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Frontiers in Pharmacology 2023Biallelic variants in are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and...
Biallelic variants in are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich's ataxia. Recent studies in yeast indicated that the mitochondrial matrix protease Ste23, which is a homologue of the human insulin-degrading enzyme (IDE), cooperates with Cym1 (homologue of ) to ensure the proper functioning of the preprotein processing machinery. In humans, IDE could be upregulated by Peroxisome Proliferator-Activated Receptor Gamma (PPARG) agonists. We investigated preprotein processing, mitochondrial membrane potential and MTS degradation in control and patients' fibroblasts, and we evaluated the pharmacological effect of the PPARG agonist Pioglitazone on mitochondrial proteostasis. We discovered that PITRM1 dysfunction results in the accumulation of MTS, leading to the disruption and dissipation of the mitochondrial membrane potential. This triggers a feedback inhibition of MPP activity, consequently impairing the processing and maturation of Frataxin. Furthermore, we found that the pharmacological stimulation of PPARG by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.
PubMed: 37576821
DOI: 10.3389/fphar.2023.1220620 -
Hepatology Communications Sep 2022The incidence of nonalcoholic fatty liver disease (NAFLD) has recently increased and is related to obesity and the associated surge in type 2 diabetes mellitus (T2DM)... (Randomized Controlled Trial)
Randomized Controlled Trial
The incidence of nonalcoholic fatty liver disease (NAFLD) has recently increased and is related to obesity and the associated surge in type 2 diabetes mellitus (T2DM) and metabolic syndromes. This trial follows up on our previous work and forms part of the ToPiND study. We aimed to combine tofogliflozin and pioglitazone treatment for hepatic steatosis in patients with NAFLD and T2DM. In this open-label, prospective, single-center, randomized clinical trial, patients with NAFLD with T2DM and a hepatic fat fraction of ≥10% were assessed based on magnetic resonance imaging proton density fat fraction. Eligible patients received either 20 mg tofogliflozin or 15-30 mg pioglitazone orally, once daily for 24 weeks, followed by combination therapy with both medicines for an additional 24 weeks. The effects on diabetes mellitus and hepatic steatosis were examined at baseline and after the completion of monotherapy and combination therapy. Thirty-two eligible patients received the combination therapy of tofogliflozin and pioglitazone. The combination therapy showed additional improvement in glycated hemoglobin compared with each monotherapy group and showed improvement in steatosis, hepatic stiffness, and alanine aminotransferase levels compared with the tofogliflozin monotherapy group. Pioglitazone monotherapy-mediated increase in body weight decreased following concomitant use of tofogliflozin. The combination therapy resulted in lower triglyceride, higher high-density lipoprotein cholesterol, higher adiponectin, and higher ketone body levels. Conclusion: In addition to the additive effects of tofogliflozin and pioglitazone in patients with T2DM and NAFLD, combination therapy was suggested to reduce weight gain and induce cardioprotective effect. Further studies with more patients are needed to investigate the combination therapy of various drugs.
Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Glucosides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease; Pioglitazone; Prospective Studies
PubMed: 35578445
DOI: 10.1002/hep4.1993 -
BMJ Open Diabetes Research & Care Nov 2023Metabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent in type 2 diabetes (T2D). Pioglitazone and glucagon-like peptide-1 receptor agonists...
INTRODUCTION
Metabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent in type 2 diabetes (T2D). Pioglitazone and glucagon-like peptide-1 receptor agonists (GLP-1RA) are medications used in T2D that can resolve MASH and should be considered in all patients with T2D and MASH. We assessed prescription rates of evidence-based T2D pharmacotherapy (EBP) in MASH, and ascertained racial/ethnic disparities in prescribing.
RESEARCH DESIGN AND METHODS
We conducted a cross-sectional study on patients in Duke University Health System with diagnosis codes for T2D and MASH between January 2019 and January 2021. Only patients with ≥1 primary care or endocrinology encounter were included. The primary outcome was EBP, defined as ≥1 prescription for pioglitazone and/or a GLP-1RA during the study period. A multivariable logistic regression model was used to examine the primary outcome.
RESULTS
A total of 847 patients with T2D and MASH were identified; mean age was 59.7 (SD 12) years, 61.9% (n=524) were female, and 11.9% (n=101) and 4.6% (n=39) were of Black race and Latino/a/x ethnicity, respectively. EBP was prescribed in 34.8% (n=295). No significant differences were noted in the rates of EBP use across racial/ethnic groups (Latino/a/x vs White patients: adjusted OR (aOR) 1.82, 95% CI 0.78 to 4.28; Black vs White patients: aOR 0.76, 95% CI 0.44 to 1.33, p=0.20).
