Effects of Rosiglitazone and Serum on the Expressions of PPARα and PPARγ Genes in the Induced Differentiation Process of Pig Preadipocyte

[Objective] The research aimed to discuss the effects of rosiglitazone and serum on the expressions of PPARα and PPARγ genes in the induced differentiation process of pig preadipocyte.[Method] The pig preadipocyte was separated by using the collagenase digestion method.Three kinds of different differentiation culture solutions were used to induce the differentiation of pig preadipocyte.The oil red O staining extraction method was used to contrast the influences of different differentiation culture solutions on the variation of cellular fat content in the differentiation process.Moreover,the variation trends of PPARα and PPARγ expressions in the cellular differentiation process in the different differentiation culture solutions were detected by the real-time quantification PCR.[Result] The cellular fat accumulation was the fastest in MII which contained rosiglitazone and was the slowest in MI which didn＇t contain rosiglitazone.Rosiglitazone could significantly increase the expression of PPARγ gene（P0.01）,but had the certain inhibition effect on the expression of PPARα gene,which wasn＇t significant.The serum had the extremely significant up-regulation effect on the expression of PPARγ gene（P0.01）,but had the extremely significant down-regulation effect on the expression of PPARα gene（P0.01）.[Conclusion] Rosiglitazone could greatly promote the expression of PPARγ gene,which increased the cellular fat deposition.Maybe the activator of PPARγ gene existed in the serum,and the inhibitor of PPARα gene existed simultaneously.

Risk factors analysis of rosiglitazone in patients with diabetes mellitus

According to the drug-related risk factors indicated in the latest product monograph, we made this research to analyze and discuss the risk factors associated with rosiglitazone in clinical application in China-Japan Friendship Hospital. We collected and reviewed all cases involving inpatients who had used rosiglitazone in the hospital over the past two years. The focus of our study is on the identification and discussion of the incidence of adverse reactions, contraindications and drug induced problems associ- ated with monotherapy or combined therapy of rosiglitazone. Three hundred and ninety eight cases were reviewed in the study including 3 patients with type 1 DM （0.75%） and 395 patients with type 2 diabetes mellitus （99.25%）. Peripheral edema developed in 9 patients （2.26%） in the course of rosiglitazone therapy; one patient （0.25%） was found to have macula edema before rosiglitazone therapy; Cardiac abnormalities were identified in 6 patients （1.51%） in the course of treatment, of which 2 patients were NYHA class 1, 3 patients were NYHA class Ⅱ and 1 patient was NYHA class IV. Abnormal hepatic function （elevated ALT） was found in 79 patients （19.85%） during their stay in hospital. In these patients, ALT levels of 1 - 2.5 times, 2.5 - 3 times over the upper limit were identified in 70 patients, 3 patients and 6 patients, respectively. Of the 398 patients on rosiglitazone, 123 patients （30.90%）, 165 patients （41.46%）, 104 patients （26.13%）, 3 patients （0.75%） and 1 patient （0.25%） were found to use concurrently insulin, metformin, organic nitrate, gemfibrozil and rifampin, respectively. We analyzed the risk factors associated with the clinical use of rosiglitazone, and identified the potential risks, and put forward suggestions to improve the effectiveness and safety of rosiglitazone therapy.

PPARγ激活剂rosiglitazone对大鼠慢性阻塞性肺疾患的防治作用

目的:评价高亲和力过氧化物酶体增生物激活的受体γ(PPARγ)激动剂rosiglitazone对大鼠慢性阻塞性肺疾患(COPD)的防治作用。方法:在第1和14d每只大鼠气管内滴入大肠杆菌脂多糖(LPS)200μg(0.2mL),第2-28d(第14d除外)每天烟熏40min,每只经食管灌入rosiglitazone0.02mg。第29d处死大鼠,取肺组织检查形态学改变;取血清测血糖、血脂变化;取脾细胞测对LPS的反应。结果:模型组大鼠肺泡明显扩张、有的肺泡融合形成较大囊腔。Rosiglitazone处理的大鼠肺体积较小,显微镜下可见肺泡扩张不明显,肺泡间隔较完整,肺泡直径为(134.997±17.568)×10-3μm,低于模型组大鼠(308.362±111.913)×10-3μm,高于正常对照大鼠(5.116±1.673)×10-3μm(P<0.01)。血糖、甘油三酯、胆固醇和低密度脂蛋白含量均无明显变化。Rosiglitazone抑制正常大鼠、模型大鼠和rosiglitazone处理的大鼠脾细胞对LPS的增殖反应。结论:Rosiglitazone可减轻熏烟和气管内滴入LPS诱导的肺气肿。

