Upregulation of PGC-1α expression by pioglitazone mediates prevention of sepsis-induced acute lung injury

Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.

Efficacy and safety of standard dose pioglitazone versus low-dose pioglitazone as an add on treatment in type 2 diabetes mellitus: A randomized controlled trial

Background: On 18th June 2013, India banned pioglitazone, a peroxisome proliferation activator gamma agonist, and a popular anti-diabetic drug used in the treatment of type 2 diabetes mellitus (T2DM), but on 21st August 2013, ban was revoked after stiff opposition from diabetologists and pioglitazone was reintroduced to the market again. Aim and Objective: The aim of this study was to assess the efficacy and safety of low-dose pioglitazone compared to standard dose pioglitazone in adults with T2DM. Materials and Methods: After obtaining permission from the Institutional Ethics Committee, 50 patients with T2DM who were not under adequate glycemic control with metformin and glimepiride combination therapy were included in the study. The patients were randomly assigned (1:1) into pioglitazone 7.5 mg group and 15 mg group as an add on treatment to the existing therapy. Results: All the glycemic parameters such as Fasting blood sugar (FBS), post prandial blood glucose (PPBS), Glycosylated Hemoglobin (HbA1c) are significantly reduced in both groups from baseline to the end of 12 weeks. FBS reduced from 183.64 ± 20.9 to 152.08 ± 15.2 in the Pioglitazone 7.5 mg group and from 177.32 ± 16.89 to 145.2 ± 11.6 in the pioglitazone 15 mg group (P < 0.05), PPBS was reduced from 260.2 ± 31.09 to 213.8 ± 29.5 and from 256.24 ± 43.72 to 203.52 ± 27.5 (P < 0.05) in 7.5 mg and 15 mg group, respectively. HbA1c was reduced from 8.969 ± 0.88 to 8.508 ± 0.9 in 7.5 mg group (P < 0.05) and in 15 mg group, it was reduced from 8.796 ± 0.79 to 8.19 ± 0.72 (P < 0.05). In the study, Pioglitazone 7.5 mg efficaciously reduced glycemic parameters similar to pioglitazone 15 mg and there was no statistically significant difference between the groups. Three patients reported with pedal edema as adverse effect in pioglitazone 15 mg therapy, whereas only one in 7.5 mg pioglitazone therapy complained of ankle edema. Conclusion: Low-dose pioglitazone offers an attractive alternative option to standard dose pioglitazone as an add on therapy for T2DM due to its effectiveness in reducing glycemic markers and also fewer side effect profile.

Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression

Neurogenesis decline in hippocampal dentate gyrus (DG) participates in stress-induced depressive-like behaviors, but the underlying mechanism remains poorly understood. Here, we observed low-expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) in hippocampus of stress-stimulated mice, being consistent with high corticosterone level. NLRP6 was found to be abundantly expressed in neural stem cells (NSCs) of DG. Both Nlrp6 knockout (Nlrp6-/-) and NSC-conditional Nlrp6 knockout (Nlrp6CKO) mice were susceptible to stress, being more likely to develop depressive-like behaviors. Interestingly, NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up. Nlrp6 deficiency promoted esophageal cancer-related gene 4 (ECRG4) expression and caused mitochondrial dysfunction. Corticosterone as a stress factor significantly down-regulated NLRP6 expression, damaged mitochondrial function and suppressed cell proliferation in NSCs, which were blocked by Nlrp6 overexpression. ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders. Pioglitazone, a well-known clinical drug, up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction. In conclusion, this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs, and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.

