Administration Of Pioglitazone Research Articles

Evaluation of the effects of pioglitazone on perivascular adipose tissue function, properties, and structure in a rat model of type-2 diabetes.

Perivascular adipose tissue (PVAT) plays an important role in many physiological and pathological processes, such as regulation of vascular tone. The aim of this study is to evaluate the effects of pioglitazone on functional, structural, and biochemical properties of PVAT in an experimental model of type-2 diabetes (T2DM). T2DM was induced by high-fat-diet/low-dose-streptozotocin in rats, and pioglitazone (20mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters, PVAT-mass, vascular-reactivity in thoracic-aorta, as well as PVAT adipocytokine and PPARG-expression levels, and histopathology were evaluated. Pioglitazone administration improved blood glucose and lipid profiles in T2DM. Pioglitazone did not change the anticontractile effect of PVAT on aortic contractile reactivity and besides, had no influence on endothelium-dependent and -independent relaxation responses. Pioglitazone administration increased PVAT-mass and tumor necrotizing factor-α levels, while adiponectin, leptin, and interleukin-6 levels were unchanged. Also, a prominent increase was observed in PPARG-expression in T2DM-Pio group. Moreover, pioglitazone decreased liver steatosis, aortic wall thickening, and myocardial damage, whereas increased adipocyte size and adiposity in PVAT. Overall, pioglitazone treatment changed the mass and in part the inflammatory profile of PVAT but did not modify vasoreactivity in T2DM. This study provides novel findings in relationship with the adipogenic effect of pioglitazone and PVAT function.

Neuroprotective effect of PPAR gamma agonist in rat model of autism spectrum disorder: Role of Wnt/β-catenin pathway

BackgroundThe clinical manifestation of autism spectrum disorder (ASD) is linked to the disruption of fundamental neurodevelopmental pathways. Emerging evidences claim to have an upregulation of canonical Wnt/β-catenin pathway while downregulation of PPARγ pathway in ASD. This study aims to investigate the therapeutic potential of pioglitazone, a PPARγ agonist, in rat model of ASD. The study further explores the possible role of PPARγ and Wnt/β-catenin pathway and their interaction in ASD by using their modulators. Material and methodsPregnant female Wistar rats received 600 mg/kg of valproic acid (VPA) to induce autistic symptoms in pups. Pioglitazone (10 mg/kg) was used to evaluate neurobehaviors, relative mRNA expression of inflammatory (IL-1β, IL-6, IL-10, TNF-α), apoptotic markers (Bcl-2, Bax, & Caspase-3) and histopathology (H&E, Nissl stain, Immunohistochemistry). Effect of pioglitazone was evaluated on Wnt pathway and 4 μg/kg dose of 6-BIO (Wnt modulator) was used to study the PPARγ pathway. ResultsASD model was established in pups as indicated by core autistic symptoms, increased neuroinflammation, apoptosis and histopathological neurodegeneration in cerebellum, hippocampus and amygdala. Pioglitazone significantly attenuated these alterations in VPA-exposed rats. The expression study results indicated an increase in key transcription factor, β-catenin in VPA-rats suggesting an upregulation of canonical Wnt pathway in them. Pioglitazone significantly downregulated the Wnt signaling by suppressing the expression of Wnt signaling-associated proteins. The inhibiting effect of Wnt pathway on PPARγ activity was indicated by downregulation of PPARγ-associated protein in VPA-exposed rats and those administered with 6-BIO. ConclusionIn the present study, upregulation of canonical Wnt/β-catenin pathway was demonstrated in ASD rat model. Pioglitazone administration significantly ameliorated these symptoms potentially through its neuroprotective effect and its ability to downregulate the Wnt/β-catenin pathway. The antagonism between the PPARγ and Wnt pathway offers a promising therapeutic approach for addressing ASD.

Pioglitazone-induced alterations of purine metabolism in healthy male subjects.

Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.