Effect of rosiglitazone on rabbit model of myocardial ischemia-reperfusion injury

To explore mechanism and protective effect of rosiglitazone on myocardial ischemia reperfusion(I/R) injury.Methods:A total of 48 male Japanese white big-ear rabbits were randomly divided into control group(A),I/R group(B),low dose of rosiglitazone group(C),high dose of rosiglitazone group(D).Plasma concentration of and also reduced the concentration of plasma serum creatine kinase(CK),CK-MB.high-sensitivity C-reactive protein(hsCRP).ultrasuperoxide dismutase(SOD),malondialdehyde(MD.A).lactic acid glutathione skin peroxidase (C-SH-PX).nitric oxide(NO)and endothelin(ET) were measured 1 h later after I/R.Twenty-four hours after I/R the hearts were harvested for pathological and ultrastructural analysis.Area of myocardial infarction were tested.Results:Plasma concentration of CK,Ck-MB.hsCRP,NO. MDA and ET were decreased in C,D group compared with group B.Plasma concentration of T-SOD and GSH-Px were increased significantly in C.D group compared with group B.Compared with group B.pathological and ullraslructural changes in C and D group were slightly.There was significant difference in myocardial infarction area between group C.D and group B(P【0.05). Myocardial infarction area and arrhythmia rate were lower in group C,D compare with group B. Rosiglitazone may protect myocardium from I/R injury by enhancing T-SOD and GSH-Px concentration,inhibit inflammatory reaction,and improve endothelial function.

A new look at auranofin,dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases

Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflamma- tory drugs （NSAIDs） is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise an- other class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neu- rodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.

Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ

AIM： To examine whether and how rosiglitazone enhances apoptosis induced by fluorouracil in human colon cancer （HT-29） cells. METHODS： Human colon cancer HT-29 cells were cultured in vitro and treated with fluorouracil and/or rosiglitazone. Proliferation and growth of HT-29 cells were evaluated by MTF assay and trypan blue exclusion methods, respectively. The apoptosis of HT-29 cells was determined by acridine orange/ethidium bromide staining and flow cytometry using PI fluorescence staining. The expressions of peroxisome proliferator-activated receptor γ （PPARγ）, Bcl-2 and Bax in HT-29 cells were analyzed by Western blot. RESULTS： Although rosiglitazone at the concentration below 30 μmol/L for 72 h exerted almost no inhibitory effect on proliferation and growth of HT-29 cells, it could significantly enhance fluorouracil-induced HT-29 cell proliferation and growth inhibition. Furthermore, 10 μmol/L rosilitazone did not induce apoptosis of HT-29 cells but dramatically enhanced fluorouracil-induced apoptosis of HT-29 cells. However, rosiglitazone did not improve apoptosis induced by fluorouracil in HT-29 cells pretreated with GW9662, a PPARγ antagonist. Meanwhile, the expression of Bax and PPAR7 was upregulated, while the expression of Bcl-2 was down regulated in HT-29 cells treated with rosiglitazone in a time-dependent manner. However, the effect of rosiglitazone on Bcl-2 and Bax was blocked or diminished in the presence of GW9662. CONCLUSION： Rosiglitazone enhances fluorouracilinduced apoptosis of HT-29 cells by activating PPARγ.

