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Scientific Reports Nov 2023The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose-lowering action,...
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.
Topics: Mice; Humans; Animals; Non-alcoholic Fatty Liver Disease; Pioglitazone; Linoleic Acid; Hepatic Stellate Cells; Gastrointestinal Microbiome; Mice, Inbred C57BL; Liver; Liver Cirrhosis; Fibrosis; Diet, High-Fat; Transforming Growth Factor beta
PubMed: 37923895
DOI: 10.1038/s41598-023-46404-5 -
Cardiovascular Diabetology Oct 2017Pioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
Pioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to assess the effects of pioglitazone treatment on the secondary prevention of CVD.
METHODS
Randomized-controlled trials of pioglitazone in patients with CVD were identified through PubMed, Embase, Cochrane and CINAHL, in a search up to May 2016. Studies were included if pioglitazone was compared with any control (usual care, placebo or active comparator) and if patients were previously diagnosed with CVD. The outcomes of interest included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, all-cause mortality and heart failure (HF). All outcomes were compared by pooled risk ratios (RR) with a 95% confidence interval (CI). Pooled estimates were calculated using a random-effects model.
RESULTS
Ten studies reported the effects of pioglitazone on any of the outcomes of interest. Pioglitazone reduced recurrent MACE (RR 0.74, 95% 0.60-0.92; I = 35), MI (RR 0.77, 95% CI 0.64-0.93; I = 0%), or stroke (RR 0.81, 95% CI 0.68-0.96; I = 0%). Pioglitazone did not reduce all-cause mortality (RR 0.94, 95% CI 0.81-1.08; I = 0%), whereas pioglitazone treatment was associated with an increased risk of HF (RR 1.33, 95% CI 1.14-1.54).
CONCLUSIONS
Pioglitazone lowers the risk of recurrent MACE, stroke, or MI in patients with clinical manifest vascular disease. Pioglitazone does not lower the risk for all-cause mortality, and increases the risk for the development of HF.
Topics: Cardiovascular Diseases; Humans; Hypoglycemic Agents; Pioglitazone; Randomized Controlled Trials as Topic; Secondary Prevention; Thiazolidinediones
PubMed: 29037211
DOI: 10.1186/s12933-017-0617-4 -
Revista de Gastroenterologia de Mexico... 2018Non-alcoholic fatty liver disease is the most prevalent hepatopathy, estimated at 30% in the general population. In the coming years, it will likely be the most common... (Review)
Review
Non-alcoholic fatty liver disease is the most prevalent hepatopathy, estimated at 30% in the general population. In the coming years, it will likely be the most common indication for liver transplantation and the most frequent cause of hepatocellular carcinoma. Current treatment for non-alcoholic fatty liver disease is based on dietary and exercise interventions that have been shown to be efficacious, even for reverting fibrosis. Unfortunately, compliance with general measures involving lifestyle modifications is very poor, making pharmacologic strategies a necessary option. At present, there are no treatments for non-alcoholic fatty liver disease approved by regulatory agencies, and the only ones with sufficient evidence and recommended by international societies are treatments with pioglitazone and vitamin E, which are not exempt from adverse effects. We review herein the current management of non-alcoholic fatty liver disease, including dietary and physical activity interventions, available treatments, equivocal therapies, emerging treatments, and treatments presently in clinical trials.
Topics: Antioxidants; Combined Modality Therapy; Diet Therapy; Exercise Therapy; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease; Pioglitazone; Thiazolidinediones; Treatment Outcome; Vitamin E
PubMed: 29655574
DOI: 10.1016/j.rgmx.2017.10.003 -
Biochimica Et Biophysica Acta.... Jul 2023Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and...
Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.
