Pioglitazone and Asthma: A Review of Current Evidence.

OBJECTIVE: This 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. DATA SOURCES: 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. STUDY SELECTIONS: 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. RESULTS: 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. CONCLUSION: 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.

Mesoporous silica and alumina nanoparticles to improve drug delivery of pioglitazone on diabetic type 1 nephropathy in rats.

Background and purpose: Diabetic nephropathy leads to end-stage renal disease. The present study aimed to evaluate the prophylactic effect of pioglitazone-loaded mesoporous silica and alumina scaffold on renal function and the underlying mechanisms in streptozotocin-induced diabetic rats. Experimental approach: The mesoporous nanoparticles were synthesized by chemical methods from tetraethylorthosilicate and aluminum isopropoxide and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy. The soaking method was applied to load pioglitazone into the mesoporous silica and alumina. Subsequently, the most capable formulation was evaluated for lipid profile, blood glucose, renal function biomarkers, malondialdehyde, and kidney histopathological changes in diabetic rats. Findings/Results: Pioglitazone loaded in the mesoporous included a superior release of about 80%. No interaction was observed in Fourier transform infrared spectroscopy and X-ray diffraction was shown crystalline. Scanning electron microscopy showed the size of the nanometer in the range of 100 - 300 nm. Mesoporous silica containing the drug significantly decreased urinary parameters, triglycerides, low-density lipoprotein, blood urea nitrogen, blood glucose, malondialdehyde, and creatinine. In addition, it showed increased high-density lipoprotein, significantly. The renal histopathological changes indicated improvement compared with the untreated diabetic group. Conclusion and implications: It was concluded that the mesoporous was potent to serve as a promising drug carrier and a platform aimed at the delivery of poorly water-soluble drugs for improving oral bioavailability. Furthermore, it has the potential to provide a beneficial effect on the changes in diabetic parameters.

PPARγ Agonist Pioglitazone Prevents Hypoxia-induced Cardiac Dysfunction by Reprogramming Glucose Metabolism.

The heart relies on various defense mechanisms, including metabolic plasticity, to maintain its normal structure and function under high-altitude hypoxia. Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ), sensitizes insulin, which in turn regulates blood glucose levels. However, its preventive effects against hypoxia-induced cardiac dysfunction at high altitudes have not been reported. In this study, pioglitazone effectively prevented cardiac dysfunction in hypoxic mice for 4 weeks, independent of its effects on insulin sensitivity. In vitro experiments demonstrated that pioglitazone enhanced the contractility of primary cardiomyocytes and reduced the risk of QT interval prolongation under hypoxic conditions. Additionally, pioglitazone promoted cardiac glucose metabolic reprogramming by increasing glycolytic capacity; enhancing glucose oxidation, electron transfer, and oxidative phosphorylation processes; and reducing mitochondrial reactive ROS production, which ultimately maintained mitochondrial membrane potential and ATP production in cardiomyocytes under hypoxic conditions. Notably, as a PPARγ agonist, pioglitazone promoted hypoxia-inducible factor 1α (HIF-1α) expression in hypoxic myocardium. Moreover, KC7F2, a HIF-1α inhibitor, disrupted the reprogramming of cardiac glucose metabolism and reduced cardiac function in pioglitazone-treated mice under hypoxic conditions. In conclusion, pioglitazone effectively prevented high-altitude hypoxia-induced cardiac dysfunction by reprogramming cardiac glucose metabolism.

