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Aims Materials and Methods Results Conclusions Both pioglitazone and glucagon‐like peptide 1 receptor agonists (GLP1RA) alone improve metabolic dysfunction‐associated steatohepatitis (MASH) in randomized clinical trials, whereas preclinical studies suggested MASH benefits with sodium glucose co‐transporter 2 inhibitors (SGLT2i). In the real world, patients with type 2 diabetes often require multiple agents for glycaemic control. Here, we investigated the benefits of combining these agents on risks of MASH.Longitudinal changes in FibroScan‐aspartate aminotransferase (FAST) score were measured in 888 patients with type 2 diabetes. Use of pioglitazone, GLP1RA and/or SGLT2i was defined as continuous prescriptions of ≥180 days prior to their last reassessment FibroScan. Multivariable logistic regression analysis was conducted to evaluate the associations between use of these agents and FAST score changes.Over a median follow‐up of 3.9 years, the increasing number of these agents used was significantly associated with more reductions in FAST score (p for trend <0.01). Dual combination was independently associated with a higher likelihood of achieving low FAST score at reassessment than single use of any of these agents (odds ratio [OR] 2.84, p = 0.01). Among the different drug combinations, using SGLT2i and pioglitazone (median dose 15 mg daily) together, as compared to not using any of these three agents, was associated with a higher likelihood of both low FAST score at reassessment (OR 6.51, p = 0.008) and FAST score regression (OR 12.52, p = 0.009), after adjusting for changes in glycaemic control and body weight during the study.Combining SGLT2i and pioglitazone is a potentially useful strategy to ameliorate ‘at‐risk’ MASH in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Parkinson's disease (PD) is the second most common, and the fastest‐growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non‐genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance.We aimed to investigate insulin resistance and its role in GBA1 mutation‐associated PD pathogenesis and phenotype severity.Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1‐N370S heterozygous mutation (GBA‐PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA‐PD and to find a potential target for GBA‐PD‐associated phenotype rescue.The insulin signaling pathway genes show dysregulation in GBA‐PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA‐PD. Additionally, our findings suggest a promising therapeutic potential of the anti‐diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA‐PD.Local insulin signaling dysfunction plays a substantial role in GBA‐PD pathogenesis, exacerbating dopaminergic neuron death. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a globally widespread complication of diabetes mellitus (DM). Research indicates that pioglitazone and linagliptin mitigate the risk of DN by reducing inflammation, oxidative stress, and fibrosis. The role of tamsulosin in DN is less studied, but it may contribute to reducing oxidative stress and inflammatory responses. The protective effects of combining pioglitazone, linagliptin, and tamsulosin on the kidneys have scarcely been investigated. This study examines the individual and combined effects of these drugs on DN in Wistar rats. Diabetic rats were treated with tamsulosin, pioglitazone, and linagliptin for six weeks. We assessed food and water intake, estimated glomerular filtration rate (eGFR), histological markers, urea, creatinine, glucose, NF-κB, IL-1, IL-10, TGF-β, and Col-IV using immunofluorescence and qPCR. The DN group exhibited hyperglycaemia, reduced eGFR, and tissue damage. Tamsulosin and linagliptin improved eGFR, decreased urinary glucose, and repaired tissue damage. Pioglitazone and its combinations restored serum and urinary markers and reduced tissue damage. Linagliptin lowered serum creatinine and tissue injury. In conclusion, tamsulosin, linagliptin, and pioglitazone demonstrated renoprotective effects in DN. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease, is known to affect a quarter of the global adults. Natural history of NAFLD shows interindividual variation, traditionally it progresses from simple steatosis to steatohepatitis to fibrosis/cirrhosis and finally yet rarely to hepatocellular carcinoma. It is largely a lifestyle-related disease and is often labeled as the hepatic manifestation of metabolic syndrome. Both prevention and control of NAFLD include controlling risk factors (obesity, diabetes mellitus, hypertension and dyslipidemia), through lifestyle modification and medications. Drug therapy for NAFLD per se is still evolving and till date, no drugs are approved. It is clinically silent, especially in the early stages, and is a diagnosis of exclusion. Certain easily calculated indices can stratify cases into high or low risk for advanced fibrosis, thereby dictating appropriate monitoring and treatment measures. In addition to complications specific to liver disease in those who do progress to advanced fibrosis or cirrhosis, an increased risk of nonliver disease-related morbidity and mortality is also present. Challenges are manifold and include rising burden due to ever-growing epidemic of diabetes and obesity, low public awareness, fragmented healthcare, no approved drugs, and dearth of data on magnitude and epidemiology of the disease. The recent integration of NAFLD into the National Program for Prevention and Control of Non-Communicable Diseases (NPCDCS) by the Ministry of Health and Family Welfare of India is a welcome step in this direction as the contributory factors are mostly the same for all diseases and controlling any one or all of them will have a desired impact on the prevalence of all the diseases under this program. [ABSTRACT FROM AUTHOR]

