To explore the protective effect of rosiglitazone (RGZ) on hepatic ischemia reperfusion injury (HIRI) and the underlying mechanisms.
 Methods: A rat model of ischemia-reperfusion injury was established by clamping the left and middle lobe of liver with noninvasive vascular clamp. A total of 30 Sprague-Dawley rats were randomly divided into a sham group, an HIRI group, and a RGZ group (10 rats in each group). Two hours after reperfusion, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, lactate dehydrogenase (LDH) level, malondialdehyde (MDA) content and catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were examined. HE staining was used to observe liver pathological morphology. The liver peroxisome proliferators-activated receptor γ (PPAR-γ), p-PPAR-γ, nuclear factor related factor 2 (Nrf-2), antioxidant response element (ARE), heme oxygenase 1 (HO-1) and quinone oxidoreductase-1 (NQO-1) were detected by Western blot.
 Results: Compared with the HIRI group, the levels of ALT, AST, LDH and MDA in the RGZ group were significantly decreased (all P<0.05), while the levels of Nrf-2, ARE, HO-1 and NQO-1 in the RGZ group were significantly increased. The hepatic swelling, necrosis and pathological damage were decreased (all P<0.05). In addition, there was no difference in the level of PPAR-γ between the 2 groups (P>0.05).
 Conclusion: PPAR-γ agonist RGZ can attenuate HIRI, which may be related to activating Nrf2/ARE signaling pathway and enhancement of antioxidant ability.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Catalase ; blood ; Disease Models, Animal ; Glutathione Peroxidase ; blood ; L-Lactate Dehydrogenase ; blood ; Ligation ; Liver ; blood supply ; metabolism ; Malondialdehyde ; blood ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; blood ; etiology ; prevention & control ; Rosiglitazone ; Superoxide Dismutase ; blood ; Thiazolidinediones ; therapeutic use

BACKGROUNDIn vitro experiments have revealed that toll-like receptor 4 (TLR4) pathway is involved in the progression of immunoglobulin A nephropathy (IgAN) by induction of proinflammatory cytokines. Evidence showed that, in other disease models, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been shown to exert anti-inflammatory effects through suppression of the expression and activity of TLR4. However, the interaction between PPAR-γ and TLR4 in IgAN has not been fully studied both in vitro and in vivo. In this study, we explored whether TLR4 pathway attributed to the progression of IgAN in experimental rats.

METHODSBovine gamma globulin was used to establish IgAN model. Fifty-four Lewis rats were randomly divided into six groups: ControlTAK242, IgANTAK242, toll-like receptor 4 inhibitor (TAK242) groups (rats were administrated with TLR4 inhibitor, TAK242) and ControlPio, IgANPio, Pio groups (rats were administrated with PPAR-γ agonist, pioglitazone). Urinary albumin-to-creatinine ratio (ACR), serum creatinine, and blood urea nitrogen were detected by automatic biochemical analyzer. Renal histopathological changes were observed after hematoxylin-eosin staining, and the IgA deposition in glomeruli was measured by immunofluorescence staining. Real-time polymerase chain reaction and Western blotting were used to detect TLR4 and interleukin-1 beta (IL-1β) message ribonucleic acid (mRNA) and protein expression in renal tissues. Results were presented as mean ± standard deviation. Differences between groups were analyzed by one-way analysis of variance.

RESULTSCompared to normal rats, experimental rats showed higher ACR (4.45 ± 1.33 mg/mmol vs. 2.89 ± 0.96 mg/mmol, P < 0.05), obvious IgA deposition with mesangial hypercellularity, hyperplasia of mesangial matrix accompanied by increased serum IL-1β (48.28 ± 13.49 pg/ml vs. 35.56 ± 7.41pg/ml, P < 0.05), and renal expression of IL-1β and TLR4. The biochemical parameters and renal pathological injury were relieved in both TAK242 group and Pio group. The expressions of renal tissue TLR4, IL-1β, and serum IL-1β were decreased in rats treated with TAK242, and the expression of TLR4 mRNA and protein was significantly reduced in Pio group compared to IgANPiogroup (1.22 ± 0.28 vs. 1.72 ± 0.45, P < 0.01, and 0.12 ± 0.03 vs. 0.21 ± 0.05, P < 0.01).