Pioglitazone attenuates white matter injury in mice with cerebral ischemia-reperfusion / 国际脑血管病杂志

Objective:To investigate the effect of pioglitazone on white matter injury after cerebral ischemia-reperfusion in mice and its mechanism.Methods:Forty-two young male C57BL/6J mice were randomly divided into sham operation group, model group, and pioglitazone group ( n=14 in each group). The model of cerebral ischemia-reperfusion was induced by transient middle cerebral artery occlusion with suture-occluded method. On the 3 rd and 7 th day after the establishment of the model, the neural function was assessed by the adhesive removal test. The mice were killed on the 7 th day after the establishment of the model. HE staining was used to detect the extent of cerebral infarction. Immunofluorescence staining and Western blot analysis were used to detect the degree of white matter damage and the changes of microglia phenotype. Results:On the 7 th day after cerebral ischemia-reperfusion, the adhesive removal time in the PGZ group was significantly shortened compared with the model group ( P<0.05), the percentage of cerebral infarction volume was significantly reduced ( P<0.05), the ratio of MBP/NF200 fluorescence intensity in the cortical and striatal areas was significantly increased (all P<0.05), and the number of CD16 +/Iba1 + microglia was significantly decreased ( P<0.01), while the number of CD206 +/Iba1 + microglia tended to increase, but there was no statistical difference. Conclusion:Pioglitazone may reduce the degree of white matter injury and nerve function damage in mice with cerebral ischemia-reperfusion, and its mechanism may be associated with regulating the transformation of microglia from M1 type to M2 type.

The role of pioglitazone in antioxidant, anti-inflammatory, and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance

We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.

Exploration on the mechanism of pioglitazone in alleviating severe acute pancreatitis induced lung injury by inhibiting the expression of TLR2 and TLR4's mRNA in lung tissue / 中华急诊医学杂志

Objective:To explore the mechanism of pioglitazone in reducing lung injury induced by acute pancreatitis.Methods:Thirty healthy male SD rats were randomly(random number) divided into the sham operation group, model group and pioglitazone group, with 10 rats in each group. After anesthesia, the rats in the sham operation group were injected with normal saline retrogradely through the pancreaticobiliary duct. In the model group, after anesthesia, the rats were retrogradely injected with sodium taurocholate into the pancreaticobiliary duct to construct the lung injury model of severe acute pancreatitis. In the pioglitazone group, the model was established after intraperitoneal injection of pioglitazone. Six rats in each group were randomly selected and killed 12 h after operation, and then lung tissue and venous blood were collected. The levels of serum amylase and TNF-α and NO in lung tissue homogenate were detected and compared among the three groups; the expression of TLR2 mRNA and TLR4 mRNA in lung tissue was detected by RT-PCR and compared among the three groups; the lung tissue pathological injury score and lung leakage index were calculated and compared among the three groups. The correlation of TLR2 and TLR4’s mRNA expression with lung tissue pathological injury score and lung leakage index was analyzed.Results:The levels of serum amylase and the levels of TNF-α and NO in lung tissue homogenate in the model group were significantly higher than those in the sham operation group, and the above indexes in the pioglitazone group were significantly lower than those in the model group ( P<0.05). The expression levels of TLR2 mRNA and TLR4 mRNA in lung tissue, the lung tissue pathological injury score and lung leakage index in the model group were significantly higher than those in the sham operation group, and the above indexes in the pioglitazone group were significantly lower than those in the model group ( P<0.05). Spearman correlation analysis showed that the expression levels of TLR2 mRNA and TLR4 mRNA in lung tissue were significantly positively correlated with the lung tissue pathological injury score ( rs=0.959, P<0.001; rs=0.924, P<0.001). Pearson correlation analysis showed that the expression levels of TLR2 mRNA and TLR4 mRNA in lung tissue were significantly positively correlated with the lung leakage index ( r=0.957, P<0.001; r=0.958, P<0.001). Conclusions:Pioglitazone may reduce the severity of severe acute pancreatitis induced lung injury by inhibiting the expression of TLR2 mRNA and TLR4 mRNA in lung tissue.

