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Mediators of Inflammation 2022Traumatic brain injury (TBI) is still a major cause of concern for public health, and out of all the trauma-related injuries, it makes the highest contribution to death... (Review)
Review
Traumatic brain injury (TBI) is still a major cause of concern for public health, and out of all the trauma-related injuries, it makes the highest contribution to death and disability worldwide. Patients of TBI continue to suffer from brain injury through an intricate flow of primary and secondary injury events. However, when treatment is provided in a timely manner, there is a significant window of opportunity to avoid a few of the serious effects. Pioglitazone (PG), which has a neuroprotective impact and can decrease inflammation after TBI, activates peroxisome proliferator-activated receptor-gamma (PPAR). The objective of the study is to examine the existing literature to assess the neuroprotective and anti-inflammatory impact of PG in TBI. It also discusses the part played by microglia and cytokines in TBI. According to the findings of this study, PG has the ability to enhance neurobehavior, decrease brain edema and neuronal injury following TBI. To achieve the protective impact of PG the following was required: (1) stimulating PPAR; (2) decreasing oxidative stress; (3) decreasing nuclear factor kappa B (NF-B), interleukin 6 (IL-6), interleukin-1 (IL-1), cyclooxygenase-2 (COX-2), and C-C motif chemokine ligand 20 (CCL20) expression; (4) limiting the increase in the number of activated microglia; and (5) reducing mitochondrial dysfunction. The findings indicate that when PIG is used clinically, it may serve as a neuroprotective anti-inflammatory approach in TBI.
Topics: Animals; Anti-Inflammatory Agents; Brain Injuries, Traumatic; Disease Models, Animal; Humans; Microglia; Neuroprotective Agents; PPAR gamma; Pioglitazone
PubMed: 35757108
DOI: 10.1155/2022/9860855 -
International Journal of Molecular... Feb 2023The failure of arteriovenous fistulas (AVFs) following intimal hyperplasia (IH) increases morbidity and mortality rates in patients undergoing hemodialysis for chronic...
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.
Topics: Humans; Pioglitazone; PPAR-gamma Agonists; Umbilical Veins; Arteriovenous Shunt, Surgical; Cell Proliferation; PPAR gamma; Myocytes, Smooth Muscle; Arteriovenous Fistula; Thiazolidinediones
PubMed: 36901853
DOI: 10.3390/ijms24054424 -
Frontiers in Pediatrics 2021The pathophysiology of bilirubin neurotoxicity in course of hypoxic-ischemic encephalopathy (HIE) in term and preterm infants is still poorly understood. We...
The pathophysiology of bilirubin neurotoxicity in course of hypoxic-ischemic encephalopathy (HIE) in term and preterm infants is still poorly understood. We hypothesized that oxidative stress may be a common mechanism that link hyperbilirubinemia and HIE. The objective of the present study was to evaluate whether unconjugated bilirubin (UCB) may enhance the HI brain injury by increasing oxidative stress and to test pioglitazone and allopurinol as new antioxidant therapeutic drugs . The effects of UCB were tested on organotypic hippocampal slices subjected to 30 min oxygen-glucose deprivation (OGD), used as model of HIE. The experiments were performed on mature (14 days in culture) and immature (7 days in culture) slices, to mimic the brains of term and preterm infants, respectively. Mature and immature slices were exposed to UCB, human serum albumin (HSA), pioglitazone, and/or allopurinol for 24 h, immediately after 30 min OGD. Neuronal injury was assessed using propidium iodide (PI) fluorescence. ROS formation was quantified by using the 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) method. In mature slices, we found that the neurotoxicity, as well as oxidative stress, induced by OGD were enhanced by UCB. HSA significantly prevented UCB-increased neurotoxicity, but had a slight reduction on ROS production. Allopurinol, but not pioglitazone, significantly reduced UCB-increased neurotoxicity induced by OGD. In immature slices exposed to OGD, no increase of neuronal death was observed, whereas oxidative stress was detected after UCB exposure. HSA, pioglitazone and allopurinol have no protective effects on both OGD-induced neuronal death and on UCB-induced oxidative stress. For this reason, UCB, pioglitazone and allopurinol was also tested on ischemic preconditioning protocol. We found that UCB abolished the neuroprotection induced by preconditioning and increased oxidative stress. These effects were restored by allopurinol but not pioglitazone. UCB characterized a different path of neuronal damage and oxidative stress in mature and immature hippocampal slice model of HIE. Management of hyperbilirubinemia in a complex pathological condition, such as HIE and hyperbilirubinemia, should be very careful. Allopurinol could deserve attention as a novel pharmacological intervention for hyperbilirubinemia and HIE.