CONCLUSIONS
EBP prescriptions, especially pioglitazone, are low in patients with T2D and MASH, regardless of race/ethnicity. These data underscore the need for interventions to close the gap between current and evidence-based care.
Topics: Female; Humans; Male; Middle Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Ethnicity; Hispanic or Latino; Pioglitazone; Black or African American; White; Aged; Glucagon-Like Peptide-1 Receptor; Fatty Liver
PubMed: 38030391
DOI: 10.1136/bmjdrc-2023-003763 -
Molecular Genetics & Genomic Medicine Mar 2023Although pioglitazone, a well-known anti-diabetic agent, has recently established itself as a pillar of cancer treatment, its therapeutic value could be attenuated by...
BACKGROUND
Although pioglitazone, a well-known anti-diabetic agent, has recently established itself as a pillar of cancer treatment, its therapeutic value could be attenuated by the aberrant activation of the PI3K/Akt pathway.
AIM
To evaluate whether the PI3K/Akt suppression in leukemic cells could potentiate the anti-leukemic effects of pioglitazone.
METHODS
To assess the anti-leukemic effects of PI3K/Akt inhibitors on anti-leukemic effects of pioglitazone, we used MTT and trypan blue assays. Flow cytometric analysis and qRT-PCR were also applied to evaluate cell cycle and apoptosis.
RESULT
The resulting data revealed that upon PPARγ stimulation in different leukemic cell lines using pioglitazone, the survival and the proliferative capacity of the cells were significantly halted. Then, we evaluated the impact of the PI3K/Akt axis on the effectiveness of the drug in the most sensitive leukemic cell line; NB4 cells. Our results showed that treatment of NB4 cells with the PI3K inhibitors increased the sensitivity of leukemic cells to pioglitazone to the degree that even lower concentrations of the agent succeeded to induce apoptotic as well as the anti-proliferative effects. Moreover, it seems that PI3K inhibition could potentiate the anti-leukemic effect of pioglitazone through induction of p21-mediated sub-G1 cell cycle arrest and altering the balance between the pro-and anti-apoptotic genes.
CONCLUSION
This study sheds light on the significance of the PI3K/Akt pathway in APL cell sensitivity to pioglitazone and proposed that the presence of the PI3K inhibitor in the therapeutic regimen containing pioglitazone could be promising in the treatment of this malignancy.
Topics: Humans; Apoptosis; Leukemia, Promyelocytic, Acute; Phosphatidylinositol 3-Kinases; Pioglitazone; Proto-Oncogene Proteins c-akt; Protein Kinase Inhibitors
PubMed: 36398521
DOI: 10.1002/mgg3.2106 -
Biochemical and Biophysical Research... Aug 2023Iron-sulfur clusters play a central role in cellular function and are regulated by the ATM protein. Iron-sulfur clusters are part of the cellular sulfide pool, which...
BACKGROUND
Iron-sulfur clusters play a central role in cellular function and are regulated by the ATM protein. Iron-sulfur clusters are part of the cellular sulfide pool, which functions to maintain cardiovascular health, and consists of free hydrogen sulfide, iron-sulfur clusters, protein bound sulfides, which constitute the total cellular sulfide fraction. ATM protein signaling and the drug pioglitazone share some cellular effects, which led us to examine the effects of this drug on cellular iron-sulfur cluster formation. Additionally, as ATM functions in the cardiovasculature and its signaling may be diminished in cardiovascular disease, we examined pioglitazone in the same cell type, with and without ATM protein expression.
METHODS
We examined the effects of pioglitazone treatment on the total cellular sulfide profile, the glutathione redox state, cystathionine gamma-lyase enzymatic activity, and on double-stranded DNA break formation in cells with and without ATM protein expression.
RESULTS
Pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions and reduced cystathionine gamma-lyase enzymatic activity in cells with and without ATM protein expression. Interestingly, pioglitazone also increased reduced glutathione and lowered DNA damage in cells without ATM protein expression, but not in ATM wild-type cells. These results are interesting as the acid-labile (iron-sulfur cluster), bound sulfur cellular fractions, and reduced glutathione are low in cardiovascular disease.
CONCLUSION
Here we found that pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions, impinges on hydrogen sulfide synthesis, and exerts beneficial effect on cells with deficient ATM protein signaling. Thus, we show a novel pharmacologic action for pioglitazone.