A study of effectiveness of addition of drug teneligliptin to metformin, glimepiride, pioglitazone combination in type II diabetic patients

Background: Diabetes is a most prevalent chronic disease and has reached to alarming stage in almost all developed and developing countries. Worldwide approximately four hundred millions of people are living with diabetes and it is a leading cause of death. Aims and objectives is to study effectiveness of addition of drug Teneligliptin to Metformin, Glimepiride, Pioglitazone combination in type II Diabetic patients.Methods: This was a cross sectional study carried out in the department of Medicine of a tertiary health care centre during the one year period i.e. January 2017 to January 2018 in the type II diabetic patients. Out of all type II diabetic patients 40 patients who were on the treatment for hypoglycemia with drugs Metformin, Glimepiride, Pioglitazone were selected out of these randomly 20 patients were continued on the previous treatment (Group B) and remaining 20 were given additional drug Teneligliptin (Group A). The statistical analysis was done by unpaired t-test and chi-square test analyzed by SPSS 19 version of software.Results: In this study Authors have seen that the average age in both the groups was comparable i.e. 36.78±6.74 and 38.92±5.87 (p>0.05, t=1.24, df=38), the sex ration was also similar in both the group (p>0.43, χ2=0.43, df=1) and the HbA1C was comparable at 1st Wk. 10±4.56 - 9.87±3.42 (p>0.05, t=1.023, df=38) and 4th Wk. 8±5.23 - 9.67±4.52 (p>0.05, t=1.0804, df=38) but significantly differed at 8th Wk. 7.12±2.34 - 9.92±3.56 (p<0.01, t=3.82, df=38), 12th Wk. 5.98±1.98 - 9.24±2.79 (p<0.001, t=4.26, df=38) respectively in Group A and B.Conclusions: It can be concluded from this study that the addition of Teneligliptin significantly reduced the HbA1c level at the end of 4th wk. and hence superior to conventional Metformin, Glimepiride, Pioglitazone only combination treatment.

Effects and Mechanism Study of Pioglitazone on High Glucose-induced Epithelial-mesenchymal Transition in Renal Tubular Epithelial Cells of Rat / 中国药房

OBJECTIVE：To investigate the effects o f pioglitazone （PIO）on high glucose-induced epithelial-mesenchymal transition（EMT）in renal tubular epithelial cells of rat and its possible mechanism ，and to provide theoretic reference and new target for the prevention and treatment of diabetic nephropathy. METHODS ：The rat renal tubular epithelial NRK- 52E cells were randomly divided into control group （5.5 mmol/L glucose ），high-glucose group （30 mmol/L glucose ），PIO intervention group （30 mmol/L glucose+ 5.0 μmol/L PIO），GW9662 intervention group （30 mmol/L glucose+ 5.0 μmol/L PIO+5.0 μmol/L specific anta- gonist GW 9662）. The cells of the first 3 groups were detected at 6，12，24，48 h of culture ，while those in GW 9662 intervention group were detected at 48 h of culture. mRNA expression of PTEN and PPARγ were detected by real-time PCR. The protein expression of PTEN ，PPARγ，α-SMA and E-cadherin as well as the changes of PI 3K/AKT signaling pathway were determined by Western blotting assay. RESULTS ：With the extension of culture time ，compared with control group ，the mRNA and protein expression of PPARγ（except for protein expression at 6 h）and PTEN in high-glucose group reduced significantly ，while the protein expression of α-SMA and p-AKT （Thr308）increased significantly ，and the protein expression of E-cadherin reduced significantly （P＜0.05），showing time-dependent trend. Compared with high-glucose group ，the mRNA and the protein expression （except for 6 h） of PPAR γ and PTEN were increased significantly in PIO intervention group ， while the protein expression of α-SMA and p-AKT （Thr308） were decreased significantly，and the protein expression of E-cadherin wasincreased significantly （P＜0.05）， showing time-dependent trend. There was no statistical significance in mRNA and protein expression of PPAR γ and PTEN，protein expression of E-cadherin ，α-SMA and p-AKT （Thr308） between GW 9662 intervention group and high-glucose group ；the effect of PIO was blocked by PPAR γ antagonist GW9662. CONCLUSIONS ：PIO may up-regulate the expression of PTEN by activating PPARγ，inhibit PI 3K/AKT signaling pathway so as to inhibit the occurrence of EMT of renal tubular epithelial cells .