PubMed: 33959576
DOI: 10.3389/fped.2021.659477 -
Journal of Analytical Methods in... 2021Combination therapy is a common approach for clinical treatment of type 2 diabetes mellitus, especially for patients with poor monotherapy. Meta-analysis suggested that...
Simultaneous Quantification of Pioglitazone and Omarigliptin in Rat Plasma by UHPLC-MS/MS and Its Application to Pharmacokinetic Study after Coadministration of the Two Drugs.
Combination therapy is a common approach for clinical treatment of type 2 diabetes mellitus, especially for patients with poor monotherapy. Meta-analysis suggested that omarigliptin, a long-acting DPP-4 inhibitor, combined with pioglitazone might improve the side effects of pioglitazone. However, little is known about the pharmacokinetic properties after a coadministration. In this study, a rapid and reliable method for the simultaneous determination of the pioglitazone and omarigliptin in rat plasma by UHPLC-MS/MS was established and validated for the first time. An exsil mono C18 column (2.0 × 50 mm, 3 m) was used to separate the analytes and the column temperature was kept at 30°C. Sitagliptin was selected as the internal standard. 0.02% formic acid aqueous solution (A) and methanol-acetonitrile (B) were used as mobile phases with gradient elution at a flow rate of 0.3 mL/min. The elution procedure was as follows: 20%B (0-0.1 min), 80%B (0.1-0.3 min), 80%B (0.3-2.0 min), and 20%B (2.1-3.0 min). A multiple reaction monitor (MRM) was used under positive ionization mode with electrospray ion source to detect pioglitazone (357.1 ⟶ 134.1), omarigliptin (399.2 ⟶ 153.0), and sitagliptin (408.2 ⟶ 235.0). The linear ranges of pioglitazone and omarigliptin were 5-2000 ng/mL and 10-4000 ng/mL, respectively. Good linear relationships were exhibited in the corresponding linear ranges ( ≥ 0.9944). The bioanalytical method was validated, and the selectivity, linearity, sensitivity, accuracy, precision, stability, recovery, and matrix effect were acceptable. The validated method was then successfully applied to pharmacokinetic study of pioglitazone combined with omarigliptin in rats. Results suggested that the combination of the two drugs had little effect on the pharmacokinetic parameters of each other in rats.
PubMed: 34211797
DOI: 10.1155/2021/6693366 -
Veterinary Research Forum : An... 2023Sepsis is an acute condition caused by the systemic inflammatory response syndrome to an infection. There are very few drugs that could improve the severe conditions in...
Sepsis is an acute condition caused by the systemic inflammatory response syndrome to an infection. There are very few drugs that could improve the severe conditions in patients with sepsis. Hence, it is important to consider different treatment options. In this survey, we studied the effect of adenosine N1-oxide (ANO) and pioglitazone on rats with cecal ligation and perforation (CLP). They were randomly divided to four groups (n = 10) including Group A: as control group receiving normal saline, Group B: the rats with CLP as surgical control group, Group C: the rats receiving ANO, and Group D: the rats receiving pioglitazone. Interleukin (IL) -6, IL-1β, tumor necrosis factor alpha (TNF-α), nitric-oxide (NO) in serum blood and superoxide dismutase (SOD), catalase (CAT) malondialdehyde, (MDA) and myeloperoxidase (MPO) in liver and spleen homogenates were measured. The amount of antioxidant enzymes in the spleen and liver, and finally cell viability and rats' survival were investigated. The measurement of blood serum nitric-oxide and survival of all groups of rats were also performed. The results indicated that both drugs could cause a decrease in IL-1β, IL-6, TNF-α and NO in rat blood serum and MDA and MPO in the liver and spleen homogenates, however, a significant increase in SOD and CAT in the liver and spleen homogenates in rats that received ANO and pioglitazone was observed compared to rats with CLP group. Cell viability and rats' survival were significantly improved in rats that received ANO and pioglitazone compared to rats with CLP group. Adenosine N1-oxide showed stronger and more effective effects.