Combination of methylprednisolone and rosiglitazone promotes recovery of neurological function after spinal cord injury

Methylprednisolone exhibits anti-inflammatory antioxidant properties, and rosiglitazone acts as an anti-inflammatory and antioxidant by activating peroxisome proliferator-activated receptor-y in the spinal cord. Methylprednisolone and rosiglitazone have been clinically used during the early stages of secondary spinal cord injury. Because of the complexity and diversity of the inflammatory process after spinal cord injury, a single drug cannot completely inhibit inflammation. Therefore, we assumed that a combination of methylprednisolone and rosiglitazone might promote recovery of neurological function after secondary spinal cord injury. In this study, rats were intraperitoneally rejected with methylprednisolone （30 mg/kg） and rosiglitazone （2 mg/kg） at 1 hour after injury, and methylprednisolone （15 mg/kg） at 24 and 48 hours after injury. Rosiglitazone was then administered once every 12 hours for 7 consecutive days. Our results demonstrated that a combined treatment with methylprednisolone and rosiglitazone had a more pronounced effect on attenuation of inflammation and cell apoptosis, as well as increased functional recovery, compared with either single treatment alone, indicating that a combination better pro- moted recovery of neurological function after injury.

Effect of Rosiglitazone Maleate on Inflammation Following Cerebral Ischemia/Reperfusion in Rats

In order to evaluate the neuroprotective effect of Rosiglitazone Maleate (RSG) against brain ischemic injury, the effects of Rosiglitazone Maleate on the inflammation following cerebral ischemia/reperfusion were investigated. Focal cerebral ischemia was induced by the intraluminal thread for cerebral middle artery (MCA) occlusion. Rosiglitazone Maleate at concentrations of 0.5, 2 and 5 mg/kg was infused by intragastric gavage twice immediately and 2 h after MCA occlusion, respectively. The effects of Rosiglitazone Maleate on brain swelling, myeloperoxidase and inter- leukin-6 mRNA level in brain tissue after MCA occlusion and reperfusion were evaluated. The results showed that as compared with the model control group, RSG (0.5 mg/kg) had no significant influence on brain swelling (P>0.05), but 2 mg/kg and 5 mg/kg RSG could significantly alleviate brain swell- ing (P<0.05). All different doses of RSG could obviously reduce MPO activity in brain tissue after MCA occlusion and reperfusion in a dose-dependent manner. RSG (0.5 and 2 mg/kg) could decrease the expression levels of IL-6 mRNA in brain tissue after MCA occlusion and reperfusion to varying degrees (P<0.05) with the difference being significant between them. It was concluded that RSG could effectively ameliorate brain ischemic injury after 24 h MCA occlusion and inhibit the inflam- matory response after ischemia-reperfusion in this model.

Rosiglitazone prevents murine hepatic fibrosis induced by Schistosoma japonicum

AIM: To evaluate the effect of rosiglitazone in a murine model of liver fibrosis induced by Schistosoma japonicum infection. METHODS: A total of 50 mice were randomly and averagely divided into groups A, B, C, D and E. The mice in group A served as normal controls, while those in the other four groups were infected with Schistosoma japonicum to induce the model of liver fibrosis. Besides, the mice in groups C, D and E were treated with praziquantel, rosiglitazone and praziquantel plus rosiglitazone, respectively. NF-κB binding activity and expression of PPARγ-mRNA were determined by Western blot assay and real-time quantitative PCR. Radioimmunonassay technique was used to detect the serum content changes of TNF-α and IL-6. Histological specimens were stained with HE. Expression of TGF-β1, a-smooth muscle actin and type ?Ⅰ?and type Ⅲ collagen was detected by immunohistochemistry and multimedia color pathographic analysis system. RESULTS: Inflammation and fibrosis in the rosiglitazone plus praziquantel treatment group (group E) were lightest among the mice infected with Schistosoma (P < 0.05). To further explore the mechanism of rosiglitazone action, we found that rosiglitazone can significantly increase the expression of PPARγ [E: -18.212 ± (-3.909) vs B: -27.315 ± (-6.348) and C: -25.647 ± (-5.694), P < 0.05],reduce the NF-κB binding activity (E: 88.89 ± 19.34 vs B: 141.11 ± 15.37, C: 112.89 ± 20.17 and D: 108.89 ± 20.47, P < 0.05), and lower the serum level of TNF-α (E: 1.613 ± 0.420 ng/mL vs B: 2.892 ± 0.587 ng/mL, C: 2.346 ± 0.371 ng/mL and D: 2.160 ± 0.395 ng/mL, P < 0.05) and IL-6 (E: 0.106 ± 0.021 ng/mL vs B: 0.140 ± 0.031 ng/mL and C: 0.137 ± 0.027 ng/mL, P < 0.05) in mice with liver fibrosis. Rosiglitazone can also substantially reduce the hepatic expression of TGF-β1, α-SMA type Ⅰand type Ⅲ collagen in mice with liver fibrosis. CONCLUSION: The activation of PPARγ by its ligand can retard liver fibrosis and suggest the use of rosiglitazone for the treatment of liver fibrosis due to Schistosoma japonicum infection.