The preventive effectiveness of Crocus sativus extract in treating lung injuries caused by inhaled paraquat in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The herbicide paraquat (PQ) is highly toxic, capable of inducing severe lung inflammation and oxidative stress, resulting in lung fibrosis and respiratory failure. Previous research has demonstrated a range of pharmacological effects associated with Crocus sativus. L (Cs) through its anti-inflammatory, antioxidant and immunomodulatory properties. Pharmacological studies support the widespread use of Cs in traditional medicine to treat respiratory disorders such as coughs and asthma. AIM OF STUDY: This study aimed to investigate the preventive impact of Cs extract and pioglitazone (Pio) on lung inflammation, oxidative stress, pathological alterations, and tracheal reactivity induced by inhaled PQ in rats as compared to dexamethasone (Dexa). METHODS: The control (Ctrl) group of rats was administered with saline aerosol, while the remaining six groups received PQ aerosol eight times every other day. The six PQ exposure groups were treated daily during the exposure period to PQ with either; saline alone, low dose Cs, High dose Cs, Pio alone, Pio combined with low dose Cs, or Dexa of 16 days. RESULTS: In the PQ group, the levels of superoxide dismutase (SOD), catalase (CAT), and thiol in the bronchoalveolar lavage fluid (BALF) were declined whereas, the levels of MDA, total and differential WBC, and lung tissue levels of tumor necrosis factor (TNF-α) and Interleukin 10 (IL-10), tracheal responsiveness (TR) to methacholine and lung pathological changes were enhanced. The measured variables showed significant improvement in all treated groups, except for a few variables in Cs (L). The combined Cs (L) + Pio showed higher effects than Cs (L) and Pio alone. For all comparisons, p values were <0.05 to <0.001. CONCLUSIONS: The results showed preventive effect of Cs comparable to that of Dexa and the potential additive preventive capabilities of the Cs and Pio indicate that the involvement of the PPARγ receptor is implicated in the effects induced by Cs.

Chronic glial activation and behavioral alterations induced by acute/subacute pioglitazone treatment in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) is a disabling neurotraumatic condition and the leading cause of injury-related deaths and disability in the United States. Attenuation of neuroinflammation early after TBI is considered an important treatment target; however, while these inflammatory responses can induce secondary brain injury, they are also involved in the repair of the nervous system. Pioglitazone, which activates peroxisome proliferator-activated receptor gamma, has been shown to decrease inflammation acutely after TBI, but the long-term consequences of its use remain unknown. For this reason, the impacts of treatment with pioglitazone during the acute/subacute phase (30 min after injury and each subsequent 24 h for 5 days) after TBI were interrogated during the chronic phase (30- and 274-days post-injury (DPI)) in mice using the controlled cortical impact model of experimental TBI. Acute/subacute pioglitazone treatment after TBI results in long-term deleterious consequences, including disruption of tau homeostasis, chronic glial cell activation, neuronal pathology, and worsened injury severity particularly at 274 DPI, with male mice being more susceptible than female mice. Further, male pioglitazone-treated TBI mice exhibited increased dominant and offensive-like behavior while having a decreased non-social exploring behavior at 274 DPI. After TBI, both sexes exhibited glial activation at 30 DPI when treated with pioglitazone; however, while injury severity was increased in females it was not impacted in male mice. This work reveals that although pioglitazone has been shown to lead to attenuated TBI outcomes acutely, sex-based differences, timing and long-term consequences of treatment with glitazones must be considered and further studied prior to their clinical use for TBI therapy.

Effect of pioglitazone on inflammatory response and clinical outcome in T2DM patients with COVID-19: a randomized multicenter double-blind clinical trial.

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 C-reactive 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. Clinical trial registration: https://clinicaltrials.gov, identifier NCT04604223.

The brain and systemic oxidative stress and memory changes induced by inhaled paraquat in rat improved by Crocus sativus.

The present study aimed to investigate the effect of Crocus sativus (Cs) on paraquat (PQ)-induced learning and memory deficits as well as brain and lung oxidative stress and systemic inflammation, and oxidative stress in rats. Rats were exposed to saline (Ctrl) or PQ (PQ groups) aerosols. PQ groups were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day Cs-L and Cs-H, 5 mg/kg/day pioglitazone (Pio), and Cs-L+Pio for 16 days during PQ exposure period. Learning and memory abilities were assessed by Morris water maze (MWM) and passive avoidance tests. PQ group showed increased numbers of total and differential WBCs in blood, and increased malondialdehyde (MDA), in the serum, brain, and lung but reduced thiol, catalase (CAT), and superoxide dismutase (SOD) levels compared to the control group (for all, 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 the latency to enter 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 compared to PQ group (p < 0.05 to p < 0.001). The combination of Cs-L+Pio showed more pronounced effects compared to either treatment alone (p < 0.05 to p < 0.001). These findings suggest that Cs has neuroprotective properties and may be beneficial in the treatment of neurodegenerative diseases induced by noxious agents such as PQ.

Index assessment of periodontal status in patients on the background of administering a drug with circadian activity.