Development of stability indicating method for the simultaneous estimation of alogliptin and pioglitazone in bulk and tablet dosage form by reversed-phase ultra-performance liquid chromatography method

The objective of the work is to develop and validate a new reverse phased ultra-performance chromatography method and its stability studies for the simultaneous estimation of alogliptin and pioglitazone in bulk and tablet dosage form. The column of the method was BEH C18 (2.1× 50 mm, 1.7 µ) used as a stationary phase and the mobile phase was 45:55 v/v of phosphate buffer (pH 3) and methanol, respectively. The injection volume was 2 µl and flow rate was maintained at 0.3 ml/minute. The wavelength was 280 nm and the runtime was 3 minutes. The retention time of alogliptin was 0.4 minutes and pioglitazone was 0.529 minutes. The Linearity of the alogliptin was 6.25–37.5 µg/ml and pioglitazone was 15–90 µg/ml. The newly developed method could be used for the routine analysis of pure drug and its formulations in accordance with the ICH Q2 (R1) guidelines.

A Rapid Validated Uni-Dimensional Double Development Hptlc-Densitometry Method For Simultaneous Estimation Of Metformin Hydrochloride, Gliclazide And Pioglitazone Hydrochloride

Objective: To develop and validate a uni-dimensional double development high-performance thin layer chromatography (UDDD-HPTLC) for estimation of anti-diabetic medicine compromising of metformin (MET) gliclazide (GLZ) and pioglitazone hydrochloride (PIO). Methods: The chromatographic separation of these drugs was carried out on precoated TLC plates silica gel 60F254by two mobile phases consisting of Ammonium Sulphate: Methanol: Acetonitrile: Water (4:3:2:1) for MET and PIO and Toluene: Ethyl Acetate: Formic Acid (6:4:0.5) for GLZ respectively for ideal separation and good resolution. The densitometric detection and quantification were carried out at 237 nm for MET and 200 nm for GLZ and PIO. The validation parameters were strictly followed as per the ICH guidelines. Results: The linearity range was obtained at 3000-8000ng/spot, 360-960 ng/spot, 90-240 ng/spot for MET, GLZ and PIO with r2value>0.999. The other parameters such as precision, reproducibility, robustness were efficiently obtained within the limits. The proposed method was successfully applied for simultaneous determination of MET, GLZ and PIO in the commercial formulation. Conclusion: In simultaneous estimation, the different polarity of drugs makes it more cumbersome to develop and validate any chromatographic method. In the present study, a uni-dimensional double development high-performance thin layer chromatography (UDDD-HPTLC) for estimation of these drugs have been developed and validated to resolve the estimation problem. It is an effortless and speedy method which was developed and validated using ICH guidelines. The developed and validated method using ICH guidelines is effortless and speedy technique.

Pioglitazone-metformin and basal insulin for type 2 diabetes mellitus patients with overweight or obesity and poor blood glucose control: A comparison of efficacy and metabolic effects / 第二军医大学学报

Objective: To compare the efficacy and metabolic effects of pioglitazone-metformin and basic insulin therapy on type 2 diabetes mellitus (T2DM) patients with overweight or obesity and poor blood glucose control. Methods: A total of 153 T2DM patients with overweight or obesity and poor blood glucose control were enrolled in this study. They received treatment with pioglitazone-metformin (pioglitazone-metformin group, n = 77) or insulin glargine (basal insulin group, n = 76) for 6 months in addition to their previous oral hypoglycemic drugs. At baseline, 3 months and 6 months after treatment, glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), 2 h post-prandial blood glucose (2hBG), fasting insulin (FINS), 2 h post-prandial insulin (2hINS), fasting C peptide (FCp), 2 h post-prandial C peptide (2hCp), body mass index (BMI), total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and hepatic fatty degeneration (expressed as controlled attenuation parameter [CAP] value) were observed and recorded. Results: At baseline, there were no significant differences in gender, age, BMI, HbA1c, FBG, 2hBG, FINS, 2hINS, FCp, 2hCp, TC, TG, HDL-C, LDL-C, CAP value, underlying diseases, or concomitant medicine between the two groups (all P>0.05). At 3 and 6 months after treatment, the HbA1c, FBG and 2hBG levels were significantly decreased versus those at the baseline in the two groups (all P0.05). Compared with the basal insulin group, the FINS, BMI and CAP values were significantly decreased in the pioglitazone-metformin group 3 and 6 months after treatment (P<0.05, P<0.01). After 6 months of treatment, there were no significant changes of blood lipid levels in both groups. Conclusion: In T2DM patients with overweight or obesity and poor blood glucose control, adding pioglitazone-metformin and basal insulin to their previous oral hypoglycemic drugs has similar hypoglycemic effect. However, patients receiving pioglitazone-metformin have better metabolic benefts such as lower BMI, lower insulin and improved hepatic fatty degeneration.

