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Cells Dec 2019Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.
Topics: Chalcones; Diabetes Mellitus, Type 2; Drug Development; Fatty Liver; Humans; Hypoglycemic Agents; Inflammation; Liver; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Phenylpropionates; Pioglitazone; Propionates; Pyrroles
PubMed: 31877771
DOI: 10.3390/cells9010037 -
Cardiovascular Diabetology May 2021Since 1985, the thiazolidinedione pioglitazone has been widely used as an insulin sensitizer drug for type 2 diabetes mellitus (T2DM). Although fluid retention was early... (Review)
Review
Since 1985, the thiazolidinedione pioglitazone has been widely used as an insulin sensitizer drug for type 2 diabetes mellitus (T2DM). Although fluid retention was early recognized as a safety concern, data from clinical trials have not provided conclusive evidence for a benefit or a harm on cardiac function, leaving the question unanswered. We reviewed the available evidence encompassing both in vitro and in vivo studies in tissues, isolated organs, animals and humans, including the evidence generated by major clinical trials. Despite the increased risk of hospitalization for heart failure due to fluid retention, pioglitazone is consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention, without any proven direct harm on the myocardium. Moreover, it reduces atherosclerosis progression, in-stent restenosis after coronary stent implantation, progression rate from persistent to permanent atrial fibrillation, and reablation rate in diabetic patients with paroxysmal atrial fibrillation after catheter ablation. In fact, human and animal studies consistently report direct beneficial effects on cardiomyocytes electrophysiology, energetic metabolism, ischemia-reperfusion injury, cardiac remodeling, neurohormonal activation, pulmonary circulation and biventricular systo-diastolic functions. The mechanisms involved may rely either on anti-remodeling properties (endothelium protective, inflammation-modulating, anti-proliferative and anti-fibrotic properties) and/or on metabolic (adipose tissue metabolism, increased HDL cholesterol) and neurohormonal (renin-angiotensin-aldosterone system, sympathetic nervous system, and adiponectin) modulation of the cardiovascular system. With appropriate prescription and titration, pioglitazone remains a useful tool in the arsenal of the clinical diabetologist.
Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; PPAR gamma; Pioglitazone; Risk Assessment; Risk Factors; Signal Transduction; Treatment Outcome
PubMed: 34006325
DOI: 10.1186/s12933-021-01294-7 -
International Journal of Environmental... Jan 2023Arsenic (As) is a common contaminant in drinking water in northeastern Mexico, which reduces the expression of cytochrome P450 (CYP 450). This enzyme group metabolizes...
UNLABELLED
Arsenic (As) is a common contaminant in drinking water in northeastern Mexico, which reduces the expression of cytochrome P450 (CYP 450). This enzyme group metabolizes numerous drugs, such as oral antidiabetic drugs such as pioglitazone (61% CYP 3A4, 49% CYP 2C8). When CYP 450's function is inadequate, it has decreased therapeutic activity in type 2 diabetes mellitus (T2DM). This study aimed to establish the effect of As on pioglitazone metabolism in patients with T2DM.
METHODOLOGY
Urine, water, and plasma samples from a healthy population ( = 11) and a population with T2DM ( = 20) were obtained. Samples were analyzed by fluorescence spectroscopy/hydride generation (As) and HPLC (pioglitazone). Additionally, CYP 3A4 and CYP 2C8 were studied by density functional theory (DFT).
RESULTS
The healthy and T2DM groups were exposed via drinking water to >0.010 ppm, Ka values with a factor of 4.7 higher, Cl 1.42 lower, and ABCt 1.26 times higher concerning the healthy group. In silico analysis (DFT) of CYP 3A4 and CYP 2C8 isoforms showed the substitution of the iron atom by As in the active sites of the enzymes.
CONCLUSIONS
The results indicate that the substitution of Fe for As modifies the enzymatic function of CYP 3A4 and CYP 2C8 isoforms, altering the metabolic process of CYP 2D6 and CYP 3A4 in patients with T2DM. Consequently, the variation in metabolism alters the bioavailability of pioglitazone and the expected final effect.
Topics: Humans; Pioglitazone; Arsenic; Diabetes Mellitus, Type 2; Biological Availability; Drinking Water; Cytochrome P-450 Enzyme System; Microsomes, Liver
PubMed: 36767268
DOI: 10.3390/ijerph20031901 -
European Review For Medical and... Oct 2023OBJECTIVE: The anticancer drug doxorubicin (DOX) is effective but is associated with complications such as hypothyroidism and cardiotoxicity. Pioglitazone (PIO), which...