OBJECTIVE: Aim: The aim of this study was to determine the effect of application of drug with circadian activity (pioglitazone) for treatment of patients with periodontist. PATIENTS AND METHODS: Materials and Methods: Group I - 18 individuals with healthy periodontium. Group II - 12 participants with stage II, grade B periodontitis treated with a standard treatment protocol. Group III - 12 participants with stage II, grade B periodontitis, treated with a regimen that included the standard protocol along with the administration of pioglitazone prescribed at recommended times of intake. Group IV - 12 participants with stage II, grade B periodontitis treated with the standard protocol and pioglitazone against the recommended intake hours. RESULTS: Results: The Simplified Oral Hygiene Index in Group I was 0.406±0.034. In Group II, it was 2.5±0.06. In Group III, the hygiene index was 2.633±0.056 and in Group IV it was 2.5±0.059. The Papillary-Marginal-Alveolar Index in Group I was 0.033±0.004. In Group II, it was 0.366±0.011. For Group III, the PMA index was 0.38±0.012 and for Group IV it was 0.378±0.01. The Russell's Periodontal Index in Group I was 0.111±0.008. In Group II, it was 4.668±0.155. For Group III - 4.708±0.132 and for Group IV it was 4.575±0.089. The Gingival Bleeding Index (GBI) in Group I was 0.031±0.003, while in Group II, it was 0.266±0.009, in Group III, it was 0.273±0.007 and in Group IV it was 0.278±0.006. CONCLUSION: Conclusions: The administration of pioglitazone (the drug with circadian activity) according to its circadian stage indeed has a positive effect on the periodontal status changes of patients with stage II, grade B periodontitis.

Reassessment of pioglitazone and bladder cancer based on FAERS database.

BACKGROUND: The association between pioglitazone (PLZ) and bladder cancer (BC) remains controversial in several randomized control trials, meta-analyses of multiple prospective studies, and large-scale observational studies. RESEARCH DESIGN AND METHODS: Adverse event (AE) data from 1 January 2004 to 31 March 2024 were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Disproportionality analysis were applied to quantify the signals of PLZ related BC. RESULTS: In total, 17,627,524 AE reports were recorded in the FAERS database, of which 1366 were PLZ-related BCs. More male than female patients were reported. The median age of patients was 70 years old. The peak in the annual report occurred in 2011. A total of 602 AEs reported time to onset (TTO) and the median TTO was 1023 days. In this study, BC and BC recurrence were strong signal, whereas BC stage 0 (with cancer in situ), stage ii and iii were weak signals. CONCLUSIONS: This study comprehensively demostrated the PLZ-induced risk of BC in patients with diabetes mellitus using the FAERS database. The results demonstrated that the patients treated with PLZ were more likely to develop BC. The male and aging attributed more cases to BC-related reports of PLZ treated patients.

Systemic and Lung Inflammation and Oxidative Stress Associated With Behavioral Changes Induced by Inhaled Paraquat Are Ameliorated by Carvacrol.

Paraquat (PQ) is an herbicide toxin that induces injury in different organs. The anti-inflammatory and antioxidant effects of carvacrol were reported previously. The effects of carvacrol and pioglitazone (Pio) alone and their combination on inhaled PQ-induced systemic and lung oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (control [Ctrl]) or PQ (PQ groups) aerosols. PQ-exposed animals were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day carvacrol (C-L and C-H), 5 mg/kg/day Pio, and Pio+C-L for 16 days. Inhaled PQ markedly enhanced total and differential white blood cell (WBC) counts, nitric oxide (NO), and malondialdehyde (MDA) levels but decreased catalase (CAT) and superoxide dismutase (SOD) activities and thiol levels both in the bronchoalveolar lavage fluid (BALF) and blood and increased interferon-gamma (INF-γ) and interleukin-10 (IL-10) levels in the BALF (p < 0.001 for all cases) except lymphocyte count in blood which was not significantly changed. The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the Morris water maze (MWM) test and the duration of time latency in the dark room in the shuttle box test were reduced after receiving an electrical shock (p < 0.05-p < 0.001). Inhaled PQ-induced changes were significantly improved in carvacrol, Pio, Dexa, and especially in the combination of the Pio+C-L treated groups (p < 0.05-p < 0.001). Carvacrol and Pio improved PQ-induced changes similar to Dexa, but ameliorative effects produced by combination treatments of Pio+C-L were more prominent than Pio and C-L alone, suggesting a potentiating effect for the combination of the two agents.

The AXL inhibitor bemcentinib overcomes microenvironment-mediated resistance to pioglitazone in acute myeloid leukemia.

