terms of lipid indices, weight gain, and SBP. The current study confirmed that both sitagliptin and pioglitazone are effective treatment options and the decision should be made for each individual based on the baseline characteristics.

背景与目标：

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：