Topics: Humans; PPAR gamma; Podocytes; Pioglitazone; Thiazolidinediones; Kidney Diseases; Bexarotene
PubMed: 37156296
DOI: 10.1016/j.bbalip.2023.159329 -
Cancer Medicine Apr 2018Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the... (Meta-Analysis)
Meta-Analysis
Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose-response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Odds Ratio; Pioglitazone; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Urinary Bladder Neoplasms
PubMed: 29476615
DOI: 10.1002/cam4.1354 -
Drug Design, Development and Therapy 2022Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is known to have anti-inflammatory and anti-oxidant effects on the brain, and its... (Review)
Review
Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is known to have anti-inflammatory and anti-oxidant effects on the brain, and its clinical potential in the treatment of cognitive impairment in diseases such as Alzheimer's disease (AD) and Parkinson disease (PD) is currently being explored. This review focused on the reported beneficial effects of pioglitazone on cognitive dysfunction and summarized the associated mechanisms associated with pioglitazone-induced improvement in cognitive dysfunction. Our review of the relevant literature indicated that there is conclusive evidence of the effect of pioglitazone on improving cognitive impairment via its agonistic effect on PPAR-γ. Further, several mechanisms of action have been reported, and these include enhanced NF-kB and p38 activity; regulation of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α; inhibition of Aβ production; alterations in the levels of mitochondrial proteins such as mitoNEET; regulation of protein kinases such as CDK5 and JNK; regulation of ROS and MDA levels and the levels of the antioxidant proteins TRX1 and PON2; and increased expression of thyroid hormone receptors. Despite these promising findings, pioglitazone treatment is also associated with cardiovascular risks, such as weight gain and edema, which subsequently increase the risk of mortality. Further, it has been documented that pioglitazone may be unable to cross the blood-brain barrier when administered in certain forms, and it can also cause cell death when administered at high concentrations. Therefore, further research is required to explore the effects of acute and chronic pioglitazone treatment on memory function and the associated risks, in order to determine its clinical applicability in the treatment of cognitive disorders. Nonetheless, the current literature does demonstrate that pioglitazone promotes the function of PPAR receptors in ameliorating inflammation, oxidative stress, amyloidogenesis, and hypothyroidism, and enhancing neurogenesis, synaptic plasticity, and mitochondrial function. Therefore, these mechanisms of PPAR receptors warrant further investigation in order to establish the clinical applicability of pioglitazone in the treatment of cognitive disorders, such as PD and AD, and neuronal impairment in conditions such as diabetes.
Topics: Alzheimer Disease; Antioxidants; Cognitive Dysfunction; Humans; Hypoglycemic Agents; PPAR gamma; Parkinson Disease; Pioglitazone; Thiazolidinediones
PubMed: 36068789
DOI: 10.2147/DDDT.S367229 -
International Journal of Nanomedicine 2023Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is...
BACKGROUND
Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is limited because achieving the desired local drug concentration after administration is challenging.
PURPOSE
Herein, we constructed HA-based cartilage-targeted nanomicelles (C-HA-DOs) to deliver pioglitazone in a sustained manner and evaluated their efficacy in vitro and in vivo.
METHODS
C-HA-DOs were chemically synthesized with HA and the WYRGRL peptide and dodecylamine. The products were characterized by FT-IR, H NMR, zeta potential and TEM. The drug loading rate and cumulative, sustained drug release from Pio@C-HA-DOs were determined, and their biocompatibility and effect on oxidative stress in chondrocytes were evaluated. The uptake of C-HA-DOs by chondrocytes and their effect on OA-related genes were examined in vitro. The nanomicelle distribution in the joint cavity was observed by in vivo small animal fluorescence imaging (IVIS). The therapeutic effects of C-HA-DOs and Pio@C-HA-DOs in OA rats were analysed histologically.
RESULTS
The C-HA-DOs had a particle size of 198.4±2.431 nm, a surface charge of -8.290±0.308 mV, and a critical micelle concentration of 25.66 mg/Land were stable in solution. The cumulative drug release from the Pio@C-HA-DOs was approximately 40% at pH 7.4 over 24 hours and approximately 50% at pH 6.4 over 4 hours. Chondrocytes rapidly take up C-HA-DOs, and the uptake efficiency is higher under oxidative stress. In chondrocytes, C-HA-DOs, and Pio@C-HA-DOs inhibited HO-induced death, reduced intracellular ROS levels, and restored the mitochondrial membrane potential. The IVIS images confirmed that the micelles target cartilage. Pio@C-HA-DOs reduced the degradation of collagen II and proteoglycans by inhibiting the expression of MMP and ADAMTS, ultimately delaying OA progression in vitro and in vivo.
CONCLUSION
Herein, C-HA-DOs provided targeted drug delivery to articular cartilage and improved the role of pioglitazone in the treatment of OA.
Topics: Rats; Animals; Hyaluronic Acid; Pioglitazone; Hydrogen Peroxide; Spectroscopy, Fourier Transform Infrared; Osteoarthritis; Chondrocytes; Cartilage, Articular
PubMed: 37873552
DOI: 10.2147/IJN.S428938 -
Archives of Gynecology and Obstetrics Oct 2017Pioglitazone was used to treat patients of PCOS in many researches, but the treatment has not been recognized by public or recommended by all the guidelines. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pioglitazone was used to treat patients of PCOS in many researches, but the treatment has not been recognized by public or recommended by all the guidelines.