Potential Therapeutic Strategy in Chronic Obstructive Pulmonary Disease Using Pioglitazone-Augmented Wharton's Jelly-Derived Mesenchymal Stem Cells / 결핵

BACKGROUND: A recent study reported that mesenchymal stem cells possess potential cellular therapeutic properties for treating patients with chronic obstructive pulmonary disease, which is characterized by emphysema. We examined the potential therapeutic effect of Wharton's Jelly-derived mesenchymal stem cells (WJMSCs), following pretreatment with pioglitazone, in lung regeneration mouse emphysema models. METHODS: We used two mouse emphysema models, an elastase-induced model and a cigarette smoke-induced model. We intravenously injected WJMSCs (1×104/mouse) to mice, pretreated or not, with pioglitazone for 7 days. We measured the emphysema severity by mean linear intercepts (MLI) analysis using lung histology. RESULTS: Pioglitazone pretreated WJMSCs (pioWJMSCs) were associated with greater lung regeneration than non-augmented WJMSCs in the two mouse emphysema models. In the elastase-induced emphysema model, the MLIs were 59.02±2.42 µm (n=6), 72.80±2.87 µm (n=6), for pioWJMSCs injected mice, and non-augmented WJMSCs injected mice, respectively (p<0.01). Both pioWJMSCs and non-augmented WJMSCs showed regenerative effects in the cigarette smoke emphysema model (MLIs were 41.25±0.98 [n=6] for WJMSCs and38.97±0.61 µm [n=6] for pioWJMSCs) compared to smoking control mice (51.65±1.36 µm, n=6). The mean improvement of MLI appeared numerically better in pioWJMSCs than in non-augmented WJMSCs injected mice, but the difference did not reach the level of statistical significance (p=0.071). CONCLUSION: PioWJMSCs may produce greater lung regeneration, compared to non-augmented WJMSCs, in a mouse emphysema model.

Progress in antidepressant effects of pioglitazone / 上海交通大学学报（医学版）

As an agonist of peroxisome proliferator-activated receptor γ (PPARγ), pioglitazone may be involved in the regulation of glycolipid metabolism, oxidative stress and immune inflammatory response, thereby improving depression. Studies find that pioglitazone is effective in treating depression, especially in patients with resistance and comorbid metabolic syndrome, and is expected to be a new treatment for depression. This article reviews the research progress of pioglitazone in clinical application and related mechanisms of depression, in order to provide theoretical basis and support for subsequent research.

[RETRACTED ARTICLE] Therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis

Caspase recruitment domain-containing protein 9 (Card9) is located upstream of the nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) inflammatory pathways. This study investigated the therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis (SAP). SAP was induced by a retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct of Sprague Dawley rats (n=54), which were then treated with pioglitazone. Blood and pancreatic tissues were harvested at 3, 6, and 12 h after SAP induction. Pancreatic pathological damage was evaluated by hematoxylin and eosin staining. Serum amylase, serum pro-inflammatory cytokines, and pancreatic myeloperoxidase (MPO) activities were determined by enzyme-linked immunosorbent assay. The expression of Card9 mRNA and protein in pancreatic tissues was detected by real-time polymerase chain reaction and western blotting. Pioglitazone had a therapeutic effect in treating rats with SAP by decreasing the level of amylase activity, ameliorating pancreatic histological damage, decreasing serum pro-inflammatory cytokine levels and tissue MPO activity, and downregulating the expression of NF-κB, p38MAPK, and Card9 mRNAs and proteins (P<0.05). The present study demonstrated that the inhibition of Card9 expression could reduce the severity of SAP. Card9 has a role in the pathogenic mechanism of SAP.