Prognosis of acute myeloid leukemia (AML) remains poor especially in older patients who are ineligible for standard chemotherapy or have refractory disease. Here, we study the potential of Peroxisome Proliferator-Activated Receptor (PPAR)-γ agonist pioglitazone to improve the treatment of AML. We show that pioglitazone exerts an anti-proliferative and anti-clonogenic effect on AML cell lines KG-1a, MOLM-14 and OCI-AML3 and on primary cultures from AML patients. However, co-culture of AML cells with stromal cells mimicking the bone marrow microenvironment counteracts this effect, suggesting the existence of a stroma-mediated resistance mechanism to pioglitazone. We show that pioglitazone treatment upregulates the receptor AXL in AML cells at the mRNA and protein level, allowing AXL to be phosphorylated by its ligand Gas6, which is secreted by the stroma. Addition of exogenous Gas6 or stromal cell conditioned medium also abolishes the anti-proliferative effect of pioglitazone, with an increase in AXL phosphorylation observed in both conditions. Co-incubation with the AXL inhibitor bemcentinib restored the anti-leukemic activity of pioglitazone in the presence of stromal cells by reducing AXL phosphorylation to its baseline level. We also confirm that this resistance mechanism is PPAR-γ-dependent as stromal cells invalidated for PPAR-γ are unable to inhibit the antileukemic effect of pioglitazone. Altogether, we suggest that pioglitazone treatment exerts an anti-leukemic effect but concomitantly triggers a stroma-mediated resistance mechanism involving the Gas6/AXL axis. We demonstrate that a combination of pioglitazone with an AXL inhibitor overcomes this mechanism in primary cultures and AML cell lines and exerts potent anti-leukemic activity requiring further evaluation in vivo through murine xenograft pre-clinical models.

Efficacy and Safety of Pioglitazone/Metformin Fixed-Dose Combination Versus Uptitrated Metformin in Patients with Type 2 Diabetes without Adequate Glycemic Control: A Randomized Clinical Trial.

INTRODUCTION: We aim to evaluate the efficacy and safety of pioglitazone/metformin fixed-dose combination (FDC) versus uptitrated metformin in patients with type 2 diabetes mellitus (T2DM) without adequate glycemic control. METHODS: A total of 304 patients were recruited from 15 hospitals in China and randomly assigned (1:1) to the test group (pioglitazone/metformin FDC, 15/500 mg) or the control group (uptitrated metformin, 2000-2500 mg/day). The primary endpoint was the proportion of patients with glycated hemoglobin A1c (HbA1c) ≤ 6.5% and ≤ 7.0% at week 16. The secondary outcomes included the change from baseline in glucose, serum lipids, and liver function. Full analysis set (FAS) and per-protocol set (PPS) were used for analyses. RESULTS: In the test group, 103 (69.59%) patients reached HbA1c ≤ 7.0% (FAS, P = 0.009), with 68 (45.95%) patients achieved HbA1c ≤ 6.5 (FAS, P = 0.043). More reduction in HbA1c, homeostatic model assessment for insulin resistance, and diastolic pressure was found. Bodyweight, body mass index, and high-density lipoprotein cholesterol increased markedly. The changes of triglycerides, alanine transaminase, aspartate aminotransferase, and high-sensitivity C-reactive protein decreased noticeably. There were no significant differences in rates of adverse events between the two groups. CONCLUSIONS: Pioglitazone/metformin FDC was superior to uptitrated metformin among patients with T2DM without adequate glycemic control. TRIAL REGISTRATION NUMBER: This trial is registered with the Chinese Clinical Trial Registry (ChiCTR1900028606).

Pioglitazone as a potential modulator in autoimmune diseases: a review on its effects in systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis.