Topics: Humans; Hydrogen Sulfide; Ataxia Telangiectasia Mutated Proteins; Pioglitazone; Cystathionine gamma-Lyase; Cardiovascular Diseases; Sulfides; Sulfur; Glutathione; Iron; Iron-Sulfur Proteins
PubMed: 37285721
DOI: 10.1016/j.bbrc.2023.05.118 -
Frontiers in Pharmacology 2022Metformin and pioglitazone monotherapy have been proven to alter gut microbiota in diabetes and obesity. The present study aimed to investigated whether the combined...
Metformin and pioglitazone monotherapy have been proven to alter gut microbiota in diabetes and obesity. The present study aimed to investigated whether the combined administration of pioglitazone and metformin achieved superior protective effects on high-fat diet (HFD)-fed obese mice and elucidated its molecular mechanism the gut microbiota and its metabolites. C57BL/6 males were randomly divided into five groups: the control group, fed a normal control diet; the HFD group, fed an HFD; the metformin monotherapy group, fed an HFD and treated with metformin; the pioglitazone monotherapy group, fed an HFD and treated with pioglitazone; and the combination therapy group, fed an HFD and treated with metformin and pioglitazone combination therapy. The cecal contents were collected for 16S rDNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the combination therapy of metformin and pioglitazone significantly improved insulin sensitivity and glucolipid metabolism in HFD-fed mice. Combination therapy markedly altered gut microbiota by increasing beneficial bacteria, such as Christensenellaceae and , and decreasing harmful bacteria, such as and . Fecal metabolites were significantly changed in the combination therapy group, including a reduction in amino acid metabolism and augmentation of lipid metabolism, such as citrulline, sarcosine, D-glutamine, lipoxin A4, prostaglandin E2, stearidonic acid and lucidenic acid A. These results revealed that combined metformin and pioglitazone therapy had synergistic effects or at least have an additive effect on modifying gut microbiota and metabolites, closely associated with improved glucolipid metabolic parameters in HFD-fed mice, which provides novel evidence and promising targets for metformin and pioglitazone combination therapy in type 2 diabetes.
PubMed: 36304148
DOI: 10.3389/fphar.2022.1004617 -
Antioxidants (Basel, Switzerland) Jul 2020Parkinson's disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra... (Review)
Review
Parkinson's disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra (SN). Studies have suggested the potential involvement of dopamine, iron, calcium, mitochondria and neuroinflammation in contributing to overwhelmed oxidative stress and neurodegeneration in PD. Function studies on PD-causative mutations of , , , , , and further indicate the role of oxidative stress in the pathogenesis of PD. Therefore, it is reasonable that molecules involved in oxidative stress, such as DJ-1, coenzyme Q10, uric acid, 8-hydroxy-2'-deoxyguanosin, homocysteine, retinoic acid/carotenes, vitamin E, glutathione peroxidase, superoxide dismutase, xanthine oxidase and products of lipid peroxidation, could be candidate biomarkers for PD. Applications of antioxidants to modulate oxidative stress could be a strategy in treating PD. Although a number of antioxidants, such as creatine, vitamin E, coenzyme Q10, pioglitazone, melatonin and desferrioxamine, have been tested in clinical trials, none of them have demonstrated conclusive evidence to ameliorate the neurodegeneration in PD patients. Difficulties in clinical studies may be caused by the long-standing progression of neurodegeneration, lack of biomarkers for premotor stage of PD and inadequate drug delivery across blood-brain barrier. Solutions for these challenges will be warranted for future studies with novel antioxidative treatment in PD patients.
PubMed: 32650609
DOI: 10.3390/antiox9070597 -
Pathogens and Global Health Oct 2023This study examines the effects of three different drugs with metformin, acarbose and pioglitazone active ingredients used for antidiabetic purposes on cysts and...
This study examines the effects of three different drugs with metformin, acarbose and pioglitazone active ingredients used for antidiabetic purposes on cysts and trophozoites. Cultures of trophozoites and cysts were prepared to test the anti-amoebic activity of metformin, acarbose and pioglitazone. Cultures were then prepared for cyst and trophozoite forms and parasites were exposed to different concentrations (0.750 mg/mL, 0.375 mg/mL, 0.186 mg/mL and 0.093 mg/mL) of metformin, acarbose and pioglitazone. As a result of the study, the reproductive potential suppressive effects and conversion from trophozoite form to cyst form of all three substances on trophozoites and cysts were determined. Parasites were counted at 12, 24 and 48 hours in the cell counter after staining with trypan blue. In comparison of the effects of metformin, acarbose and pioglitazone used in the study on trophozoites and cysts, it was observed that all three substances were statistically effective against cysts and trophozoites at a concentration of 0.750 mg/mL. Furthermore, it was determined that all concentrations of the three active substances included in the study significantly decreased the rate of cyst formation even at the end of the 7th day. In this context, it was determined that all three substances have amebicidal effects, and they significantly inhibit the transformation of trophozoites to cyst form. It is thought that these active substances, which are currently used as anti-diabetic, can be used in combination with other drugs in infections based on our study findings.