Pioglitazone does not affect exogenous glucose oxidation or metabolic clearance rate during steady-state aerobic exercise at high altitude

Background: Hypoxia-induced insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR, proxy for peripheral glucose uptake) in native lowlanders exercising during the initial hours of high-altitude (HA) exposure compared sea level. These data suggest that administering an insulin sensitizing drug before HA exposure may increase exogenous glucose oxidation rate by stimulating peripheral glucose uptake. Objective: To compare the effects of pioglitazone (PIO) and placebo (PLA) on exogenous glucose oxidation and MCR during steady-state aerobic exercise at HA. We hypothesized that exogenous glucose oxidation and MCR would be higher with PIO than PLA. Methods: Using a randomized, crossover design, native lowlanders (n = 7 males, mean ± SD, age: 23 ± 6 y, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (1.43 ± 0.16 VȮ2 L/min) treadmill exercise at HA (460 mmHg) after being administered PIO (15 mg) or PLA (microcrystalline cellulose pill) daily for five days. Substrate oxidation and glucose turnover were determined using indirect calorimetry, oral 13C-glucose and [6,6-2H2]-glucose primed, continuous infusions. Results: Exogenous glucose oxidation rate was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation with PIO (1.65 ± 0.22 g/min) was the same as PLA (1.68 ± 0.32 g/min). There were no treatment effects on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min) disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), and MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Conclusion: These data do not support our hypothesis that exogenous glucose oxidation during exercise at HA can be restored through the short-term administration of PIO. Findings from this study may suggest that hypoxia-induced insulin resistance may be a symptom and not the primary etiology of dysregulated glucose metabolism during acute HA exposure. Supported by MOMRP; authors’ views not offcial US Army or DoD policy. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pioglitazone Antagonized the Effects of Advanced Glycation End Products on Achilles Tendon Healing and Improved the Recovery of Tendon Biomechanical Properties.

Advanced glycation end products (AGEs) often accumulate in the Achilles tendon during the course of diabetes. This study aims to determine the impact of AGEs on tendon repair and explore the role of pioglitazone in mitigating this impact. Forty-eight male 8week-old Sprague Dawley rats were selected in this study. After transection of Achilles tendon, the rats were randomly divided into four groups. The Achilles tendons of rats were injected with 1000mmol/L D-ribose to elevate the content of AGEs within the tendons in two groups, the remaining two groups received injections of phosphate buffered saline (PBS) solution. Subsequently, the first two groups were respectively received oral administration of pioglitazone (20mg/kg/day) and PBS. The remaining two groups were given the same treatment. The expression of the collagen-I, TNF-α, IL-6 of the repaired tendon were detected. The macroscopic, pathologic and biomechanical aspects of tendon healing were also evaluated. AGEs accumulation in tendon during the healing process increases the expression of inflammatory factors such as TNF-α and IL-6, leading to insufficient synthesis of collagen-I and delayed recovery of the tendon's tensile strength. Pioglitazone significantly attenuated the damage caused by AGEs to the tendon healing process, effectively improving the recovery of tendon tensile strength. Pioglitazone could not inhibit the generation of AGEs in the tissue and also had no impact on the normal healing process of the tendon. Pioglitazone could prevent the deleterious impact of AGEs on the Achilles tendon healing and improve the biomechanical properties of the tendon.

Endogenous metabolites change associated with pioglitazone administration in healthy male subjects

Endogenous metabolites change associated with pioglitazone administration in healthy male subjects

A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-β signaling in hepatic stellate cells

The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose–lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-β–induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.

PPARG stimulation restored lung mRNA expression of core clock, inflammation- and metabolism-related genes disrupted by reversed feeding in male mice.

The circadian rhythm system regulates lung function as well as local and systemic inflammations. The alteration of this rhythm might be induced by a change in the eating rhythm. Peroxisome proliferator-activated receptor gamma (PPARG) is a key molecule involved in circadian rhythm regulation, lung functions, and metabolic processes. We described the effect of the PPARG agonist pioglitazone (PZ) on the diurnal mRNA expression profile of core circadian clock genes (Arntl, Clock, Nr1d1, Cry1, Cry2, Per1, and Per2) and metabolism- and inflammation-related genes (Nfe2l2, Pparg, Rela, and Cxcl5) in the male murine lung disrupted by reversed feeding (RF). In mice, RF disrupted the diurnal expression pattern of core clock genes. It decreased Nfe2l2 and Pparg and increased Rela and Cxcl5 expression in lung tissue. There were elevated levels of IL-6, TNF-alpha, total cells, macrophages, and lymphocyte counts in bronchoalveolar lavage (BAL) with a significant increase in vascular congestion and cellular infiltrates in male mouse lung tissue. Administration of PZ regained the diurnal clock gene expression, increased Nfe2l2 and Pparg expression, and reduced Rela, Cxcl5 expression and IL-6, TNF-alpha, and cellularity in BAL. PZ administration at 7 p.m. was more efficient than at 7 a.m.