UNLABELLED
OBJECTIVE: The anticancer drug doxorubicin (DOX) is effective but is associated with complications such as hypothyroidism and cardiotoxicity. Pioglitazone (PIO), which is used to treat diabetes mellitus, has shown potential for treating hypothyroidism and cardiac dysfunction. Therefore, this study explores whether PIO can also ameliorate DOX-induced hypothyroidism and cardiotoxicity. MATERIALS AND METHODS: Forty female Wistar rats were separated into control and three treated groups (DOX, PIO, and DOX+PIO), and their blood samples were examined for the thyroid hormones, including thyroid-stimulating hormone (TSH), thyroxine in total and free forms (T4 and FT4, respectively), and triiodothyronine in total and free forms (T3 and FT3, respectively), and the cardiotoxicity biomarkers [troponin I, creatine kinase (CK), and creatine kinase-myocardial band (CK-MB)]. RESULTS: The control and PIO groups did not exhibit significant alterations in any of the examined hormones and markers. In contrast, in the DOX group, T4, FT4, T3, and FT3 levels decreased significantly, whereas troponin I, CK, and CK-MB levels increased significantly, but no significant changes were detected in TSH levels. PIO co-treatment ameliorated these effects of DOX significantly in FT4, FT3, and troponin I. CONCLUSIONS: PIO may provide protection against hypothyroidism and cardiotoxicity caused by DOX treatment, by significant reversal of FT4, FT3, and troponin I levels.
GRAPHICAL ABSTRACT
https://www.europeanreview.org/wp/wp-content/uploads/Graphical-abstract1.jpg.
Topics: Female; Rats; Animals; Pioglitazone; Cardiotoxicity; Troponin I; Rats, Wistar; Hypothyroidism; Thyroxine; Doxorubicin; Thyrotropin; Creatine Kinase, MB Form; Creatine Kinase
PubMed: 37843360
DOI: 10.26355/eurrev_202310_33966 -
Zygote (Cambridge, England) Feb 2023Polycystic ovary syndrome (PCOS) is a complex disorder in which the aetiology is still not explained very well. The PI3K/PTEN (phosphatidylinositol 3-kinase/phosphatase...
Polycystic ovary syndrome (PCOS) is a complex disorder in which the aetiology is still not explained very well. The PI3K/PTEN (phosphatidylinositol 3-kinase/phosphatase and tensin homolog deleted on chromosome 10) pathway is an important pathway that is involved in many mechanisms, including proliferation, growth and motility. PTEN plays a role in granulosa cell proliferation and regulates the differentiation process. The aim of this study was to investigate the expression levels of and in PCOS mouse models with and without any treatment procedures. Three groups of mouse models, PCOS, a PCOS group with clomiphene citrate treatment, and a PCOS group with the combination of clomiphene citrate, metformin and pioglitazone treatment, were established. Ovarian tissues, which were obtained from these groups and a control group with no PCOS, were embedded in paraffin and RNA was extracted. cDNA was synthesized and real-time PCR was conducted to evaluate the expression levels of and . The results of this study showed that both and genes were expressed in the ovarian tissues from the mouse models. Although one-way analysis of variance results showed that was expressed significantly differently in the samples, individual Student's -tests did not show any significantly different expression levels in each group. This study is important as it shows the expression patterns of two genes in PCOS mouse models with different treatment strategies, including clomiphene citrate, metformin and pioglitazone. The results of this study formed the basis of research studies and investigations into different genes within the PTEN pathway, as well as other pathways that are under investigation.
Topics: Animals; Female; Mice; Clomiphene; Metformin; Oogenesis; Ovulation Induction; Phosphatidylinositol 3-Kinases; Pioglitazone; Polycystic Ovary Syndrome; PTEN Phosphohydrolase
PubMed: 36533329
DOI: 10.1017/S0967199422000661 -
Aging Apr 2023The prevalence of type 2 diabetes (T2DM) in elderly people has expanded rapidly. Considering cognitive impairment and being prone to hypoglycemia of the elder, the pros...
The prevalence of type 2 diabetes (T2DM) in elderly people has expanded rapidly. Considering cognitive impairment and being prone to hypoglycemia of the elder, the pros and cons of oral hypoglycemic agents (OHA) should be reassessed in this population. Pioglitazone might be appropriate for elderly DM patients because of its insulin-sensitizing effect and low risk of hypoglycemia. By using Taiwan's National Health Insurance Research Database, 191,937 types 2 diabetes patients aged ≥65 years under treatment between 2005 and 2013 were identified and further divided into two groups according to whether they received pioglitazone (pioglitazone group) or other OHAs (non-pioglitazone group) in the 3 months preceding their first outpatient visit date after 65 years of age, with a diagnosis of T2DM. Propensity score stabilization weight (PSSW) was used to balance the baseline characteristics. In results, the pioglitazone group ( = 17,388) exhibited a lower rate (per person-years) of major advanced cardiovascular events MACCE (2.76% vs. 3.03%, hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.87-0.95), new- diagnosis dementia (1.32% vs. 1.46%, HR: 0.91, 95% CI: 0.84-0.98) but a higher rate of new-diagnosis bone fractures (5.37% vs. 4.47%, HR: 1.24, 95% CI: 1.19-1.28) than the non-pioglitazone group ( = 174,549). In conclusion, using pioglitazone may reduce the risks of MACCE and dementia but increases the probability of bone fractures in the elderly DM population.