Effects of piogiltazone on the expression of hemooxygenase-1 in aortic atherosclerosis plaque area in rabbits / 西安交通大学学报(医学版)

Objective To investigate the effects of piogiltazone on the expression of hemooxygenase-1 in aortic atherosclerosis plaque area in rabbits .Methods We randomly divided 36 Watanabe heritable hyperlipidemic rabbits into 3 groups:control group ,high-cholesterol diet group ,and high-cholesterol diet with pioglitazone [8 mg/(kg · d)] group ,with 12 in each .All the animals were fed for 12 weeks and then sacrificed .Rabbit aortic atherosclerosis pathological features were observed by Masson staining ;the expression of hemooxygenase-1 in aortic atherosclerosis plaque area in rabbits was detected by immunohistochemistry , real-time quantitative PCR and Western blot techniques .Results Hemooxygenase-1 expression was obvious in the smooth muscle in aortic vessels and atherosclerosis plaques in the three groups of rabbits . The expression of hemooxygenase-1 was lower in high-cholesterol diet with pioglitazone group than in high-cholesterol diet group and significantly higher than in control group (P<0 .05) .Conclusion Pioglitazone can slow down the progression of atherosclerosis by up-regulating the expression of hemooxygenase-1 .

Effects of low-intensity pulsed ultrasound and pioglitazone on chondrocytes in osteoarthritis / 中华物理医学与康复杂志

Objective To investigate any protective effect of low-intensity pulsed ultrasound (LIPUS) and pioglitazone on chondrocytes in osteoarthritic patients using the pathway from peroxisome proliferator-activated γreceptor (PPARγ) to nuclear factor kappa B (NF-κB) to inducible nitric oxide synthase (iNOS).Methods Normal chondrocytes of 24 healthy adult New Zealand white rabbits were extracted and divided into a normal group,a lipopolysaccharide (LPS) group,a LIPUS group (LPS+LIPUS) and a pioglitazone group (LPS+pioglitazone),each of 6 using a random number table.Each group was given the intervention their names implies.The levels of tumor necrosis factor-α (TNF-α),leptin (LEP) and nitric oxide (NO) in the chondrocytes were detected using enzyme-linked immune sorbent assays.The expression of type Ⅱ collagen (COL2) in the chondrocytes of each groups was detected using immunocytochemistry and fluorescent staining.The mRNA and protein expressions of PPARγ,NF-κB and iNOS were detected using reverse transcription polymerase chain reactions and western blotting respectively.Results Compared with the LPS group,the average level of TNF-α,LEP and NO in the LIPUS and pioglitazone groups was significantly lower,with the levels in the pioglitazone group significantly lower than in the LIPUS group.Compared with the LPS group,COL2 expression in the LIPUS group was significantly greater.The mRNA and protein expressions of PPARγ in the chondrocytes in the LIPUS and pioglitazone groups were significantly higher than those in the LPS group.Compared with the LPS group,the mRNA and protein expressions of NF-κB and iNOS in the pioglitazone and LIPUS groups were significantly lower,with the pioglitazone group's levels significantly below those of the LIPUS group.Conclusion LIPUS and pioglitazone may promote anti-inflammatory action and COL2 synthesis in chondrocytes through the PPARγ/ NF-κB/iNOS pathway and play a protective role,at least in rabbits.

