-
Mediators of Inflammation 2021The effects of () and pioglitazone (a PPAR- agonist) alone and in combination, on systemic inflammation and oxidative stress induced by inhaled paraquat (PQ) as a...
The effects of () and pioglitazone (a PPAR- agonist) alone and in combination, on systemic inflammation and oxidative stress induced by inhaled paraquat (PQ) as a herbicide, which induced inflammation in rats, were examined. Rats were exposed to (1) saline (control) and (2) 54 mg/m PQ aerosols (8 times, every other day, each time for 30 min) without treatment or treated with (3 and 4) two doses of (200 and 800 mg/kg/day), (5 and 6) two doses of pioglitazone (5 and 10 mg/kg/day), (7) low doses of . + pioglitazone, (Pio-5+Z-200 mg/kg/day) or (8) dexamethasone (0.03 mg/kg/day) for 16 days, after the last PQ exposure. Different variables were measured at the end of the treatment period. Exposure to PQ significantly increased total and differential white blood cells (WBC) counts, serum levels of nitrite (NO), malondialdehyde (MDA), interleukin- (IL) 17, and tumor necrosis factor alpha (TNF-), but reduced thiol, superoxide dismutase (SOD), catalase (CAT), IL-10, and interferon-gamma (INF-) ( < 0.05 to < 0.001). Most measured parameters were significantly improved in groups treated with either doses of the extract, pioglitazone, Pio-5+Z-200 mg/kg/day, or dexamethasone compared to the PQ group ( < 0.05 to < 0.001). The combination of low doses of Pio-5+Z-200 mg/kg/day showed significantly higher effects compared to each one alone ( < 0.05 to < 0.001). Systemic oxidative stress and inflammation due to inhaled PQ were improved by and pioglitazone. Higher effects of Pio-5+Z-200 mg/kg/day compared to each one alone suggest modulation of PPAR- receptors by the plant extract, but further studies using PPAR- antagonists need to be done in this regard.
Topics: Animals; Inflammation; Lamiaceae; Oxidative Stress; Paraquat; Pioglitazone; Rats
PubMed: 34054344
DOI: 10.1155/2021/5575059 -
PloS One 2022There is limited information on the efficacy of pioglitazone in diabetic kidney diseases (DKD). We evaluated whether pioglitazone exerts renal-protective effects in DKD...
There is limited information on the efficacy of pioglitazone in diabetic kidney diseases (DKD). We evaluated whether pioglitazone exerts renal-protective effects in DKD patients. We designed a retrospective cohort study, which included 742 type 2 diabetes mellitus (T2DM) patients with DKD in Taiwan, with eGFR between 30 and 90 ml/min/1.73 m2 and UACR level 300-5000 mg/g. Patients not meeting the target range for HbA1c (above 7%) were given additional medication with pioglitazone (n = 111) or received standard care (non-pioglitazone group, n = 631). The primary endpoint was the occurrence of composite renal endpoints, which was defined as sustained eGFR<15 ml/min/1.73 m2 (confirmed by two measurements within 90 days); doubling of serum creatinine (compared to baseline); and the presence of hemodialysis or renal transplantation. The median follow-up duration was two years. At baseline, the mean HbA1C levels in the pioglitazone and non-pioglitazone groups were 8.8% and 8.1%, respectively; mean ages were 64.4 and 66.2 years old, respectively; diabetes durations were 14.3 and 12.3 years, respectively. Baseline eGFR showed no significant difference between the pioglitazone and non-pioglitazone groups (55.8 and 58.8 mL/min/1.73 m2, respectively). In terms of gender, 63% of patients were male in the pioglitazone group compared with 57% in the non-pioglitazone group. Pioglitazone use did not reduce the risk of composite renal endpoints in DKD patients (HR: 0.97, 95% CI = 0.53-1.77), including persistent eGFR<15 ml/min/1.73 m2 (HR = 1.07, 95% CI = 0.46-2.52), doubling of serum creatinine (HR = 0.97, 95% CI = 0.53-1.77), or ESRD (HR = 2.58, 95% CI = 0.29-23.04). The results were not changed after various adjustments. A non-significant albuminuria reduction was also noted after pioglitazone prescription in DKD patients. Further randomized controlled studies are needed to establish the effects of pioglitazone definitively.
Topics: Aged; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Kidney; Male; Middle Aged; Pioglitazone; Retrospective Studies; Taiwan
PubMed: 35176115
DOI: 10.1371/journal.pone.0264129 -
Trials Sep 2023Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide....
SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind,...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs.
METHODS
In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO.
DISCUSSION
The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention.
TRIAL REGISTRATION
EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .
Topics: Adolescent; Female; Humans; Carotid Intima-Media Thickness; Clinical Trials, Phase II as Topic; Insulin; Life Style; Metformin; Multicenter Studies as Topic; Pioglitazone; Polycystic Ovary Syndrome; Quality of Life; Randomized Controlled Trials as Topic; Spironolactone; Young Adult
PubMed: 37715279
DOI: 10.1186/s13063-023-07593-6 -
Journal of Inherited Metabolic Disease Jul 2022X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and...
X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and β-oxidation, leading to accumulation in plasma and tissues. Excess VLCFA drives impaired cellular functions (e.g. disrupted mitochondrial function), inflammation, and neurodegeneration. Major disease phenotypes include: adrenomyeloneuropathy (AMN), progressive spinal cord axonal degeneration, and cerebral ALD (C-ALD), inflammatory white matter demyelination and degeneration. No pharmacological treatment is available to-date for ALD. Pioglitazone, an anti-diabetic thiazolidinedione, exerts potential benefits in ALD models. Its mechanisms are genomic (PPARγ agonism) and nongenomic (mitochondrial pyruvate carrier-MPC, long-chain acyl-CoA synthetase 4-ACSL4, inhibition). However, its use is limited by PPARγ-driven side effects (e.g. weight gain, edema). PXL065 is a clinical-stage deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonism but retains MPC activity. Here, we show that incubation of ALD patient-derived cells (both AMN and C-ALD) and glial cells from Abcd1-null mice with PXL065 resulted in: normalization of elevated VLCFA, improved mitochondrial function, and attenuated indices of inflammation. Compensatory peroxisomal transporter gene expression was also induced. Additionally, chronic treatment of Abcd1-null mice lowered VLCFA in plasma, brain and spinal cord and improved both neural histology (sciatic nerve) and neurobehavioral test performance. Several in vivo effects of PXL065 exceeded those achieved with pioglitazone. PXL065 was confirmed to lack PPARγ agonism but retained ACSL4 activity of pioglitazone. PXL065 has novel actions and mechanisms and exhibits a range of potential benefits in ALD models; further testing of this molecule in ALD patients is warranted.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Animals; Deuterium; Fatty Acids; Fatty Acids, Nonesterified; Inflammation; Mice; Mice, Knockout; PPAR gamma; Pioglitazone
PubMed: 35510808
DOI: 10.1002/jimd.12510 -
International Journal of Molecular... Jun 2022The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently...
The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.
Topics: Antiviral Agents; Diabetes Mellitus, Type 2; Humans; Pioglitazone; Pyridones; Pyrimidines; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35743273
DOI: 10.3390/ijms23126830 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Jun 2024This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing...
BACKGROUND
This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model.
METHODS
Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-β), and fibronectin levels were measured in serum and peritoneal lavage samples.
RESULTS
The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-β levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005).
CONCLUSION
Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.
Topics: Animals; Pioglitazone; Metformin; Tissue Adhesions; Rats, Wistar; Rats; Disease Models, Animal; Hypoglycemic Agents; Male; Thiazolidinediones; Postoperative Complications
PubMed: 38863295
DOI: 10.14744/tjtes.2024.61732 -
Frontiers in Physiology 2021Renal ischemia-reperfusion injury (IRI) is considered as a major cause of acute kidney injury. In this study, we investigated the role of the NF-κB signaling pathway...
Renal ischemia-reperfusion injury (IRI) is considered as a major cause of acute kidney injury. In this study, we investigated the role of the NF-κB signaling pathway and inflammation in the amelioration of renal IRI using pioglitazone. Sprague-Dawley (SD) rats were subjected to bilateral renal artery clamping for 45 min followed by perfusion restoration for establishing a simulated renal IRI model. At 24 h post-operatively, we assessed the serum levels of creatinine and urea nitrogen, expression levels of peroxisome proliferator-activated receptor gamma (PPAR-γ) and NF-κB-related (p-IKK-β and IκB-α) proteins, and mRNA expression levels of the inflammatory cytokines, including TNF-α and MCP-1, in the renal tissue of various study groups. The histopathological evaluation of renal tissue was also conducted. In rat renal tissue, pioglitazone treatment decreased the serum levels of post-renal IRI creatinine and urea nitrogen, as well as necrosis. Furthermore, it elevated the expression of PPAR-γ protein and decreased the expression of NF-κB-related proteins. Pioglitazone also decreased the mRNA expression of TNF-α and MCP-1 in the renal tissue. Thus, pioglitazone ameliorates renal IRI by inhibiting the NF-κB signaling pathway and inflammatory response in rats.