CONCLUSIONSOur study proves that inflammation mediated by TLR4 signaling pathway is involved in the progression of IgAN in rat models. Moreover, pioglitazone can inhibit the expression of TLR4 in IgAN.

Animals ; Blotting, Western ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Glomerulonephritis, IGA ; drug therapy ; genetics ; metabolism ; Interleukin-1beta ; genetics ; metabolism ; Male ; Random Allocation ; Rats ; Rats, Inbred Lew ; Real-Time Polymerase Chain Reaction ; Signal Transduction ; drug effects ; genetics ; Thiazolidinediones ; therapeutic use ; Toll-Like Receptor 4 ; genetics ; metabolism

Renal tubulointerstitial fibrosis is the common ending of progressive renal disease. It is worth developing new ways to stop the progress of renal fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have been studied to treat diabetic nephropathy, cisplatin-induced acute renal injury, ischemia reperfusion injury and adriamycin nephropathy. In this study, unilateral ureteral obstruction (UUO) was used to establish a different renal fibrosis model. PPAR? agonist pioglitazone was administrated by oral gavage and saline was used as control. At 7th and 14th day after the operation, mice were sacrificed for fibrosis test and T lymphocytes subsets test. Unexpectedly, through MASSON staining, immunohistochemistry for α-SMA, and Western blotting for a-SMA and PDGFR-β, we found that pioglitazone failed to attenuate renal fibrosis in UUO mice. However, flow cytometry showed that pioglitazone down-regulated Th1 cells, and up-regulated Th2 cells, Th17 cells and Treg cells. But the Th17/Treg ratio had no significant change by pioglitazone. Real-time PCR results showed that TGF-β and MCP-1 had no significant changes, at the same time, CD4(+) T cells associated cytokines were partially regulated by pioglitazone pretreatment. Taken together, pioglitazone failed to suppress renal fibrosis progression caused by UUO.
Animals ; Chemokine CCL2 ; metabolism ; Fibrosis ; Kidney ; pathology ; Kidney Diseases ; drug therapy ; etiology ; Male ; Mice ; Mice, Inbred C57BL ; PPAR gamma ; agonists ; T-Lymphocyte Subsets ; drug effects ; Thiazolidinediones ; administration & dosage ; pharmacology ; therapeutic use ; Transforming Growth Factor beta ; metabolism ; Urethral Obstruction ; complications

It has not yet been determined whether chronic exposure to relatively low doses of pioglitazone increases risk of bladder cancer. We aimed to assess the risk of bladder cancer associated with pioglitazone in Korean patients. This was a retrospective cohort study of diabetic patients who had > or = 2 clinic visits between November 2005 and June 2011 at one of four tertiary referral hospitals in Korea. A prevalent case-control analysis nested within the cohort was conducted to further adjust confounders. A total of 101,953 control patients and 11,240 pioglitazone-treated patients were included, in which there were 237 and 30 cases of incidental bladder cancer (64.9 and 54.9 per 100,000 person-years; age, sex-adjusted HR 1.135, 95% confidence interval [CI] 0.769-1.677), respectively. In the prevalent case-control analysis nested within the cohort, use of pioglitazone for a duration of > 6 months, but not ever use of pioglitazone, was associated with an increased rate of bladder cancer as compared to never use of pioglitazone. In conclusion, we failed to exclude the possible association between use of pioglitazone for a duration of > 6 months and bladder cancer.
Aged ; Asian Continental Ancestry Group ; Case-Control Studies ; Cohort Studies ; Diabetes Mellitus, Type 2/complications/*drug therapy ; Female ; Humans ; Hypoglycemic Agents/*therapeutic use ; Male ; Middle Aged ; Prevalence ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Tertiary Care Centers ; Thiazolidinediones/*therapeutic use ; Urinary Bladder Neoplasms/complications/*diagnosis/epidemiology