Topics: Animals; Trophozoites; Acanthamoeba castellanii; Hypoglycemic Agents; Acarbose; Pioglitazone; Metformin
PubMed: 36436006
DOI: 10.1080/20477724.2022.2151859 -
Scientific Reports Apr 2021Exposed rats to normal saline and paraquat (PQ) aerosol as control and PQ group, rats exposed to PQ and treated with 20 and 80 mg/kg/day carvacrol, 5 and 10 mg/kg/day... (Comparative Study)
Comparative Study
Exposed rats to normal saline and paraquat (PQ) aerosol as control and PQ group, rats exposed to PQ and treated with 20 and 80 mg/kg/day carvacrol, 5 and 10 mg/kg/day pioglitazone, low dose of pioglitazone + carvacrol and 0.03 mg/kg/day dexamethasone (Dexa) for 16 days after the end of PQ exposure were studied (n = 6 in each group). Lung pathological changes, tracheal responsiveness to methacholine and ovalbumin (OVA) as well as transforming growth factor beta (TGF-β) and interleukin (IL)-6 level in the lung tissue homogenize as well as TGF-β, IL-6, oxidant and antioxidant levels oxidant and antioxidants were increased in PQ group (p < 0.01 to p < 0.001). Lung pathological changes, tracheal responsiveness to methacholine and OVA as well as TGF-β, IL-6 oxidant and antioxidant levels were improved in all treated groups except lung pathological changes in treated group with low dose of pioglitazone (p < 0.05 to p < 0.001). The effects of low dose of pioglitazone and carvacrol alone were significantly lower than in the combination group of low dose of pioglitazone + carvacrol (p < 0.05 to p < 0.001). Carvacrol treatment improved inhaled PQ-induced lug injury similar to the effects of dexamethasone. The synergic effect of carvacrol and pioglitazone suggests PPAR-γ receptor mediated effects of carvacrol on inhaled PQ-induced lung injury.
Topics: Animals; Case-Control Studies; Cymenes; Dexamethasone; Disease Models, Animal; Drug Synergism; Gene Expression Regulation; Interleukin-6; Lung Injury; Male; Oxidative Stress; Paraquat; Pioglitazone; Rats; Rats, Wistar; Transforming Growth Factor beta; Treatment Outcome
PubMed: 33854134
DOI: 10.1038/s41598-021-87546-8 -
Saudi Journal of Gastroenterology :... May 2024Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe...
BACKGROUND
Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe MASLD can demonstrate a more aggressive disease phenotype as they more commonly develop liver fibrosis than BMI matched adults. Therefore, MASLD is the fastest growing indication for liver transplants in young adults.
METHODS
Pioglitazone has been shown to improve liver histology in adult patients with MASLD, and in some studies, it attenuated liver fibrosis. Despite its perceived efficacy, pioglitazone is not widely used, likely due to its side effect profile, specifically increased weight gain. Topiramate lowers body weight in adolescents and in combination with phentermine, is one of the few FDA-approved medications for the management of obesity in children over 12 years of age. We performed a retrospective review of the outcomes in pediatric patients with severe MASLD, treated with the combined pioglitazone and topiramate therapy.
RESULTS
Here, we report a case series of seven adolescents with severe MASLD and ≥F2 liver fibrosis treated with the combined pioglitazone and topiramate therapy. The combined therapy improved mean serum ALT from 165 ± 80 U/L to 89 ± 62 U/L after 12 months mean duration of treatment. One patient who completed 24 months of the combined therapy demonstrated a decrease in liver stiffness from 8.9 kPa to 5.6 kPa, as assessed by FibroScan elastography. There was a significant increase in body weight during this time, however, body mass index as a percentage of the 95th percentile adjusted for age and gender did not increase significantly, 151 ± 29% vs. 152 ± 28%. Moreover, waist circumference, mid-upper arm circumference, percent body fat, and muscle mass were not significantly different before and after treatment. Serum lipid levels and hemoglobin A1c also did not change with the treatment.
CONCLUSION
In summary, this case series provides encouraging results about the efficacy of the combined pioglitazone and topiramate therapy for the management of adolescents with severe MASLD, which should be further explored in clinical studies.
PubMed: 38726916
DOI: 10.4103/sjg.sjg_428_23