Pioglitazone ameliorates cisplatin-induced testicular toxicity by attenuating oxidative stress and inflammation via TLR4/MyD88/NF-κB signaling pathway

BackgroundCisplatin (CIS) is a chemotherapeutic agent widely used to cure several cancers. It exerts detrimental cellular effects that restrain its clinical application as an antineoplastic agent, as testicular damage. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is used to treat type-2 diabetes mellitus. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. The present study aimed to investigate the effect of PIO in a rat model of cisplatin-induced testicular toxicity and address the possible role of the Toll-like receptors (TLR4) / myeloid differentiation factor 88 (MyD88) / nuclear factor-kappa B (NF-kB) signal pathway. MethodsRats received a single dose of cisplatin (7 mg/kg, IP) on the first day and PIO (10 mg/kg, P.O.) for 7 days. At the end of the treatment period, rats were killed. Testicular weights, histopathological alterations, and serum testosterone levels were determined. Moreover, tissue samples were collected for the estimation of oxidative stress parameters, inflammatory markers, and the determination of TLR4 /MyD88/NF-kB signaling. ResultsConcurrent PIO administration with CIS markedly improved testicular weights, histopathological alteration, and serum testosterone level changes. Moreover, Concurrent PIO administration abrogated oxidative stress status and inflammatory markers caused by CIS administration. Furthermore, PIO inhibited the expression levels of TLR4, MyD88, and NF-κBp65, proteins that are activated by CIS administration. Conclusion: These findings suggested that PIO can protect against cisplatin-induced testicular toxicity in rats through inhibition of the TLR4 /MyD88/NF-kB signal pathway.

Pioglitazone, a PPAR-y agonist, as one of the new therapeutic candidates for C3 glomerulopathy

BackgroundC3-glomerulopathy (C3G) is a rare pediatric kidney disease characterised by dysregulation of the alternative complement pathway, with glomerular deposition of C3. C3G may often present as a steroid-resistant nephrotic syndrome (SRNS), and there is no established effective therapy: the usual treatment involves corticosteroids and immunosuppressive drugs. Pioglitazone, a PPAR-γ agonist with a protective action on podocytes, was reported in a few cases as helpful in reducing proteinuria when combined with steroids.Case-Diagnosis/TreatmentWe report the case of a 13-year-old girl with silent past medical history who presented with SRNS. A kidney biopsy showed findings indicative of C3G. A low sodium diet and angiotensin-converting enzyme inhibitor were started; immunosuppressive treatment with mycophenolate mofetil (MMF) was administered due to the cortico-resistance. Because of poor response to the immunosuppressant, a trial with eculizumab was attempted without significant response and persistence of proteinuria in the nephrotic range. A further therapeutic trial was performed with tacrolimus with no disease remission. Due to a severe deterioration in her condition, the girl was hospitalized and treated with high-dose steroid bolus. A daily dose of oral prednisone and MMF were re-started without benefit with persistent levels of nephrotic range proteinuria. The administration of pioglitazone consistently lowered proteinuria levels for the first time since the onset of the disease, with a maintenance of the effect and normalization (< 0.15 g/24 h) at the 10-month follow-up.ConclusionsIn this patient affected by C3G, pioglitazone proved effective in reducing proteinuria levels.

