Double antioxidant activities of rosiglitazone against high glucose-induced oxidative stress in hepatocyte.

Chronic hyperglycemia is the hallmark of diabetes and its complication. High glucose-induced excessive reactive oxygen species (ROS) production has been considered to play an important role in the development of diabetes. However, the influence of high glucose on the liver remains to be clarified. Rosiglitazone (RSG) is a member of thiazolidinediones (TDZs) family, which is the ligand of the of nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ), being used clinically for the treatment of type 2 diabetic patients through their insulin-sensitizing effect. In the present study, we investigated the cytotoxicity of high glucose in QZG hepatocytes and evaluated the protective effect of RSG. The results showed that high glucose significantly reduced cell viability through generation of ROS via activation of PKC, which was inhibited by RSG. On the one hand, RSG notably inhibited the activation of PKC induced by high glucose independent of PPARγ, leading to the decrease of ROS generation. On the other hand, RSG notably increased the expression of key antioxidant transcription factor Nrf2 and antioxidant enzyme HO-1 in a PPARγ-dependent manner, leading to the elimination of excessive ROS. In addition, RSG also inhibited the decrease of COX-2 expression induced by high glucose through activating PPARγ. Furthermore, the activation of Akt and MAPKs was involved in the effect of RSG on Nrf2, HO-1 and COX-2. In summary, our study supports the hypothesis that RSG protect hepatocytes from high glucose-induced toxicity through PPARγ-dependent and PPARγ-independent pathways.

Wang X ，Wang Z ，Liu JZ ，Hu JX ，Chen HL ，Li WL ，Hai CX ... -  《-》

Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism.

Ceolotto G ，Gallo A ，Papparella I ，Franco L ，Murphy E ，Iori E ，Pagnin E ，Fadini GP ，Albiero M ，Semplicini A ，Avogaro A ... -  《-》

Protective effect of the peroxisome proliferator-activated receptor (PPAR)-γ, ligand rosiglitazone on tert-butyl hydroperoxide-induced QZG cell injury.

Tert-butyl hydroperoxide (t-BHP) can induce cell injury by forming free radical intermediates. Peroxisome proliferator-activated receptor (PPAR)-γ is a ligand-activated transcription factor belonging to nuclear hormone receptor superfamily, and is involved in oxidative stress response. Thiazolidinedione rosiglitazone is a potent PPARγ agonist. The main aim of this study was to investigate the protective effect of rosiglitazone on QZG cells from t-BHP-induced toxicity. MTT assay showed that t-BHP treatment resulted in decreased cell viability in a concentration dependent manner. Under 400 μM t-BHP treatment, QZG cell displayed significant loss of viability and dramatic morphological changes characterized by changing in shape from triangle to spherical, disappearance of cell cilia, swollen mitochondrial and typical apoptotic alteration such as condensation of chromatin, and appearance of crescent under light microscopy and electronic microscopy, respectively. Flow cytometry analysis indicated that 30.90±1.70% QZG cells were undergoing apoptosis compared to that of the control cells (2.80±0.85%, P<0.05). There was substantial population of the cells undergoing necrosis (28.5.%). 25 μM rosiglitazone treatment inhibited the t-BHP-induced cell toxicity significantly by restoring the cell viability, reducing cell population undergone apoptosis to normal level (3.5%) and ameliorating t-BHP-induced pathological changes. Real-time RT-PCR results showed that 400 μM t-BHP caused dramatic down-regulation of PPARγ expression in QZG cells, whereas combining treatment with 25 μM rosiglitazone resistant to PPARγ expression to normal level partially. Overall, our results indicate that rosiglitazone has protective effect against t-BHP-induced QZG cell injury. The protective effect of rosiglitazone is involved in its regulation on the function of PPARγ.

Li WL ，Liang X ，Wang X ，Zhang XD ，Liu R ，Zhang W ，Chen HL ，Qin XJ ，Bai H ，Hai CX ... -  《-》

Rosiglitazone, a PPARγ agonist, ameliorates palmitate-induced insulin resistance and apoptosis in skeletal muscle cells.

Palmitate induces insulin resistance and apoptosis in insulin target tissues. Rosiglitazone (RSG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, can activate both pro-apoptotic and anti-apoptotic pathways in different cells; however, its effect on palmitate-induced apoptosis in skeletal muscle cells remains to be elucidated. After differentiation of C2C12 cells, myotubes were treated with palmitate, RSG and GW9662 (PPARγ antagonist). MTT and terminal deoxynucleotide transferase dUTP nick end labelling (TUNEL) assays and caspase-3 activity were used to investigate the apoptosis. To study the underlying mechanism, glucose uptake, gene expression and protein levels were evaluated. A total of 0.75 mM palmitate reduced cell viability by 43% and increased TUNEL-positive cells and caspase-3 activity by 15-fold and 6.6-fold, respectively. RSG (10 μM) could markedly decrease the level of TUNEL-positive cells and caspase-3 activity in palmitate-treated cells. The protective effect of RSG on apoptosis was abrogated by GW9662. To investigate the molecular mechanism of this effect, gene expression and protein level of protein tyrosine phosphatase 1B (PTP1B) were evaluated. Palmitate and RSG individually increased the expression and protein level of PTP1B, whereas combined treatment (palmitate and RSG) were able to further increase the expression of PTP1B in C2C12 cells. We also evaluated the effect of RSG on palmitate-induced insulin resistance in muscle cells. RSG could significantly improve glucose uptake by 0.4-fold in myotubes treated with palmitate. Moreover, RSG could restore the phosphorylation of Akt in palmitate-treated cells. These data suggest that RSG protects skeletal muscle cells against palmitate-induced apoptosis and this effect appears to be mediated via the PPARγ-dependent and PTP1B-independent mechanisms. Saturated free fatty acids (FFAs), such as palmitate, have been shown to induce cellular apoptosis. Strategies for preventing the cytotoxic effect of palmitate are useful in reduction of diabetes complications. In this study, we introduced RSG as an agent that protects skeletal muscle cells against palmitate-induced apoptosis and insulin resistance. It appears that RSG protects skeletal muscle cells against palmitate-induced apoptosis via the PPARγ-dependent and PTP1B-independent mechanisms. Given the role of FFAs in skeletal muscle apoptosis, these findings support the idea that RSG can ameliorate diabetes complications such as skeletal muscle loss.

Meshkani R ，Sadeghi A ，Taheripak G ，Zarghooni M ，Gerayesh-Nejad S ，Bakhtiyari S ... -  《-》

Metabolic action of peroxisome proliferator-activated receptor gamma agonism in rats with exogenous hypercorticosteronemia.

Berthiaume M ，Laplante M ，Tchernof A ，Deshaies Y ... -  《INTERNATIONAL JOURNAL OF OBESITY》