A clinical trial of combined use of rosiglitazone and 5-aminosalicylate for ulcerative colitis

AIM: To investigate the therapeutic effects of the combined use of rosiglitazone and aminosalicylate on mild or moderately active ulcerative colitis (UC).METHODS: According to the national guideline for diagnosis and treatment of inflammatory bowel disease (IBD) in China, patients with mild or moderately active UC in our hospital were selected from July to November, 2004. Patients with infectious colitis, amoebiasis, or cardiac, renal or hepatic failure and those who had received corticosteroid or immunosuppressant treatment within the last month were excluded. Following a quasi-randomization principle, patients were allocated alternatively into the treatment group (TG) with rosiglitazone 4 mg/d plus 5-ASA 2 g/d daily or the control group (CG) with 5-ASA 2 g/d alone, respectively, for 4 wk. Clinical changes were evaluated by Mayo scoring system and histological changes by Truelove-Richards' grading system at initial and final point of treatment.RESULTS: Forty-two patients completed the trial, 21 each in TG and CG. The Mayo scores in TG at initial and final points were 5.87 (range: 4.29-7.43) and 1.86 (range: 1.03-2.69) and those in CG were 6.05 (range: 4.97-7.13) and 2.57 (range: 1.92-3.22) respectively. The decrements of Mayo scores were 4.01 in TG and 3.48 in CG, with a remission rate of 71.4% in TG and 57.1% in CG, respectively. Along with the improvement of disease activity index (DAI), the histological grade improvement was more significant in TG than in CG (P < 0.05).CONCLUSION: Combined treatment with rosiglitazone and 5-ASA achieved better therapeutic effect than 5-ASA alone without any side effects. Rosiglitazone can alleviate colonic inflammation which hopefully becomes a novel agent for UC treatment.

Inhibition of hepatic interleukin-18 production by rosiglitazone in a rat model of nonalcoholic fatty liver disease

AIM:To investigate the effects of rosiglitazone(RGZ) on expression of interleukin-18(IL-18) and caspase-1 in liver of non-alcoholic fatty liver disease(NAFLD) rats.METHODS:Twenty-eight Sprague-Dawley(SD) rats were randomly divided into control,NAFLD,and RGZ treated NAFLD groups.A NAFLD rat model of NAFLD was established by feeding the animals with a high-fat diet for 12 wk.The NAFLD animals were treated with RGZ or vehicle for the last 4 wk(week 9-12) and then sacrificed to obtain liver tissues.Histological changes were analyzed with HE,oil red O and Masson's trichrome staining.Expressions of IL-18 and caspase-1 were detected using immunohistochemical staining and semi-quantitative reverse-transcription polymerase chain reaction(RT-PCR) analysis.RESULTS:The expression levels of both IL-18 and caspase-1 were higher in the liver of NAFLD group than in the control group.Steatosis,inflammation and fibrosis,found in the liver of NAFLD rats,were significantly improved 4 wk after RGZ treatment.The elevated hepatic IL-18 and caspase-1 expressions in NAFLD group were also significantly attenuated after RGZ treatment.CONCLUSION:RGZ treatment can ameliorate increased hepatic IL-18 production and histological changes in liver of NAFLD rats.The beneficial effects of RGZ on NAFLD may be partly due to its inhibitory effect on hepatic IL-18 production.

PPARγ activator,rosiglitazone:Is it beneficial or harmful to the cardiovascular system?

Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with type II diabetes. Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity. Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction, inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation, and the protection of myocardial injury during ischemic/reperfusion in different animal models. Previous clinical studies in type II diabetes patients demonstrated that rosiglitazone played an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system. Despite these benefits, inconsistent findings have been reported, and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system, including increased risk of acute myocardial infarction, heart failure and chronic heart failure. As a result, rosiglitazone has been recently withdrawn from EU countries. Nevertheless, the effect of rosiglitazone on ischemic heart disease has not yet been firmly established. Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.