Multispectral optoacoustic tomography (MSOT): Monitoring neurovascular changes in a mouse repetitive traumatic brain injury model

BackgroundEvidence suggests that mild TBI injuries, which comprise > 75% of all TBIs, can cause chronic post-concussive symptoms, especially when experienced repetitively (rTBI). rTBI is a major cause of cognitive deficit in athletes and military personnel and is associated with neurovascular changes. Current methods to monitor neurovascular changes in detail are prohibitively expensive and invasive for patients with mild injuries. New MethodWe evaluated the potential of multispectral optoacoustic tomography (MSOT) to monitor neurovascular changes and assess therapeutic strategies in a mouse model of rTBI. Mice were subjected to rTBI or sham via controlled cortical impact and administered pioglitazone (PG) or vehicle. Oxygenated and deoxygenated hemoglobin were monitored using MSOT. Indocyanine green clearance was imaged via MSOT to evaluate blood-brain-barrier (BBB) integrity. ResultsMice subjected to rTBI show a transient increase in oxygenated/total hemoglobin ratio which can be mitigated by PG administration. rTBI mice also show BBB disruption shortly after injury and reduction of oxygenated/total hemoglobin in the chronic stage, neither of which were affected by PG intervention. Comparison with existing methodsMSOT imaging has the potential as a noninvasive in vivo imaging method to monitor neurovascular changes and assess therapeutics in mouse models of rTBI. In comparison to standard methods of tracking inflammation and BBB disruption, MSOT can be used multiple times throughout the course of injury without the need for surgery. Thus, MSOT is especially useful in research of rTBI models for screening therapeutics, and with further technological improvements may be extended for use in rTBI patients.

The PPAR-γ Agonist Pioglitazone Modulates Proliferation and Migration in HUVEC, HAOSMC and Human Arteriovenous Fistula-Derived Cells.

The failure of arteriovenous fistulas (AVFs) following intimal hyperplasia (IH) increases morbidity and mortality rates in patients undergoing hemodialysis for chronic kidney disease. The peroxisome-proliferator associated receptor (PPAR-γ) may be a therapeutic target in IH regulation. In the present study, we investigated PPAR-γ expression and tested the effect of pioglitazone, a PPAR-γ agonist, in different cell types involved in IH. As cell models, we used Human Endothelial Umbilical Vein Cells (HUVEC), Human Aortic Smooth Muscle Cells (HAOSMC), and AVF cells (AVFCs) isolated from (i) normal veins collected at the first AVF establishment (T0), and (ii) failed AVF with IH (T1). PPAR-γ was downregulated in AVF T1 tissues and cells, in comparison to T0 group. HUVEC, HAOSMC, and AVFC (T0 and T1) proliferation and migration were analyzed after pioglitazone administration, alone or in combination with the PPAR-γ inhibitor, GW9662. Pioglitazone negatively regulated HUVEC and HAOSMC proliferation and migration. The effect was antagonized by GW9662. These data were confirmed in AVFCs T1, where pioglitazone induced PPAR-γ expression and downregulated the invasive genes SLUG, MMP-9, and VIMENTIN. In summary, PPAR-γ modulation may represent a promising strategy to reduce the AVF failure risk by modulating cell proliferation and migration.

The association between pioglitazone consumption and incidence of bladder cancer in type II diabetic patients: a systematic review and meta-analysis of observational studies