Application of two coformers, l-tartaric acid (TA) and ascorbic acid (AA) was evaluated on the solubility of pioglitazone hydrochloride (PGZ.HCl). Solid dispersions were prepared using the solvent evaporation method. Drug solubility was evaluated in bio-relevant media and the results were compared to the physical mixtures (PM) of the drug + coformer, and the pure drug. Physicochemical characterisation of the developed products was characterised using Fourier transformation-infrared spectroscopy (FT-IR), Differential scanning calorimeter (DSC), and X-ray powder diffractometry (XPRD). Physical mixtures of PGZ-AA (PM) were able to enhance drug solubility to the same extent as the solvent evaporation method (PGZ-AA). This indicates that the preparation process has little effect on drug solubility. Up to 7-fold enhancement was observed for drug solubility in distilled water and buffer pH 1.2. Physical mixtures seem more feasible method to significantly enhance drug solubility without the need to use toxic solvents and time-consuming evaporation methods. [ABSTRACT FROM AUTHOR]

AbstractObjectiveData SourcesStudy SelectionsResultsConclusionThis review aims to present existing evidence on the impact of pioglitazone, a thiazolidinedione class anti-diabetic drug, on asthma control and lung function, providing a comprehensive understanding of its potential as a treatment for asthma.The review draws upon data from preclinical animal studies and clinical trials investigating the effects of pioglitazone on asthma, focusing on its role in reducing airway inflammation, hyperreactivity, and remodeling, and its impact on pulmonary function.Relevant studies were selected based on their examination of pioglitazone’s therapeutic effects in asthma, including both animal models and clinical trials involving human asthma patients.Animal studies have suggested that pioglitazone could alleviate inflammation, airway hyperreactivity, and airway remodeling, thereby improving pulmonary function in asthma. However, clinical trials have not demonstrated significant therapeutic benefits, with minimal improvements observed in asthma control and lung function, and the presence of notable side effects.Despite promising preclinical data, the efficacy of pioglitazone in treating human asthma remains unproven, with safety concerns and limited clinical benefits observed in trials. Further research is needed to assess the safety and effectiveness of pioglitazone in asthma treatment and to explore its impact on other inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, and an increased malignancy risk. Cells derived from individuals with AT show multiple defects, including high oxidant and ionizing radiation sensitivities, poor DNA repair, low iron–sulfur cluster levels, and low reduced glutathione. The clinical course of AT is progressive and unrelenting, with most individuals having a survival time of approximately twenty-five years. Presently, AT has no effective treatments, and most patients receive supportive care only. Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT. Here, I will discuss the possible molecular mechanisms of pioglitazone's favorable effects on the AT phenotype and why it may have utility in treating some aspects of AT. [ABSTRACT FROM AUTHOR]