Significance of Rosiglitazone Inhibiting TLR4 Expression in Partial Hepatic Ischemia/Reperfusion of Mice

The effect of rosiglitazone as the ligand of peroxisome proliferator-activated receptor γ （PPARγ） inhibiting the TLR4 expression in ischemic lobes in partial hepatic ischemia/reperfusion injury （IRI） in BABL/C mice and the action of rosiglitazone inhibiting the TLR4 receptor-mediated inherent immune response were investigated. The model of the mouse partial hepatic ische- mia/reperfusion injury was established. All the animals were randomly divided into 3 groups： rosiglitazone group, vehicle （dimethylsulphoxide, DMSO） group and sham operation group. The hepatic samples were collected when mice were sacrificed 0, 2, 4 and 6 h after reperfusion following 1 h ischemia to analyze the acute phase of hepatic IRI. The dynamic expression of TlR4 mRNA was de- tected quantitatively by real-time-PCR, and the levels of TNF-α, IL-10 and ALT in portal vein were determined in all groups. After restoration of blood supply, the expression of TLR4 mRNA in ischemic lobes was detected in 0, 2, 4 and 6 h after reperfusion following 1 h ischemia in rosiglitazone group and vehicle group. The most intensive expression of TLR4 mRNA was present at 4 h after reperfusion in ischemic lobes in vehicle group. As compared with vehicle group, the expression of TLR4 mRNA in ischemic lobes in rosiglitazone group was significantly decreased at 4 h after reper- fusion. The level of IL-10 in portal vein was markedly up-regulated in rosiglitazone group as compared with vehicle group. Contrarily, the levels of TNF-α and ALT in portal vein were markedly down-regulated in rosiglitazone group as compared with vehicle group at every time point in mouse partial hepatic IRI model. Rosiglitazone could alleviate the hepatic IRI by inhibiting TLR4 receptor-mediated inherent immune response.

Rosiglitazone防治慢性支气管炎肺气肿的作用机制研究

目的:探讨Rosiglitazone防治慢性支气管炎肺气肿的作用机制。方法:(1)Rosiglitazone对烟熏和气管内滴入LPS大鼠肺组织氧化应激的调节作用:随机将SD大鼠分为3组:(a)慢性支气管炎/肺气肿模型组;(b)Rosiglitazone处理组;(c)对照组,不进行任何处理。测定3组大鼠肺组织上清中丙二醛(MDA)、超氧化物歧化酶(SOD)和一氧化氮(NO)含量。(2)Rosiglitazone对LPS刺激的脾脏巨噬细胞的NO分泌与MMP-9表达的调节作用:制作以上3组大鼠脾细胞悬液,取上清检测NO含量,结果表明加入Rosiglitazone,NO含量增加。48h后收集细胞调浓度至5×106/ml,加trizol1ml提取细胞总RNA用RT-PCR方法检测MMP-9表达。结果:(1)Rosiglitazone处理组大鼠肺组织中MDA含量较模型组明显降低。Rosiglitazone处理组大鼠肺组织中SOD含量较模型组明显增加。Rosiglitazone处理组大鼠肺组织中NO含量较模型组显著增加。(2)RT-PCR结果显示,加入Rosiglitazone使MMP-9表达降低;单用Rosiglitazone刺激脾脏巨噬细胞中MMP-9的表达与正常脾脏巨噬细胞中MMP-9的表达无显著性差异。结论:PPARγ激动剂Rosiglitazone可明显减轻烟熏和气管内滴入IPS所致慢性支气管炎/肺气肿大鼠肺组织的氧化应激反应,并提高其抗氧化能力,抑制脾脏巨噬细胞:MMP-9表达的作用,这些变化都有助于减轻吸烟和LPS所致的肺组织损伤。这些结果提示Rosiglitazone等PPARγ激动剂对防治慢性支气管炎/肺气肿有一定作用。