Background: Bladder cancer is the single most prevalent urinary tract malignancy in humans with a higher risk in diabetic patients. Pioglitazone is among the conventional antidiabetic drugs. The present study thus seeks to investigate the association between the administration of pioglitazone and the incidence of bladder cancer in type II diabetic patients through a meta-analysis and systematic analysis. Materials and Methods: International databases including Web of Science, Medline/PubMed, Scopus, and Google Scholar search engine were explored. To integrate the results of studies odds ratio (OR), risk ratio (RR) or hazard ratio (HR) logarithm was extracted from each study, and the I2 index or the Cochran’s Q test were conducted to examine the heterogeneities across studies. Data analysis was carried out in STATA version14 considering a significance level of p&lt;0.05. Results: The 15 examined studies had investigated a total of 5,353,528 patients (1,536,723 patients in case groups and 3,816,805 patients in control groups). The relative risk of bladder cancer was [RR: 1.20 (95% CI: 1.09-1.32)] in pioglitazone users. Bladder cancer risk in pioglitazone users was higher by [RR: 1.14 (95% CI: 1.03-1.25)] compared to those who had never taken pioglitazone, [RR: 1.32 (95% CI: 1.02-1.70] compared to sulfonylurea users, and [RR: 1.57 (95% CI: 1.23-2)] compared to dipeptidyl peptidase-4 (DPP-4) users. Moreover, the relative risk between pioglitazone consumption and bladder cancer was reported to be [RR: 1.27 (95% CI: 0.96-1.68)] in patients with a follow-up shorter than five years and [RR: 1.24 (95% CI: 1.09-1.41)] is patients with a follow-up of five years or longer. On the other hand, the relative risk between pioglitazone consumption and bladder cancer was [RR: 1 (95% CI: 0.69-1.45)] in 50-59 age group, [RR: 1.20 (95% CI: 1.04-1.38)] in the 60-69 age group, and [RR: 1.33 (95% CI: 1.14-1.56)] in the 70-79 age group. Conclusion: Patients who receive pioglitazone had a 20% higher risk of bladder cancer compared to those who had not taken pioglitazone or prescribed other medication such as sulfonylurea and DPP-4s. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO website (ID: CRD42023391151).

Pioglitazone Induces Dysplastic Urothelial Changes in Urinary Bladder of Experimental Diabetes.

Pioglitazone (PIO) is a widely prescribed oral antidiabetic drug that has concerns regarding a potential risk of developing carcinoma of the urinary bladder. The objective of the current study was to assess this potential risk. The potential risk of PIO-induced urinary bladder carcinoma was assessed in the current study by examining urinary bladder of rats for urothelial cytokeratin (CK) expression and proliferative activity by Ki67 immunostaining. Histological examination revealed dysplastic urothelial changes in PIO per se and diabetes mellitus + PIO (diabetic rats receiving PIO). In addition, a significantly (P < 0.05) decreased CK7 and CK8 expression together with a significantly increased CK20 as well as Ki67 expression was detected in the urothelial cells of groups administrated PIO, contrary to those which did not. The manifestations of urothelial dysplasia evidenced by histological examination as well as by the aberrant expression in CK and Ki67 after PIO administration add supporting evidence at cellular and experimental level to the previous clinical suspicions.

Decreased PPARgamma in the trigeminal spinal subnucleus caudalis due to neonatal injury contributes to incision-induced mechanical allodynia in female rats

Whisker pad skin incision in infancy causes the prolongation of mechanical allodynia after re-incision in adulthood. A recent study also proposed the importance of sex differences in pain signaling in the spinal cord. However, the sex difference in re-incision-induced mechanical allodynia in the orofacial region is not fully understood. In the rats that experienced neonatal injury in the whisker pad skin, the mechanical allodynia in the whisker pad was significantly prolonged after re-incision in adulthood compared to sham injury in infancy. No significant sex differences were observed in the duration of mechanical allodynia. The duration of mechanical allodynia in male rats was shortened by intracisternal administration of minocycline. However, minocycline had no effects on the duration of mechanical allodynia in female rats. In contrast, intracisternal administration of pioglitazone markedly suppressed mechanical allodynia in female rats after re-incision. Following re-incision, the number of peroxisome proliferator-activated receptor gamma (PPARgamma)-positive cells were reduced in the trigeminal spinal subnucleus caudalis (Vc) in female rats that experienced neonatal injury. Immunohistochemical analyses revealed that PPARgamma was predominantly expressed in Vc neurons. Pioglitazone increased the number of PPARgamma-positive Vc neurons in female rats whose whisker pad skin was incised in both infancy and adulthood stages. Pioglitazone also upregulated heme oxygenase 1 and downregulated NR1 subunit in the Vc in female rats after re-incision. Together, PPARgamma signaling in Vc neurons is a female-specific pathway for whisker pad skin incision-induced mechanical allodynia.

Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice.