Background: Renal ischemia-reperfusion injury (RIRI) is a critical phenomenon that compromises renal function and is the most serious health concern related to acute kidney injury (AKI). Pioglitazone (Pio) is a known agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ). PPAR-γ is a nuclear receptor that regulates genes involved in inflammation, metabolism, and cellular differentiation. Activation of PPAR-γ is associated with antiinflammatory and antioxidant effects, which are relevant to the pathophysiology of RIRI. This study aimed to investigate the protective effects of Pio in RIRI, focusing on oxidative stress and inflammation. Methods: We conducted a comprehensive literature search using electronic databases, including PubMed, ScienceDirect, Web of Science, Scopus, and Google Scholar. Results: The results of this study demonstrated that Pio has antioxidant, anti-inflammatory, and anti-apoptotic activities that counteract the consequences of RIRI. The study also discussed the underlying mechanisms, including the modulation of various pathways such as TNF-α, NF-κB signaling systems, STAT3 pathway, KIM-1 and NGAL pathways, AMPK phosphorylation, and autophagy flux. Additionally, the study presented a summary of various animal studies that support the potential protective effects of Pio in RIRI. Conclusion: Our findings suggest that Pio could protect the kidneys from RIRI by improving antioxidant capacity and decreasing inflammation. Therefore, these findings support the potential of Pio as a therapeutic strategy for preventing RIRI in different clinical conditions. Pioglitazone (Pio) plays a protective role in renal ischemia–reperfusion injury (RIRI) by regulating oxidative stress and inflammation responses. In an animal model of RIRI, Pio reduced inflammation, and oxidative stress renal tubule damage through several cellular pathways. It also promotes cell viability and inhibits autophagy. Pioe targets various pathways such as TNF-α, NF-κB signaling systems, KIM-1 and NGAL pathways, and AMPK phosphorylation. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a prevalent disease in the general population and also a well-established risk factor for the development of ischemic stroke. Patients who have been diagnosed with diabetes have a 20% higher risk for developing ischemic stroke in comparison to non-diabetic individuals. The aim of the current systematic review is to provide the latest evidence regarding the association between antidiabetic treatment and the prevention of ischemic stroke. Methods: A comprehensive search in scientific literature databases PUBMED, COCHRANE, and SCOPUS was conducted. The studies that were deemed as eligible for this review were those that examined the clinical benefits of therapeutic strategies in terms of preventing ischemic strokes. Results: A total of 32 studies met the established selection criteria. The included studies showed that pioglitazone treatment significantly reduced the risk for recurrent stroke in patients with DM. Furthermore, in the context of primary prevention, the improvement in glycemic control after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide and dulaglutide was associated with a reduction in the risk of ischemic stroke in diabetic subjects. Metformin monotherapy may reduce stroke risk, while dipeptidyl peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and insulin do not seem to affect the incidence of stroke. Conclusions: The findings of the present systematic review suggest that pioglitazone and GLP-1RA may decrease the risk of stroke. Further studies are needed to provide additional data regarding the preventive effect of novel antidiabetic drugs, such as dual glucose-dependent insulinotropic polypeptide/GLP-1RA agents, on stroke. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) caused by the coronavirus SARS-CoV-2, has emerged as a rapidly spreading contagious disease across the globe. Recent studies showed that people with diabetes mellitus, severe obesity, and cardiovascular disease are at higher risk of mortality from COVID-19. It has been suggested that the increased risk is due to the chronic inflammatory state associated with type 2 diabetes. This study aimed to evaluate the efficacy of pioglitazone, a strong insulin sensitizer with anti-inflammatory properties, in improving the clinical outcomes of patients with type 2 diabetes admitted with moderate-severe COVID-19. Method: We enrolled 350 patients with type 2 diabetes who were admitted to hospitals in Qatar and Kuwait with COVID-19. Patients were randomized to receive, in a double-blind fashion, pioglitazone (n = 189) or a matching placebo (n = 161) for 28 days. The study had two primary outcomes: (1) the incidence of a composite outcome composed of (a) the requirement for mechanical ventilation, (b) death, and (c) myocardial damage; and (2) an increase in Creactive protein (CRP) levels. Results: The first primary outcome occurred in 28 participants (8%), and the secondary outcome occurred in 17. Treatment with pioglitazone showed a significant reduction in interleukin (IL)-3 levels compared with placebo treatment (mean (SD) 2.73 (± 2.14) [95% CI: 0.02, 1.1], p = 0.043 vs. 2.28 (± 1.67) [95% CI: - 0.23, 0.86], p = 0.3, respectively), with no effect seen in the levels of other inflammatory markers. Even though not significant, a few of the patients on pioglitazone exhibited serum troponin levels > 3 times higher than the normal range seen in patients on placebo. On the other hand, more patients on pioglitazone were admitted to the ICU than those with placebo, and no significant difference in the CRP reduction was observed between the two groups. Conclusion: The results of the present study demonstrate that pioglitazone treatment did not independently provide any additional clinical benefit to patients with type 2 diabetes admitted with a COVID-19 infection. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have cardiovascular (CV) benefits, particularly in reducing the risk of heart failure (HF). Pioglitazone (Pio) has shown potential in decreasing the risks of recurrent stroke, non-fatal myocardial infarction (MI), and all-cause mortality but increasing risks of HF. Our study aimed to examine the synergistic effects on CV outcomes in patients with type 2 diabetes mellitus (T2DM) who received the combined treatment of SGLT2i and Pio. Materials and Methods: A total of 117,850 patients with T2DM and without a history of HF were selected as the observational study cohort from the Chang Gung Research Database (CGRD) in Taiwan between January 1, 2016, and December 31, 2019. The primary composite outcome was 4-point major adverse CV events (4P-MACE), including CV death, non-fatal MI, non-fatal ischemic stroke, and hospitalization for HF. The study was divided into four groups: a combined treatment group in which SGLT2i and Pio were used, two individual groups in which SGLT2i or Pio was used separately, and a reference group (non-study drugs). Results: Combined treatment of SGLT2i and Pio had the lowest risk of 4P-MACE (adjusted hazard ratio [aHR], 0.66; 95% confidence interval [CI], 0.54-0.80) compared with the reference group after a mean follow-up of 2.2 years. There was no significant difference in risks of hospitalization for HF (adjusted subdistribution hazard ratio, 0.73; 95% CI, 0.49-1.07) compared with the reference group. Conclusions: In T2DM patients without HF, the combined treatment with SGLT2i and Pio may synergistically provide CV benefits without increasing risks of HF. [ABSTRACT FROM AUTHOR]