Effect of Rosiglitazone on Endocrine, Metabolism and Ovulatory Performance in Patients with Polycystic Ovary Syndrome and Insulin Resistance

The effect of rosiglitazone on endocrine, metabolism and ovulatory performance in the paitents with polycystic ovary syndrome(PCOS) and insulin resistance was investigated. Twenty-five patients diagnosed as having polycystic ovary syndrome (PCOS) combined with insulin resistance were treated with rosiglitazone for 12 weeks. Before and after treatment, serum luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), testosterone (T), androstenedione (A), sex hormone binding globulin (SHBG), insulin and glucose concentration, total cholesterol, triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholestero (LDL-C), apolipoprotein A, apolipoprotein B levels and ovulatory performance were determined. The results showed that after treatment serum insulin levels was decreased significantly (P<0.01). The HDL-C was increased while LDL-C decreased significantly (P<0.05, P<0.01). The serum LH, T, A concentrations and the ratio of LH/FSH were decreased, while SHBG levels increased significantly (P<0.01). The ovulation rate during clomiphene citrate therapy was 72 %, significantly higher than that before treatment. It is likely that reduction of hyperinsulinemia that is produce by rosiglitazone may effectively improve the endocrine, metabolism and ovulatory performance in the patients with PCOS and insulin resistance.

Rosiglitazone prevents gliosis,oxidative/nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats

Objective To study the preventive effect of rosiglitazone glial activation,oxidative/nitrative stress and spatial memory deficits induced by intracerebroventricular(ICV)injection of streptozotocin(STZ)in rats.Methods 24 male Wistar rats were randomly divided into sham operated group,model group and rosiglitazone group.The model of Alzheimer's was induced by injection with ICV 10% STZ bilaterally,on day 1 and 3(3 mg·kg-1).The rats were treated with rosiglitazone(2 mg·kg-1,p.o.)for a consecutive 21 days,once a day,beginning 7 days prior to STZ injection.The learning and memory behavior was assessed using Morris water maze task and Y-maze 21 d after ICV STZ injection.Malondialdehyde(MDA),superoxide dismutase(SOD),glutathione(GSH)levels and nitrotyrosine immunoreactivity in brain were estimated as parameters of oxidative/nitrative stress.Brain acetyl cholinesterase(AchE)activity was measured by EllMann's method and activated microglia and astrocytes were detected by immunohistochemistry.Results ICV STZ injection resulted in a severe deficit in spatial learning and memory associated with increased MDA level(+69.5%)and nitrotyrosine immunoreactivity(+23.7%),decreased SOD activity(-29.2%)and GSH(-25.1%)in brain.It also showed the activated microglia and astrocytes in the cortex and hippocampal CA1 region and a significant decrease in acetylcholinesterase activity(-40.2%).Compared with model group,chronic administration of rosiglitazone significantly shorten the escape latency time from the third day in place navigation test,increase the number of passing through primary flat place in spatial probe test in Morris water maze test,and decrease the error times in Y-maze test(P<0.05 or P<0.01).In addition,it also prevented the glial changes,decreased the elevated MDA and nitrite levels and restored the depleted GSH and acetylcholinesterase activity in cortex(P<0.05),but had no effect on SOD activity in cortex.Conclusions Rosiglitazone has a neuroprotective role against streptozotocin-induced cognitive impairment and associated oxidative/nitrative stress.

The Impact of a Drug Safety Warning on Discussions between Doctors and Their Patients;the Case of Rosiglitazone