Metformin and pioglitazone monotherapy have been proven to alter gut microbiota in diabetes and obesity. The present study aimed to investigated whether the combined administration of pioglitazone and metformin achieved superior protective effects on high-fat diet (HFD)-fed obese mice and elucidated its molecular mechanism via the gut microbiota and its metabolites. C57BL/6 males were randomly divided into five groups: the control group, fed a normal control diet; the HFD group, fed an HFD; the metformin monotherapy group, fed an HFD and treated with metformin; the pioglitazone monotherapy group, fed an HFD and treated with pioglitazone; and the combination therapy group, fed an HFD and treated with metformin and pioglitazone combination therapy. The cecal contents were collected for 16S rDNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the combination therapy of metformin and pioglitazone significantly improved insulin sensitivity and glucolipid metabolism in HFD-fed mice. Combination therapy markedly altered gut microbiota by increasing beneficial bacteria, such as Bifidobacterium, Christensenellaceae_R-7_group, Faecalibacterium and Roseburia, and decreasing harmful bacteria, such as Oscillibacter and Eubacterium_xylanophilum_group. Fecal metabolites were significantly changed in the combination therapy group, including a reduction in amino acid metabolism and augmentation of lipid metabolism, such as citrulline, sarcosine, D-glutamine, lipoxin A4, prostaglandin E2, stearidonic acid and lucidenic acid A. These results revealed that combined metformin and pioglitazone therapy had synergistic effects or at least have an additive effect on modifying gut microbiota and metabolites, closely associated with improved glucolipid metabolic parameters in HFD-fed mice, which provides novel evidence and promising targets for metformin and pioglitazone combination therapy in type 2 diabetes.

Effect of pioglitazone on oxidative stress of skeletal muscle in the insulin resistance rat model induced by high sucrose diet

Background: Metabolic syndrome is associated with some medical disorders such as central obesity, being overweight, insulin resistance and hypertension. This study was designed to determine the effect of pioglitazone on oxidative stress in the insulin resistance rat model.Methods: In this study, the model was induced by high sucrose (935 mm) diet for 20 weeks. Three groups were used in the experiment. Control group received standard laboratory diet and drinking water. Metabolic syndrome induced group received 32% sucrose containing drinking water for 20 weeks. Pioglitazone-treated metabolic syndrome group has received pioglitazone treatment (30 mg/kg/day, via oral gavage) for two weeks at the end of the 18th week of metabolic syndrome group. After experimental period, skeletal muscle tissues were homogenized to measure important enzymes such as aspartate aminotransferase, lactate dehydrogenase and as the marker of oxidative stress; total-antioxidant-status, total-oxidant-status and malondialdehyde. Western blot technique was used to determine protein level of thioredoxin1.Results: Aspartate aminotransferase and lactate dehydrogenase levels increased in metabolic syndrome group but pioglitazone treatment decreased these levels. In metabolic syndrome group the oxidative stress status increased but the treatment of pioglitazone decreased the level of oxidative stress in the skeletal muscle. In addition, thioredoxin1 decreased in metabolic syndrome group but administration of pioglitazone increased this level.Conclusions: There was an elevated effect of oxidative stress in high sucrose fed rats but the treatment of pioglitazone improved glucose tolerance and insulin sensitivity.

Peroxisome proliferator-activated receptor-γ doesn't modify altered electrophysiological properties of the CA1 pyramidal neurons in a rat model of hepatic cirrhosis.

Regarding the low quality of life due to the cognitive complications in the patients with hepatic cirrhosis (HC), the goal of this study was to examine the possible neuroprotective effect of pioglitazone (PIO) on the electrophysiological alterations of hippocampus, a major area of cognition, in the experimental model of bile duct ligation (BDL). We used adult male Wistar rats in the present study to perform BDL or sham surgery. Pioglitazone was administered in BDL rats two weeks after the surgery for the next continuous four weeks. The effects of pioglitazone on BDL-induced electrophysiological alterations of the CA1 pyramidal neurons in the hippocampus were evaluated by whole-cell patch clamp recordings. Our findings demonstrated that chronic administration of PIO could not reverse the electrophysiological changes in the CA1 pyramidal neurons of the hippocampus in BDL rats but could improve the hepatic dysfunction.Together, the results of this study suggest that PIO administration cannot counteract altered intrinsic properties of the hippocampal neurons which has been shown recently as an involved mechanism of the cognitive impairments in hepatic encephalopathy (HE).