INTRODUCTION: Current medications for autoimmune disorders often induce broad-ranging side effects, prompting a growing interest in therapies with more specific immune system modulation. Pioglitazone, known for its anti-diabetic properties, is increasingly recognized for significant immunomodulatory potential. Beyond its traditional use in diabetes management, pioglitazone emerges as a promising therapeutic candidate for autoimmune disorders. AREAS COVERED: This comprehensive review explores pioglitazone's impact on four prominent autoimmune conditions: systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis. We focus on pioglitazone's diverse effects on immune cells and cytokines in these diseases, highlighting its potential as a valuable therapeutic option for autoimmune diseases. Here we have reviewed the latest and most current research literature available on PubMed, based on research published in the last 15 years. EXPERT OPINION: Pioglitazone as an immunomodulatory agent can regulate T cell differentiation, inhibit inflammatory cytokines, and promote anti-inflammatory macrophages. While further clinical studies are needed to fully understand its mechanisms and optimize treatment strategies, pioglitazone represents a potential therapeutic approach to improve outcomes for patients with these challenging autoimmune conditions. The future of autoimmune disease research may involve personalized treatment approaches, and collaborative efforts to improve patient quality of life.

This article explores the potential use of pioglitazone, a medication commonly used to treat diabetes, for autoimmune disorders treatment. The focus of the review centers around the effects of pioglitazone on systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis. In the case of systemic lupus erythematosus, pioglitazone appears to induce a shift in specific immune cells, leading to a reduction in systemic inflammation and damage to organs. In psoriasis, the medication shows promise in suppressing immune responses, thereby alleviating skin inflammation. For individuals with inflammatory bowel disease, pioglitazone seems to safeguard a protein with anti-inflammatory properties, aiding in the repair of bowel tissue. Regarding multiple sclerosis, pioglitazone appears to influence the behavior of immune cells and promote the restoration of nerve tissue. These diverse effects of pioglitazone on the immune system suggest its potential as a valuable treatment option for autoimmune diseases. However, it is important to note that further research is necessary to fully comprehend the mechanisms by which pioglitazone operates and to determine the optimal approaches for its utilization in clinical studies.

PPAR-γ agonist pioglitazone and the risks of malignancy among type2 diabetes mellitus patients.

AIMS: PPAR-gamma shows promise in inhibiting malignancy cell progression. However, pioglitazone, the sole current PPAR-gamma agonist, was reported to have risks of bladder cancer in previous clinical researches. This study is aimed to assess the influence of pioglitazone on the development of tumors. METHODS: By using Taiwan's National Health Insurance Research Database, this nested case-control study identified incident type2 diabetes initiating metformin treatment between 2000 and 2014, and then categorized into two groups based on whether they developed malignancies after enrollment or not. The index date was defined as the date of malignancy diagnosis in the cancer group or a matched date in the non-cancer group. We analyzed the exposure to pioglitazone preceding the index date. RESULTS: 47,931 patients in the cancer group and 47,931 patients in the matched non-cancer group were included. The non-cancer group exhibited a significantly higher rate of pioglitazone prescription before the index date for overall malignancies (odds ratios for pioglitazone use were 0.91, 0.92, 0.94, and 0.93 in the first, second, third, and fourth years before the index date). For breast cancer and prostate cancer, pioglitazone was frequently prescribed in the non-cancer group, whereas for pancreatic cancer, pioglitazone use was more common in the cancer group. CONCLUSIONS: PPAR-gamma agonists may be associated with reduced risks of overall malignancies, particularly for breast and prostate cancers. However, it may be linked to an elevated risk of pancreatic cancer.

Synergistically improved cardiovascular outcomes in type 2 diabetes mellitus patients with combined treatment of SGLT-2 inhibitors and pioglitazone.

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.

Metformin in Chemoprevention of Lung Cancer: A Retrospective Population-Based Cohort Study in Lithuania.

Background and Objectives: This study aimed to evaluate the potential chemopreventive effect of antidiabetic medications, specifically metformin and pioglitazone, on lung cancer in patients with type 2 diabetes mellitus (T2DM). Additionally, the potential dose-response relationship for metformin use was analyzed. Methods: We conducted a retrospective cohort study utilizing comprehensive national health insurance and cancer registry databases to gather a large cohort of T2DM patients. Cox proportional hazards regression models were used to assess the risk of lung cancer across different antidiabetic medication groups, adjusting for potential confounders such as age and gender. A dose-response analysis was conducted for metformin users. Results: Our results indicated that metformin users had a significantly lower lung cancer risk than the reference group (HR = 0.69, 95% CI [0.55-0.86], p = 0.001). The risk reduction increased with higher cumulative metformin doses: a metformin cumulative dose between 1,370,000 and 2,976,000 had an HR of 0.61 (95% CI [0.49-0.75], p < 0.001) vs. cumulative metformin dose >2,976,000 which had an HR of 0.35 (95% CI [0.21-0.59], p < 0.001). No significant association between pioglitazone use and the risk of lung cancer was found (HR = 1.00, 95% CI [0.25-4.02]). Conclusions: This study shows that metformin may have a dose-dependent chemopreventive effect against lung cancer in T2DM, while the impact of pioglitazone remains unclear and requires further investigation.