PURPOSE: We tested whether rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-gamma agonist, can restore alveolar development and vascular growth in a rat model of bronchopulmonary dysplasia (BPD). MATERIALS AND METHODS: A rat model of BPD was induced through intra-amniotic delivery of lipopolysaccharide (LPS) and postnatal hyperoxia (80% for 7 days). RGZ (3 mg/kg/d, i.p.) or vehicle was given daily to rat pups for 14 days. This model included four experimental groups: No BPD+vehicle (V), No BPD+RGZ, BPD+V, and BPD+RGZ. On D14, alveolarization, lung vascular density, and right ventricular hypertrophy (RVH) were evaluated. RESULTS: Morphometric analysis revealed that the BPD+RGZ group had significantly smaller and more complex airspaces and larger alveolar surface area than the BPD+V group. The BPD+RGZ group had significantly greater pulmonary vascular density than the BPD+V group. Western blot analysis revealed that significantly decreased levels of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 by the combined exposure to intra-amniotic LPS and postnatal hyperoxia were restored by the RGZ treatment. RVH was significantly lesser in the BPD+RGZ group than in the BPD+V group. CONCLUSION: These results suggest that RGZ can restore alveolar and pulmonary vascular development and lessen pulmonary hypertension in a rat model of BPD.
Animals ; Bronchopulmonary Dysplasia/*drug therapy ; Female ; Hypertension, Pulmonary/drug therapy ; Immunohistochemistry ; Lung/drug effects/pathology ; PPAR gamma/*agonists ; Rats ; Rats, Sprague-Dawley ; Thiazolidinediones/*therapeutic use ; Vasodilator Agents/*therapeutic use

OBJECTIVE: The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin. MATERIALS AND METHODS: We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results. RESULTS: One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 +/- 1.4 at 3 weeks to 0.9 +/- 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n = 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared. CONCLUSION: A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.
Animals ; Bleomycin ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; Observer Variation ; Pulmonary Fibrosis/chemically induced/*drug therapy/*radiography ; Thiazolidinediones/*therapeutic use ; *X-Ray Microtomography

OBJECTIVETo investigate the expression of phosphatase and tension homolog (PTEN) in adipose tissue of KKAy diabetic mice, a mouse model of type 2 diabetes.

METHODSKKAy diabetic mice were fed with high fat diet for 4 weeks. After blood glucose met the criteria of diabetes (over 16.7 mmol/L), mice were randomly divided into 3 groups: a control group (without any treatment), a rosiglitazone group (treated with rosiglitazone 12.5 mg/kg.d once per day), and a metformin group (treated with metformin 3 g/kg.d twice daily). After 4 weeks, we then determined the expression of PTEN and phosphoserine 473-Akt (pS473-Akt) in the epididymal adipose tissue with Western blots. The mice in each group were further divided into the insulin (-) subgroup and insulin (+) subgroup, which were intraperitoneally injected with saline and insulin (5 mU/g body weight), respectively.

RESULTSThe expression of PTEN was elevated in the epididymal adipose tissue obtained from KKAy diabetic mice compared with that from the C57BL/6J mice (P<0.001). In accordance with the enhanced expression of PTEN, the level of pS473-Akt stimulated by insulin was decreased in the adipose tissue of KKAy mice compared to the C57BL/6J mice (P<0.001). Treatment with the insulin-sensitizing agents, rosiglitazone and metformin did not inhibit the elevated expression of PTEN in adipose tissue of KKAy diabetic mice.

CONCLUSIONPTEN may play an important role in the development of insulin resistance in adipose tissue of type 2 diabetes mice model.

Adipose Tissue ; metabolism ; Animals ; Diabetes Mellitus, Experimental ; drug therapy ; genetics ; Hypoglycemic Agents ; therapeutic use ; Insulin Resistance ; genetics ; Male ; Metformin ; therapeutic use ; Mice ; Mice, Inbred C57BL ; PTEN Phosphohydrolase ; genetics ; Thiazolidinediones ; therapeutic use

UNLABELLEDOBJECTIVE; To evaluate the efficacy and safety of Jiangtang Xiaozhi Capsule (JTXZC) in treating type 2 diabetes mellitus (T2DM) of qi-yin deficiency phlegm-stasis inter-obstruction syndrome (QYDPSIOS), and to observe its effect on inflammatory factors and fibrinolytic factors.

METHODSBy adopting a randomization grouping, parallel control, and prospective study, 73 T2DM patients of QYDPSIOS were assigned to two groups by random digit table, the Pioglitazone Tablet group (36 cases, as the control) and the JTXZC group (37 cases). All patients maintained their basic therapies and lifestyle as previous after recruitment. Patients in the JTXZC group took JTXZC, 4 pills each time, three times per day, while those in control group took Pioglitazone Tablet, 15 mg each time, once daily. The therapeutic course for all was 8 weeks. The body weight (BW), the height, body mass index (BMI), waist circumference (WC), hip circumference, waist-to-hip ratio (WHR), and scoring of Chinese medicine (TCM) symptoms were observed. Levels of fasting blood glucose (FBG), 2 h postprandial blood glucose (2 h PBG), glycated hemoglobin (HbA1c), tumor necrosis factor alpha (TNF-alpha), nuclear factor kappaB (NF-kappaB), and plasminogen activator inhibitor 1 (PAL-1) were detected. The safety indices such as liver and renal functions and adverse reactions were also observed.