Effects of peroxisome proliferator-activated receptor γ-toll-like receptor 4-tumor necrosis factor-α targeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress / 中华危重病急救医学

Objective To investigate the potential effects and mechanism on peroxisome proliferator-activated receptor γ-toll-like receptor 4-tumor necrosis factor-α (PPARγ-TLR4-TNF-α) targeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress. Methods Thirty-two Japanese healthy adult rabbits were randomly divided into four groups with 8 rabbits in each group: normal control group (NC group), diabetes mellitus group (DM group), diabetes mellitus + pioglitazone 4 mg·kg-1·d-1 and 8 mg·kg-1·d-1 groups (DM+PGZ 4 mg and 8 mg groups). DM model was reproduced by alloxan of 150 mg/kg through auricular vein injection. On the same day of successful DM model reproduction, the diabetic rabbits were fed with corresponding dose of pioglitazone in DM+PGZ 4 mg and 8 mg groups, but the rabbits in NC group were not challenged. After 8 weeks of feeding, venous blood of left jugular vein bifurcation and myocardium tissue were harvested respectively for the determination of inflammation and oxidative stress parameters. TNF-α, interleukin-1 (IL-1), adiponectin (ADP), nitric oxide (NO) and total nitric oxide synthase (NOS) levels were determined by enzyme linked immunosorbent assay (ELISA), myeloperoxidase (MPO) activity was determined by colorimetric method, superoxide dismutase (SOD) activity was determined by hydroxylamine method, malondialdehyde (MDA) was determined by thiobarbituric acid colorimetric method, and catalase (CAT) activity was determined by UV spectrophotometry method. In addition, the mRNA expressions of TNF-α and TLR4 were determined by real-time quantitate reverse transcription-polymerase chain reaction (RT-qPCR). Results ① IL-1 and TNF-α in serum and myocardium of model rabbits were significantly increased, ADP was significantly decreased, and the mRNA expressions of TNF-α and TLR4 in myocardium were significantly increased, indicating a significant inflammatory reaction. The inflammatory reaction in pioglitazone intervention groups was significantly reduced, TNF-αand IL-1 levels in serum and myocardium of DM+PGZ 4 mg and 8 mg groups were significantly decreased as compared with those of DM group [serum: TNF-α(ng/L) was 268.33±46.57, 261.34±33.73 vs. 331.40±69.05, myocardium: TNF-α (ng/L) was 144.72±26.90, 139.59±14.59 vs. 177.48±27.40; serum: IL-1 (ng/L) was 24.40±2.56, 23.35±3.13 vs. 30.08±5.44, myocardium: IL-1 (ng/L) was 21.26±2.85, 20.54±2.75 vs. 24.78±3.60, all P < 0.05], and ADP levels were significantly increased [serum (μg/L): 19.64±8.85, 20.54±7.47 vs. 15.45±3.06, myocardium (μg/L): 10.31±2.22, 11.49±3.42 vs. 7.76±1.77, all P < 0.05], and the mRNA expressions of TNF-α and TLR4 in myocardium were significantly decreased (TNF-αmRNA: 0.15±0.05, 0.14±0.06 vs. 0.25±0.09; TLR4 mRNA: 0.57±0.17, 0.40±0.18 vs. 0.75±0.35, all P < 0.05). ②Oxidative stress in serum and myocardium of model rabbits was significantly increased, SOD, NO, and total NOS levels were significantly decreased while the serum CAT and MDA levels were significantly increased without effect on MPO. Compared with the DM group, SOD and NO levels in serum and myocardium were significantly increased in DM+PGZ 4 mg and 8 mg groups [serum: SOD (U/L) was 571.39±40.85, 609.28±54.47 vs. 535.10±37.08, myocardium:SOD (U/mg) was 55.74±8.12, 53.60±9.87 vs. 42.26±12.34; serum: NO (μmol/L) was 2.95±0.51, 2.99±0.43 vs. 2.03±0.78, myocardium: NO (nmol/mg) was 1.95±0.37, 2.11±0.26 vs. 1.56±0.33, all P < 0.05], the serum MDA levels were significantly decreased (μmol/L: 20.11±2.34, 19.70±2.02 vs. 23.07±3.06, both P < 0.05), while no significant effect on CAT. There was no significant difference in parameter of inflammatory and oxidative stress between the two pioglitazone intervention groups. Conclusion 4 mg·kg-1·d-1 pioglitazone could activate PPARγ-TLR4-TNF-α targeted pathway, thus inhibit inflammatory and oxidative stress factors expression, and down-regulate hyperglycemia induced myocardium inflammatory and oxidative stress level, but the effect did not show a dose dependent manner.