Topics: Aged; Humans; Pioglitazone; Diabetes Mellitus, Type 2; Cohort Studies; Hypoglycemic Agents; Cardiovascular Diseases; Dementia; Hypoglycemia; Fractures, Bone
PubMed: 37036483
DOI: 10.18632/aging.204643 -
Journal of the Egyptian National Cancer... Mar 2022Despite antitumor properties, chemotherapy medication can create conditions in tumor cells that work in favor of the tumor. Doxorubicin, commonly prescribed chemotherapy...
BACKGROUND
Despite antitumor properties, chemotherapy medication can create conditions in tumor cells that work in favor of the tumor. Doxorubicin, commonly prescribed chemotherapy agents, can increase the risk of migration and invasion of tumor cells through overexpression of the CXCR4 gene by affecting downstream signaling pathways. The regulatory role of CXCR7 on CXCR4 function has been demonstrated. Therefore, it is hypothesized that combining doxorubicin with another anticancer drug could be a promising approach.
METHODS
In this research, we evaluated the anti-invasive property of pioglitazone along with antitumor effects of doxorubicin on MDA-MB-231 breast cancer cell lines.
RESULTS
There was no significant difference between two treatment groups in neither the expression nor changes in the expression of CXCR7 and CXCR4 genes (P < 0.05). Pioglitazone-doxorubicin combination reduced cell migration in tumor cells to a significantly higher extent compared to doxorubicin alone (P < 0.05).
CONCLUSIONS
Co-administration of pioglitazone and doxorubicin might reduce cell migration in breast cancer tumor cells, and that cell migration function is independent of some specific proteins.
Topics: Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Female; Humans; Neoplasm Invasiveness; Pioglitazone
PubMed: 35342925
DOI: 10.1186/s43046-022-00110-x -
European Journal of Pharmaceutics and... Jul 2023There is a possibility of in-situ physicochemical interactions between concomitantly administered drugs. This study aimed to investigate such physicochemical...
There is a possibility of in-situ physicochemical interactions between concomitantly administered drugs. This study aimed to investigate such physicochemical interactions between pioglitazone and rifampicin. Pioglitazone exhibited significantly higher dissolution in the presence of rifampicin, while the dissolution of rifampicin remained unaffected. The solid-state characterization of precipitates recovered after pH-shift dissolution experiments revealed the conversion of pioglitazone into an amorphous form in the presence of rifampicin. The Density Function Theory (DFT) calculations showed the intermolecular hydrogen bonding between rifampicin and pioglitazone. In-situ conversion of pioglitazone in amorphous form and subsequent supersaturation of GIT milieu translated into significantly higher in-vivo exposure of pioglitazone and its metabolites (M-III and M-IV) in Wistar rats. Therefore, it is advisable to consider the possibility of physicochemical interactions between concomitantly administered drugs. Our findings may be beneficial in tailoring the dose of concomitantly administered drugs, particularly for chronic conditions that entail polypharmacy.
Topics: Rats; Animals; Pioglitazone; Rifampin; Rats, Wistar; Solubility
PubMed: 37172696
DOI: 10.1016/j.ejpb.2023.05.006 -
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 -
Molecular and Cellular Biochemistry Jul 2022The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our... (Review)
Review
The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our therapeutic strategies controlling psoriasis. Emerging evidence points to a causative relationship between altered activity of peroxisome proliferator-activated receptor γ (PPARγ) and psoriasis. The present review focuses on deeper understanding of the possible role of PPARγ in the pathogenesis of psoriasis and the potential of PPARγ agonist to improve the treatment of psoriasis. PPARγ is decreased in psoriasis. PPARγ possibly has effects on the multiple aspects of the pathogenesis of psoriasis, including abnormal lipid metabolism, insulin resistance, immune cells, pro-inflammatory cytokines, keratinocytes, angiogenesis, oxidative stress, microRNAs and nuclear factor kappa B. As defective activation of PPARγ is involved in psoriasis development, PPARγ agonists may be promising agents for treatment of psoriasis. Pioglitazone appears an effective and safe option in the treatment of patients with psoriasis, but there are still concerns about its potential side effects. Research effort has recently been undertaken to explore the PPARγ-activating potential of natural products. Among them some have been studied clinically or preclinically for treatment of psoriasis with promising results.
Topics: Humans; Hypoglycemic Agents; PPAR gamma; Pioglitazone; Psoriasis
PubMed: 35348980
DOI: 10.1007/s11010-022-04417-0