METHOD
We conducted a meta-analysis of the related literatures to objectively evaluate the clinical effectiveness and safety by comparing pioglitazone with metformin administrated by PCOS patients. Searches were performed in Cochrane Library, EMBASE and PubMed (last updated December 2016).
RESULTS
Eleven studies among 486 related articles were identified through searches. Fixed effects and random effects models were used to calculate the overall risk estimates. The results of the meta-analysis suggest that improvement of the menstrual cycle and ovulation in pioglitazone treatment group was better than metformin group [OR = 2.31, 95% CI (1.37, 3.91), P < 0.001, I = 41.8%]. Improvement of the F-G scores in metformin treatment group was better than pioglitazone group [SMD = 0.29, 95% CI (0.0, 0.59), P = 0.048, I = 0.0%]. BMI was more elevated in pioglitazone group than in metformin group [SMD = 0.83, 95% CI (0.24, 1.41), P = 0.006, I = 82.8%]. There were no significant differences of the other data between the two groups.
CONCLUSIONS
This meta-analysis indicated that pioglitazone ameliorated menstrual cycle and ovulation better than metformin and metformin ameliorated BMI and F-G scores better than pioglitazone in treating patients with PCOS. Pioglitazone might be a good choice for the patients with PCOS who were intolerant or invalid to metformin for the treatment.
Topics: Blood Glucose; Female; Humans; Hypoglycemic Agents; Metformin; Ovulation; Ovulation Induction; Pioglitazone; Polycystic Ovary Syndrome; Thiazolidinediones
PubMed: 28770353
DOI: 10.1007/s00404-017-4480-z -
Journal of Alzheimer's Disease : JAD 2023Alzheimer's disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families.... (Review)
Review
Alzheimer's disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients.
Topics: Humans; Thiazolidinediones; Pioglitazone; Alzheimer Disease; Neuroinflammatory Diseases; Neuroprotection; Ferroptosis; PPAR gamma
PubMed: 37927258
DOI: 10.3233/JAD-230593 -
European Review For Medical and... Oct 2023OBJECTIVE: The anticancer drug doxorubicin (DOX) is effective but is associated with complications such as hypothyroidism and cardiotoxicity. Pioglitazone (PIO), which...
UNLABELLED
OBJECTIVE: The anticancer drug doxorubicin (DOX) is effective but is associated with complications such as hypothyroidism and cardiotoxicity. Pioglitazone (PIO), which is used to treat diabetes mellitus, has shown potential for treating hypothyroidism and cardiac dysfunction. Therefore, this study explores whether PIO can also ameliorate DOX-induced hypothyroidism and cardiotoxicity. MATERIALS AND METHODS: Forty female Wistar rats were separated into control and three treated groups (DOX, PIO, and DOX+PIO), and their blood samples were examined for the thyroid hormones, including thyroid-stimulating hormone (TSH), thyroxine in total and free forms (T4 and FT4, respectively), and triiodothyronine in total and free forms (T3 and FT3, respectively), and the cardiotoxicity biomarkers [troponin I, creatine kinase (CK), and creatine kinase-myocardial band (CK-MB)]. RESULTS: The control and PIO groups did not exhibit significant alterations in any of the examined hormones and markers. In contrast, in the DOX group, T4, FT4, T3, and FT3 levels decreased significantly, whereas troponin I, CK, and CK-MB levels increased significantly, but no significant changes were detected in TSH levels. PIO co-treatment ameliorated these effects of DOX significantly in FT4, FT3, and troponin I. CONCLUSIONS: PIO may provide protection against hypothyroidism and cardiotoxicity caused by DOX treatment, by significant reversal of FT4, FT3, and troponin I levels.
GRAPHICAL ABSTRACT
https://www.europeanreview.org/wp/wp-content/uploads/Graphical-abstract1.jpg.
Topics: Female; Rats; Animals; Pioglitazone; Cardiotoxicity; Troponin I; Rats, Wistar; Hypothyroidism; Thyroxine; Doxorubicin; Thyrotropin; Creatine Kinase, MB Form; Creatine Kinase
PubMed: 37843360
DOI: 10.26355/eurrev_202310_33966