Effect and mechanisms of pioglitazone on post operative cognitive function induced by surgery in elderly rats / 临床麻醉学杂志

Objective To investigate the effect and mechanisms of pioglitazone on post operative cognitive function induced by surgery in elderly rats.Methods Elderly SD rats,male and weighing 220-250 g,were randomly divided into control group (group Con),surgery group (group S),pioglitazone group (group P)and pioglitazone/surgery group (group PS).The level of glycemia was measured by glucometer after completing the surgical model.The expression of advanced glycation endproducts (AGEs)in hippocampal tissues was detected by western blot and reactive oxy-gen species (ROS)and IL-6 by ELISA 1 2 h after surgery.Morris water maze was used for evaluation of cognitive function 4 days after surgery.Results Compared with group Con,group S showed a sig-nificant increase in the expression of AGEs and IL-6 and the level of ROS (P<0.05);Compared with group S,the expression of AGEs and IL-6 and the level of ROS decreased significantly in group PS (P<0.05).Compared to group Con,the surgery increased the average time of escape latencies on the 8th days and 10th days after surgery and reduced the platform-crossing times in the Morris water maze test (P<0.05).Compared with group S,group PS showed a significant decrease in the average time of escaping latencies on the 10th day after surgery (P<0.05),and an increased platform-cross-ing times in the Morris water maze test (P<0.05).Conclusion These results suggest that pioglita-zone attenuates postoperative cognitive function and its mechanism may be related to the decrease of the expression of AGEs and IL-6 and the level of ROS.

Comparative study of efficacy and safety of compound pioglitazone hydrochloride glimepiride tablet and glimepiride tablet in treating type 2 diabetes mellitus / 重庆医学

Objective To compare the efficacy and safety of compound pioglitazone hydrochloririe glimepiride tablet and glimepiride tablet in the treatment of type 2 diabetic mellitus(T2DM) for evaluating the effectiveness and safety of compound pioglitazone hydrochloride glimepiride tablet for treating T2DM.Methods The random,double-blind,double-dummy,positive drugs parallel control clinical study method was adopted.Thirty-three T2DM patients with poorly controlled blood glucose were randomly assigned to the test group(n=22) and control group(n=11) by the 2 ∶ 1 ratio.The test group was given compound pioglitazone hydrochloride glimepiride tablet,while the control group received glimepiride tablet.The treatment cycle was 12 weeks.The differences of FBG,HbA1c,FINS and HOMA-IR in the two groups were compared between before and after treatment.Moreover the changes of body mass,blood pressure and blood lipids as well as adverse events occurrence were compared between the two groups.Results Thirty-one cases finished the treatment follow up(21 cases in the test group and 10 cases in the control group);the decreased amplitudes of HbA1c levels after 12-week treatment in the test group and control group were (0.99 ± 1.87)％ and (-0.02 ± 0.90) ％ respectively,which of FPG were (0.94 ± 1.87) mmol/L and (0.37 ± 2.62) mmol/L respectively.The FPG and HbA1c levels after treatment in the test group were decreased compared with before treatment,the difference was statistically significant (P＜0.01).The change difference of FPG and HbA1c in the control group had no statistical difference(P＞0.05).FINS and HOMO-IR in the test group were significantly decreased before and after treatment,the difference was statistically significant (P＜0.01).The incidence rate of hypoglycemia had no statistically significant difference between the test group and control group.Conclusion The effectiveness of compound pioglitazone hydrochloride glimepiride tablet in treating T2 DM is superior to the single use of glimepiride,while the safety is equivalent to single use of glimepiride.