The goal of this study was to track the influence of a highly publicized report on discussions between doctors and their patients and prescribing decisions made in response to concerns about potential medication adverse side effects. This was a retrospective analysis of a primary care network’s electronic medical record database. From a diabetes registry of 12, 246 patients, 329 were identified as taking rosiglitazone prior to the June 14, 2007 release of an article in the New England Journal of Medicine;the article suggesting an increased risk of myocardial events. The entire content of all office visits, telephone messages, and medication lists for each patient were reviewed over a 2-year period subsequent to the article’s publication. Doctor/patient discussions regarding concerns for rosiglitazone were catalogued including the physician’s treatment recommendations. There were documented discussions on rosiglitazone’s potential adverse side effects for 64 patients;19.5 percent of this population. All of the discussions occurred between June 15 and October 30, 2007. Of the entire group, 59.3 percent (N = 195) remained on rosiglitazone. For those advised to continue rosiglitazone, the provider indicated that he/she wanted more data before determining if the drug was not safe or discounted the validity of the safety concerns. For those advised to discontinue rosiglitazone, 112 (83.6 percent) were placed on pioglitazone. An article suggesting potential adverse effects of rosiglitazone resulted in a documented discussion in 19.5 percent of patients on this medication. These findings suggest an awareness of this publication by patients, presumably derived from media reports. However, an awareness of this concern did not result in a substantial change in practice.The majority of patients remained on rosiglitazone. The content of these discussions suggest that most physicians’ recommended waiting for more published data before considering a change. While many factors influence physician’s prescribing behavior, this study demonstrates how a highly publicized report influences the doctor/ patient dialogue.

Expression of p-PPARγ in the aging thoracic aorta of spontaneously hypertensive rat and inhibitory effect of rosiglitazone

Objective:To investigate the expression of phosphorylated peroxisome proliferators-activated receptor y(p-PPARY) in the aging thoracic aorta of spontaneously hypertensive rat(SHR) and the inhibitory effect of rosiglitazone on the phosphorylation of PPART.Methods:16,32 and 64 week-old Wistar-Kyoto rats(WKY) and SHR were randomly and respectively divided into WKY,SHR and SHR+rosiglitazone group(9 in each group).The rats in SHR+rosiglitazone group were treated with rosiglitazone(5 mg/kg,intragastrically) for 56 d,whereas normal saline was applied in WKY and SHR groups.Systolic blood pressure(SBP)of rats was measured by tail cuff method.Histopathological damage of thoracic aorta was analyzed using Hematoxylin-Eosin(HE) staining.Immunohistochemical staining and western blot were performed to test the level of p-PPARY protein in the thoracic aorta arising from each group.Results:The SBP in 16,32 and 64 week-old SHR were significantly higher as compared with those in matched WKY rats(P【0.05,respectively).HE staining showed increased content of smooth muscle cell,wrinkled lining endothelium and increased thickness of internal elastic lamina in the thoracic aorta of SHR.Immunohistochemical staining and western blot indicated that the levels of p-PPARY in the thoracic aorta arising from SHR were obviously higher than those in the thoracic aorta arising from WKY rats(P【0.05,respectively).Importantly,the high SBP,histopathological abnormalities of the thoracic aorta and elevated p-PPARY expression were prominently abrogated by rosiglitazone treatment in SHR(P【0.05,respectively).Furthermore,the SBP,histopathological abnormalities of the thoracic aorta and p-PPARY expression were positively correlated with age in SHR(P【0.05,respectively).Conclusions:The PPARY phosphorylation was observed in the thoracic aorta of SHR and its expression was increased by the increase of age.Furthermore,rosiglitazone inhibited the PPARY phosphorylation and suppressed vascular aging in SHR.

Anti-hypertensive effects of rosiglitazone on renovascular hypertensive rats:role of oxidative stress and lipid metabolism

This study investigated the anti-hypertensive mechanismof rosiglitazone in renovascular hypertensive rats,and examined its relationship to oxidative stress and lipid metabolism. The renovascular hypertension was induced by stenosis of the left renal artery. Four groups of rats were selected： control,induced untreated,rosiglitazone（ 20 mg / kg） and captopril（ 10 mg / kg）. After 14 d of administration,compared with induced untreated group,rosiglitazone group reduced the renovascular hypertensive rats ＇ systolic blood pressure and diastolic blood pressure,and decreased total cholesterol（TCH）,triglyceride（TG）,angiotensin II（ Ang II） and angiotensin receptor（ AT1） levels（ P ＆lt; 0. 05）. Meanwhile,rosiglitazone remarkably decreased the levels of malondialdehyde（ MDA） and hydrogen peroxide（ H2O2） while improved the levels of supperoxide dismutase（ SOD） and reduced glutathione（ GSH）. These results suggested that rosiglitazone could effectively decreased the blood pressure in renovascular hypertensive rats,and this might be performed by regulating the activity of angiotensin and the lipid metabolismand improving the oxidative stress.