RESULTSCompared with before treatment, BW, BMI, HbA1c, and PBG were obviously lower after 8-week treatment than before treatment in the JTXZC group (P < 0.05). There was no statistical difference in post-treatment BW, BMI, HbA1c, or 2 h PBG between the two groups (P < 0.05). Compared with before treatment, levels of TNF-alpha and PAI-1 were lowered after 8 weeks of treatment in both groups (P < 0.01). The level of NF-kappaB was obviously lowered after 8 weeks of treatment in the control groups (P < 0.05), but it also decreased in the JTXZC group with no statistical difference. The scorings of CM symptoms were somewhat improved after treatment in the two groups (P < 0.01). Besides, better effects were obtained in the JTXZC group (P < 0.05). No severe adverse event occurred in either group during the whole therapeutic course.

CONCLUSIONSJTXZC showed similar therapeutic effect to pioglitazone. Both of them could effectively improve patients' clinical symptoms, the inflammation and fibrinolytic activities in different pathways, with no severe adverse reaction.

Adult ; Aged ; Diabetes Mellitus, Type 2 ; drug therapy ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Qi ; Thiazolidinediones ; therapeutic use ; Yin Deficiency ; drug therapy

PURPOSE: Thiazolidinediones are insulin-sensitizing agents that reduce neointimal proliferation and the adverse clinical outcomes associated with percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM). There is little data on whether or not low dose pioglitazone reduces adverse clinical outcomes. MATERIALS AND METHODS: The study population included 121 DM patients with coronary artery disease and they were randomly assigned to 60 patients taking 15 mg of pioglitazone daily in addition to their diabetic medications and 61 patients with placebo after the index procedure with drug-eluting stents (DESs). The primary end points were rate of in-stent restenosis (ISR) and change in atheroma volume and in-stent neointimal volume. The secondary end points were all-cause death, myocardial infarction (MI), stent thrombosis and re-PCI. RESULTS: There were no statistical differences in the clinical outcomes and the rate of ISR between the two groups [all-cause death; n=0 (0%) in the pioglitazone group vs. n=1 (1.6%) in the control group, p=0.504, MI; n=2 (3.3%) vs. n=1 (1.6%), p=0.465, re-PCI; n=6 (10.0%) vs. n=6 (9.8%), p=0.652, ISR; n=4 (9.3%) vs. n=4 (7.5%), p=1.000, respectively]. There were no differences in changes in neointimal volume, percent neointimal volume, total plaque volume and percent plaque volume between the two groups on intravascular ultrasonography (IVUS) study. CONCLUSION: Our study demonstrated that low dose pioglitazone does not reduce rate of ISR, neointimal volume nor atheroma volume in DM patients who have undergone PCI with DESs, despite the limitations of the study.
Aged ; Coronary Artery Disease/drug therapy/radiography/*therapy ; Coronary Restenosis/*prevention & control ; *Drug-Eluting Stents ; Female ; Humans ; Hypoglycemic Agents/therapeutic use ; Male ; Middle Aged ; Thiazolidinediones/administration & dosage/*therapeutic use

PURPOSE: Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake. MATERIALS AND METHODS: After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group). RESULTS: Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p<0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups. CONCLUSION: Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.
Adiponectin/metabolism ; Adiposity/drug effects ; Animals ; Cell Proliferation/drug effects ; Diabetes Mellitus, Type 2/diet therapy/*drug therapy ; Eating/*drug effects ; Glucose Intolerance/diet therapy/*drug therapy ; Insulin Resistance ; Insulin-Secreting Cells/*drug effects/pathology ; Male ; Piperidines/adverse effects/*therapeutic use ; Pyrazoles/adverse effects/*therapeutic use ; Rats ; Rats, Inbred OLETF ; Receptor, Cannabinoid, CB1/physiology ; Thiazolidinediones/*therapeutic use