PubMed: 37564357
DOI: 10.30466/vrf.2022.562229.3625 -
JCI Insight Mar 2021BACKGROUNDBeige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist...
BACKGROUNDBeige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages.METHODSWe measured BAT by PET CT scans, measured beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs.RESULTSTreatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments was evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The 3 treatments also had different effects on muscle fiber type switching and capillary density.CONCLUSIONThe addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants.TRIAL REGISTRATIONClinicalTrials.gov NCT02919176.FUNDINGNIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.
Topics: Acetanilides; Adipose Tissue, Beige; Drug Synergism; Female; Glucose; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Middle Aged; Obesity; Pioglitazone; Thiazoles
PubMed: 33571166
DOI: 10.1172/jci.insight.143650 -
Cardiovascular Diabetology Jan 2020Peroxisome proliferator-activated receptor-γ (PPAR-γ) modulating treatment may have cardiovascular benefits in type 2 diabetes mellitus (T2DM) patients after ischemic... (Observational Study)
Observational Study
BACKGROUND AND AIM
Peroxisome proliferator-activated receptor-γ (PPAR-γ) modulating treatment may have cardiovascular benefits in type 2 diabetes mellitus (T2DM) patients after ischemic stroke (IS). However, whether there are additional benefits from intensive PPAR-γ modulating treatments in Asian patients with T2DM and hypertension (HTN) after IS remains unknown.
METHODS
Between 2001 and 2013, patients admitted due to IS were identified from the National Health Insurance Research Database of Taiwan. Patients with T2DM and HTN using angiotensin receptor blockers were further included. Eligible patients were divided into two groups: (1) pioglitazone and (2) non-pioglitazone oral anti-diabetic agent groups. Propensity score matching (1:2) was used to balance the distribution of baseline characteristics, stroke severity and medications. The primary outcome was recurrent IS. Subgroup analysis for recurrent IS in pioglitazone and/or telmisartan users, the trend of IS risks across different PPAR-γ intensity treatments, and dose-dependent outcomes across different pioglitazone possession ratios were further studied. Statistical significance was set at p < 0.05 and p < 0.1 for clinical outcomes and interaction of subgroup analyses, respectively.
RESULTS
There were 3190 and 32,645 patients in the pioglitazone and non-pioglitazone groups. Patients of the pioglitazone group had a lower risk of recurrent IS (subdistribution hazard ratio, 0.91; 95% confidence interval 0.84-0.99). Pioglitazone was also associated with reduced recurrent IS in patients who also used telmisartan (p for interaction = 0.071). A graded correlation was found a borderline significant trend between the intensity of PPAR-γ therapy and following IS (p = 0.076). The dose-dependent outcome also showed that a borderline significant trend that higher pioglitazone possession ratio was associated with a lower risk of recurrent IS (p = 0.068).
CONCLUSIONS
The current study suggests that the use of pioglitazone in type 2 diabetic and hypertensive IS patients is associated with fewer recurrent IS events in an Asian population. Concurrent telmisartan use or a higher pioglitazone possession ratio may have a trend of increased pleiotropic effects, which could possibly be related to higher PPAR-γ effects. Future studies are warranted to confirm or refute the clinical effects and the possible mechanism of more intensive PPAR-γ-modulating treatments.
Topics: Aged; Antihypertensive Agents; Brain Ischemia; Databases, Factual; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Recurrence; Retrospective Studies; Risk Assessment; Risk Factors; Stroke; Taiwan; Telmisartan; Time Factors; Treatment Outcome
PubMed: 31910836
DOI: 10.1186/s12933-019-0979-x -
Alimentary Pharmacology & Therapeutics Oct 2021Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. There is a major need to understand the efficacy of different pharmacological agents for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. There is a major need to understand the efficacy of different pharmacological agents for the treatment of NASH.
AIM
To assess the relative rank-order of different pharmacological interventions in fibrosis improvement and NASH resolution.