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

BACKGROUND: The 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/ß-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/ß-catenin pathway and their interaction in ASD by using their modulators. MATERIAL AND METHODS: Pregnant 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-1ß, 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. RESULTS: ASD 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, ß-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. CONCLUSION: In the present study, upregulation of canonical Wnt/ß-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/ß-catenin pathway. The antagonism between the PPARγ and Wnt pathway offers a promising therapeutic approach for addressing ASD.

Neuroprotective Effects of Sulforaphane in a rat model of Alzheimer's Disease induced by Aß (1-42) peptides.

The intricate nature of Alzheimer's disease (AD) has presented significant hurdles in the development of effective interventions. Sulforaphane (SFN) is of interest due to its antioxidative, anti-inflammatory, and neuroprotective properties, which could address various aspects of AD pathology. This study explores the potential of SFN in a rat model of AD induced by Aß (1-42) peptides. AD symptoms were triggered in rats by injecting Aß (1-42) peptides directly into their cerebral ventricles. SFN (10 mg/kg and 20 mg/kg), Trigonelline (10 mg/kg), and Pioglitazone (10 mg/kg) were administered in Aß (1-42) treated animals. Behavioral assessments were performed using the Novel Object Recognition tests. Various biochemical parameters, such as soluble Aß (1-42), IRS-S312, GSK-3ß, TNF-α, acetylcholinesterase, nitrite levels, lipid peroxidation, and reduced glutathione activity, were quantified using ELISA kits and spectrophotometric assays. Histopathological analyses included Hematoxylin and Eosin, Crystal Violet, Congo red, and IRS-1 Immunohistochemistry staining. Quantification was performed to assess neuronal loss and Aß plaque burden. The novelty of this study lies in its comprehensive evaluation of SFN's impact on multiple AD-related pathways at dual doses. The Novel Object Recognition test revealed that SFN, especially at higher doses, improved memory deficits induced by Aß (1-42). Biochemically, SFN reduced hippocampal Aß levels, IRS-S312, GSK-3ß, TNF-α, and acetylcholinesterase activity, while increasing glutathione levels, all in a dose-dependent manner. Histopathological analyses further confirmed SFN's protective role against Aß-induced neuronal damage, amyloidosis, and changes in insulin signaling. These results highlight SFN's potential as a multifaceted therapeutic agent for AD, offering a promising avenue for treatment due to its antioxidative, anti-inflammatory, and neuroprotective properties. The inclusion of combination treatments with Trigonelline and Pioglitazone alongside SFN offers insights into potential synergistic effects, which could pave the way for developing combination therapies for AD.

Evaluation of Potential Furin Protease Inhibitory Properties of Pioglitazone, Rosiglitazone, and Pirfenidone: An In Silico Docking and Molecular Dynamics Simulation Approach.

Furin (Fur) is a member of the protease convertase family; its expression is crucial for cleaving and maturing many proteins. Fur also represents a therapeutic target in cancer, autoimmune diseases, and viral infections. Pioglitazone (PGZ) and rosiglitazone (RGZ) are thiazolidinediones prescribed to type 2 diabetes patients and are structurally similar to the known Fur inhibitors naphthofluorescein (NPF) and pirfenidone (PFD). Thus, this study used molecular docking and molecular dynamics to assess and compare the affinities and the molecular interactions of these four ligands with the Fur active site (FurAct) and the recently described Fur allosteric site (FurAll). The 7QXZ Fur structure was used for molecular dockings, and for the best pose complexes, molecular dynamics were run for 100 ns. The best affinities of the ligand/FurAct and ligand/FurAll complexes were with NPF, PGZ, and RGZ, while PFD presented the lowest affinity. Asp154 was the central residue involved in FurAct complex formation, while Glu488 and Asn310 were the central residues involved in FurAll complex formation. This study shows the potential of RGZ, PGZ, and PFD as Fur competitive (FurAct) and non-competitive (FurAll) inhibitors. Therefore, they are candidates for repurposing in response to future emerging diseases through the modulation of Fur activity.