Background: Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy. Methods: The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety. Results: After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were --1.38%±0.08%, -1.03%±0.08%, and -0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P< 0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and β-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy. Conclusion: Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy. [ABSTRACT FROM AUTHOR]

The instrumental analytical methods that have been developed and utilized for the determination of thiazolidinedione in bulk medications, formulations and biological fluids have been reviewed after an in-depth analysis of the literature published in a variety of analytical and pharmaceutical chemistry-related journals. The approaches covered by this research, which covers the years 2001–2022, include complex methods for analysis, chromatographic techniques and spectrometric analytical procedures. The mobile phase, flow rate, sample matrix, wavelength and other factors identified in the literature were just a few of the parameters used to evaluate thiazolidinediones. The present review focuses on the published analytical techniques for thiazolidinedione analysis that have been previously identified in the literature. The specified outcomes followed extensive learning, and the most recent advances in analytical methods for the identification of pioglitazone, pioglitazone HCl, rosiglitazone, rosiglitazone maleate and lobeglitazone were reviewed. Additionally, this article briefly discusses features of analytical discovery on thiazolidinediones, which will enable readers to access all discoveries in one place with precise outcomes. [ABSTRACT FROM AUTHOR]

Background: PGZ, a peroxisome proliferator-activated receptor γ agonist, possesses anti-inflammatory and antioxidant actions. The current study investigated an alternative molecular target of pioglitazone (PGZ) to protect against inflammatory bowel disease development. Methods: Rats were allocated into 4 groups: normal control (NC), acetic acid (AA), PGZ (25 mg/kg intraperitoneal (i.p) and PGZ+ EX527 (a sirtuin1 inhibitor) (5mg/kg, i.p) groups. Results: PGZ attenuated ulcerative colitis severity evident by decreased disease activity index, colon weight/ length ratio, gross damage, histological disruption and myeloperoxidase activity. PGZ suppressed oxidative stress by inhibition of lipid peroxidation and nitrite/nitrate content and enhancing glutathione level and antioxidant enzyme activities. PGZ reduction of colon injury was accompanied by suppressed inflammatory response as evidenced by decreased proinflammatory cytokines and IFN-γ- inducible protein 10 (CXCL 10) with restored interleukin-10. PGZ repaired the mucosal barrier integrity evident by increased claudin1expression. PGZ upregulated mRNA and protein expressions of SIRT1 (Silent information regulator 2 homologue 1) and p-IκBα (phosphory lated inhibitor kappa Balpha) protein expression. PGZ down regulated NOX4 (nicotinamide adenine dinucleotide phosphate oxidase 4), TLR4 (toll like receptor4), IKKβ kinase and p65 subunit mRNA expressions. Additionally, in RAW264.7 cells, PGZ suppressed protein expressions of H3K9ac (histone H3 lysine acetylation), NOX4 and inducible nitric oxide synthase, upregulated SIRT1 and arginase-1protein expressions. EX527 co-treatment reversed all effects of PGZ. Conclusions: Our findings indicated the beneficial effects of PGZ in UC via modulation of SIRT1/NOX4 signaling besides suppression of TLR4/NF-κB cascades and M1-M2 macrophage polarization. [ABSTRACT FROM AUTHOR]

Introduction: Curcuma longa (Cl) shows potential effects on oxidative stress and inflammation in various organs. This research sought to explore how Cl affects learning and memory deficits caused by inhaled paraquat (PQ), along with oxidative stress in the brain, as well as systemic inflammation in rats. Methods: Rats inhaled either saline (Ctrl) or PQ aerosols during the experiment. The PQ groups were administered saline (PQ group), 0.03 mg/kg/day dexamethasone (Dexa), 150 and 600 mg/kg/day Cl (Cl-L and Cl-H), 5 mg/kg/day pioglitazone (Pio), and Cl-L + Pio for 16 days during the PQ exposure period. The evaluation of learning and memory abilities was conducted by implementing the Morris water maze (MWM) and passive avoidance tests. Results and discussion: Total and differential WBC numbers were increased in the PQ group, along with malondialdehyde (MDA) levels in the serum and brain despite the levels of thiol, catalase (CAT), and superoxide dismutase (SOD) which were lower compared to the control group (p < 0.001). The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the MWM test and duration of time latency in the dark room were reduced after receiving an electrical shock (p < 0.05 to p < 0.001). In all treated groups, measured values were improved than the PQ group (p < 0.05 to p < 0.001). The combination of Cl-L + Pio showed more pronounced effects compared to either treatment alone (p < 0.05 to p < 0.001). Conclusion: Cl, Pio and their combination improved PQ-induced memory dysfunction, brain oxidative stress and systemic inflammation in rats, and PPARγ receptor contribution on the effects of Cl was suggested. [ABSTRACT FROM AUTHOR]