METHODS
A comprehensive search of several databases was conducted by an experienced librarian. We included randomised controlled-trials (RCTs) comparing pharmacological interventions in patients with biopsy-proven NASH. The primary outcome was ≥1 stage improvement in fibrosis. The secondary outcome was NASH resolution.
RESULTS
A total of 26 RCTs with 23 interventions met the eligibility criteria. Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively. For NASH resolution, semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively. Lanifibranor, obeticholic acid, pioglitazone and vitamin E were significantly better than placebo in achieving ≥1 stage of fibrosis improvement. Conversely, semaglutide, liraglutide, vitamine E plus pioglitazone, pioglitazone, lanifibranor and obeticholic acid were significantly better than placebo in achieving NASH resolution.
CONCLUSION
These data provide relative rank-order efficacy of various NASH therapies in terms of their improvements in liver fibrosis and NASH resolution. Therapies that have been shown to improve NASH resolution may be combined with therapies that have an antifibrotic effect to further boost treatment response rate in future.
Topics: Biopsy; Humans; Liver Cirrhosis; Network Meta-Analysis; Non-alcoholic Fatty Liver Disease; Pioglitazone; Vitamin E
PubMed: 34435378
DOI: 10.1111/apt.16583 -
Cureus Dec 2022Our study aimed to examine the effects of Linagliptin, Pioglitazone, and their combination on fracture healing in a diabetes rat femur fracture model.
AIM
Our study aimed to examine the effects of Linagliptin, Pioglitazone, and their combination on fracture healing in a diabetes rat femur fracture model.
MATERIAL AND METHODS
Type 2 diabetes mellitus (T2DM) induced rats were randomly divided into four groups: non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Daily oral dosage of pioglitazone (10 mg/kg/day), linagliptin (10 mg/kg/day), and their combination were administered. Femur fractures were stabilized intramedullary. At weeks 2 and 6, rats were sacrificed for evaluation radiologically, biomechanically, histopathologically, histomorphometrically, and immunohistochemically.
RESULTS
Flexural strength of the L and PL groups were significantly higher compared to the P group. The highest healing score was in the L group and lowest in the P group, while the highest inflammation score was in the P group and lowest in the L group. A cluster of differentiation (CD) CD 34 reactivity was highest in the L group and lowest in the PL group.
CONCLUSION
Linagliptin treatment significantly increased histological healing scores, callus volume, biomechanical strength, and vascularity, however, minimized the inflammatory process, which was increased by pioglitazone. The combination of linagliptin and pioglitazone restored BMD and increased biomechanical strength. Linagliptin monotherapy is rarely indicated; hence, T2DM patients with a high risk of bone fractures can be considered for combined therapy of pioglitazone and linagliptin.
PubMed: 36479259
DOI: 10.7759/cureus.32204 -
Diabetes, Obesity & Metabolism Feb 2023To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. (Meta-Analysis)
Meta-Analysis
Effects of glucose-lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta-analysis of randomized controlled trials with external adjudication of events.
AIMS
To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes.
METHODS
A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow-up ≥52 weeks, in which glucose-lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All-cause mortality, 3-point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints.
RESULTS
We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha-glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl-peptidase-4 inhibitors (n = 67), glucagon-like peptide-1 receptor agonists (n = 45) or sodium-glucose co-transporter-2 inhibitors (SGLT-2i; n = 42) and insulin (n = 18). Glucagon-like peptide-1 receptor agonist and SGLT-2i were associated with a significant reduction in all-cause mortality [Mantel-Haenszel odds ratio (MH-OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH-OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT-2i was associated with a reduced risk of HHF [MH-OR 0.68 (0.62; 0.75)], worsening albuminuria [MH-OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH-OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH-OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH-OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all-cause mortality [MH-OR 1.12 (1.01; 1.24)] and MACE [MH-OR 1.19 (1.02; 1.39)].
CONCLUSIONS
The results of this updated meta-analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose-lowering drugs on long-term glycaemic control.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Glucose; Pioglitazone; Glucagon-Like Peptide-1 Receptor; Albuminuria; Creatinine; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Metformin; Heart Failure; Cardiovascular Diseases
PubMed: 36205446
DOI: 10.1111/dom.14888