PubMed: 34349671
DOI: 10.3389/fphys.2021.707344 -
American Journal of Physiology. Lung... Jul 2021Obesity-related asthma often presents with more severe symptoms than non-obesity-related asthma and responds poorly to current treatments. Both insulin resistance and...
Obesity-related asthma often presents with more severe symptoms than non-obesity-related asthma and responds poorly to current treatments. Both insulin resistance and hyperinsulinemia are common in obesity. We have shown that increased insulin mediates airway hyperreactivity in diet-induced obese rats by causing neuronal M muscarinic receptor dysfunction, which normally inhibits acetylcholine release from parasympathetic nerves. Decreasing insulin with streptozotocin prevented airway hyperreactivity and M receptor dysfunction. The objective of the present study was to investigate whether pioglitazone, a hypoglycemic drug, prevents airway hyperreactivity and M receptor dysfunction in obese rats. Male rats fed a low- or high-fat diet were treated with pioglitazone or PBS by daily gavage. Body weight, body fat, fasting insulin, and bronchoconstriction and bradycardia in response to electrical stimulation of vagus nerves and to aerosolized methacholine were recorded. Pilocarpine, a muscarinic receptor agonist, was used to measure M receptor function. Rats on a high-fat diet had potentiated airway responsiveness to vagal stimulation and dysfunctional neuronal M receptors, whereas airway responsiveness to methacholine was unaffected. Pioglitazone reduced fasting insulin and prevented airway hyperresponsiveness and M receptor dysfunction but did not change inflammatory cytokine mRNA expression in alveolar macrophages. High-fat diet, with and without pioglitazone, had tissue-specific effects on insulin receptor mRNA expression. In conclusion, pioglitazone prevents vagally mediated airway hyperreactivity and protects neuronal M muscarinic receptor function in obese rats.
Topics: Animals; Bronchial Hyperreactivity; Diet, High-Fat; Hyperinsulinism; Hypoglycemic Agents; Insulin; Male; Neurons; Obesity; Pioglitazone; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2
PubMed: 34009030
DOI: 10.1152/ajplung.00567.2020 -
Frontiers in Chemistry 2023In this study, a new series of quinoxalinone derivatives (5a-5p, 6a-6n) was designed and its hypoglycemic activity was evaluated. The results showed that compounds 5i...
In this study, a new series of quinoxalinone derivatives (5a-5p, 6a-6n) was designed and its hypoglycemic activity was evaluated. The results showed that compounds 5i and 6b exhibited stronger hypoglycemic effects than the lead compounds and were comparable to the positive control Pioglitazone. 5i and 6b may exert hypoglycemic effects by alleviating cellular OS and modulating the interactions among GLUT4, SGLT2, and GLUT1 proteins. The alleviating cellular OS of compound 6b was better than that of 5i, and 6b was found to bind better than 5i for most of the screening targets. In summary, compound 6b is a potential lead compound with hypoglycaemic activity.3.
PubMed: 37483267
DOI: 10.3389/fchem.2023.1197124 -
Medicina (Kaunas, Lithuania) Oct 2022Guidelines have increasingly stressed the concept that adequate glycemic control is required to prevent or decrease the macro- and microvascular complications of type 2... (Review)
Review
Guidelines have increasingly stressed the concept that adequate glycemic control is required to prevent or decrease the macro- and microvascular complications of type 2 diabetes mellitus (T2DM). PPAR-gamma agonists ("glitazones") are no longer prioritized due to their effects on heart failure. However, the association between these drugs and innovative therapies could be a valuable tool to attenuate the risk factors of the metabolic syndrome. Glitazones are used for the treatment of diabetes and associated comorbidities. There is substantial scientific evidence demonstrating the effect of glitazones at a cardiometabolic level, as well as on hematological and neurological pathologies that point to their usefulness. The use of glitazones has always been controversial both for the type of patients who must take these drugs and for the side effects associated with them. Unfortunately, the recent guidelines do not include them among the preferred drugs for the treatment of hyperglycemia and rosiglitazone is out of the market in many countries due to an adverse cardiovascular risk profile. Even though real-life studies have proven otherwise, and their pleiotropic effects have been highlighted, they have been unable to achieve primacy in the choice of antihyperglycemic drugs. It would be appropriate to demonstrate the usefulness of pioglitazone and its therapeutic benefit with further cardiovascular safety studies.
Topics: Humans; Thiazolidinediones; Diabetes Mellitus, Type 2; Pioglitazone; Rosiglitazone; Peroxisome Proliferator-Activated Receptors; Hypoglycemic Agents
PubMed: 36295635
DOI: 10.3390/medicina58101475