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1.
Drug Des Devel Ther ; 16: 2919-2931, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36068789

RESUMO

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is known to have anti-inflammatory and anti-oxidant effects on the brain, and its clinical potential in the treatment of cognitive impairment in diseases such as Alzheimer's disease (AD) and Parkinson disease (PD) is currently being explored. This review focused on the reported beneficial effects of pioglitazone on cognitive dysfunction and summarized the associated mechanisms associated with pioglitazone-induced improvement in cognitive dysfunction. Our review of the relevant literature indicated that there is conclusive evidence of the effect of pioglitazone on improving cognitive impairment via its agonistic effect on PPAR-γ. Further, several mechanisms of action have been reported, and these include enhanced NF-kB and p38 activity; regulation of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α; inhibition of Aß production; alterations in the levels of mitochondrial proteins such as mitoNEET; regulation of protein kinases such as CDK5 and JNK; regulation of ROS and MDA levels and the levels of the antioxidant proteins TRX1 and PON2; and increased expression of thyroid hormone receptors. Despite these promising findings, pioglitazone treatment is also associated with cardiovascular risks, such as weight gain and edema, which subsequently increase the risk of mortality. Further, it has been documented that pioglitazone may be unable to cross the blood-brain barrier when administered in certain forms, and it can also cause cell death when administered at high concentrations. Therefore, further research is required to explore the effects of acute and chronic pioglitazone treatment on memory function and the associated risks, in order to determine its clinical applicability in the treatment of cognitive disorders. Nonetheless, the current literature does demonstrate that pioglitazone promotes the function of PPAR receptors in ameliorating inflammation, oxidative stress, amyloidogenesis, and hypothyroidism, and enhancing neurogenesis, synaptic plasticity, and mitochondrial function. Therefore, these mechanisms of PPAR receptors warrant further investigation in order to establish the clinical applicability of pioglitazone in the treatment of cognitive disorders, such as PD and AD, and neuronal impairment in conditions such as diabetes.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Parkinson , Tiazolidinedionas , Doença de Alzheimer/tratamento farmacológico , Antioxidantes/uso terapêutico , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , PPAR gama/metabolismo , Doença de Parkinson/tratamento farmacológico , Pioglitazona , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
2.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S292, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36163919

RESUMO

CONTEXT: In CML, BCR-ABL1 oncoprotein induces overexpression of STAT5 and its target genes for example CITED2 gene. This gene is involved in regulating the proliferation and quiescence states of leukemic stem cells (LSCs). Recently, studies reported that adding pioglitazone (PPARγ agonist approved for T2DM treatment) to imatinib may decrease the transcription of both STAT5 and CITED2 gene, eliminate the quiescent LSCs (resist TKIs), and ameliorate the patients' response. OBJECTIVES: The primary objective is to clarify the value of combining pioglitazone with imatinib to downregulate the CITED2 gene aiming to eradicate the LSCs in CML treatment. DESIGN: In the context of a clinical trial (approved by the Ethical Committee of the Faculty of Medicine Mansoura University), the study group patients (N=26) were treated with combination therapy after having their consent. The planned follow-up time is 2 years. SETTING: Hematology unit, Oncology Center, Mansoura University. PATIENTS OR OTHER PARTICIPANTS: The eligibility criteria for study group patients were de novo, Philadelphia+ve CML (chronic phase) aged 18-60 years old. INTERVENTIONS: Those patients were treated with imatinib 400 mg and pioglitazone 15 mg once daily for 6 months. Pre- and post-treatment samples (after 6 months) were collected to assess the expression levels of the CITED2 gene. Responders continued on the same TKI and their sequential BCR/ABL Q-PCR was monitored. MAIN OUTCOME MEASURES: The study proposed that this combination therapy can put more patients into deeper and faster molecular response via eliminating the LSCs. RESULTS: The study group included 15 males (57.7%) and 11 females (42.3%) with a mean age of 43.2 years. The BCR-ABL and CITED2 genes' pretreatment expression levels decreased significantly after 6 months of combined treatment (p<0.001 and p=0.005, respectively). Moreover, at 6 months 65.4% and 23% of the patients had response ≥ CCyR and ≥ MMR respectively. The most frequent complaints among patients were increased body weight and edema (p<0.001). CONCLUSIONS: Adding pioglitazone to imatinib improved the patients' response and downregulate the overexpressed CITED2 gene. A longer follow-up is planned and needed to confirm the safety and efficacy of the combination.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Expressão Gênica , Humanos , Mesilato de Imatinib/efeitos adversos , Cinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , PPAR gama/genética , PPAR gama/metabolismo , PPAR gama/uso terapêutico , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/uso terapêutico , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transativadores/genética , Transativadores/metabolismo , Transativadores/uso terapêutico , Adulto Jovem
3.
Nat Commun ; 13(1): 5461, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115863

RESUMO

Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.


Assuntos
Estenose da Valva Aórtica , Calcinose , Hiperlipidemias , Animais , Valva Aórtica/metabolismo , Calcinose/genética , Células Cultivadas , Células Endoteliais/metabolismo , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Imunomodulação , Inflamação/genética , Inflamação/metabolismo , Lipoproteínas LDL/metabolismo , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Pioglitazona/farmacologia , Transcriptoma
4.
Front Endocrinol (Lausanne) ; 13: 955593, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120427

RESUMO

Pioglitazone, a PPARγ agonist, is used to treat type 2 diabetes (T2D). PPARγ is highly expressed in adipose tissue (AT), however the effects of pioglitazone to improve insulin sensitivity are also evident in other tissues and PPARγ agonism has been shown to alter cancer derived extracellular vesicle (EV)-miRNAs. We hypothesized that pioglitazone modifies the cargo of circulating AT-derived EVs to alter interorgan crosstalk in people with diabetes. We tested our hypothesis in a 3-month trial in which 24 subjects with T2D were randomized to treatment with either pioglitazone 45 mg/day or placebo (NCT00656864). Levels of 42 adipocyte-derived EV-miRNAs were measured in plasma EVs using low density TaqMan arrays. Levels of differentially expressed EV-miRNAs and their most relevant target genes were also measure in adipose tissue from the same participants, using individual TaqMan assays. Levels of 5 miRNAs (i.e., miR-7-5p, miR-20a-5p, miR-92a-3p, miR-195-5p, and miR-374b-5p) were significantly downregulated in EVs in response to pioglitazone treatment relative to placebo. The opposite occurred for miR-195-5p in subcutaneous AT. Changes in miRNA expression in EVs and AT correlated with changes in suppression of lipolysis and improved insulin sensitivity, among others. DICER was downregulated and exosomal miRNA sorting-related genes YBX1 and hnRNPA2B1 displayed a downregulation trend in AT. Furthermore, analysis of EV-miRNA targeted genes identified a network of transcripts that changed in a coordinated manner in AT. Collectively, our results suggest that some beneficial pharmacologic effects of pioglitazone are mediated by adipose-specific miRNA regulation and exosomal/EV trafficking. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00656864.


Assuntos
Diabetes Mellitus Tipo 2 , Vesículas Extracelulares , Resistência à Insulina , MicroRNAs , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Pioglitazona/metabolismo
5.
Biomed Res Int ; 2022: 1480345, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36124070

RESUMO

In order to achieve a sufficient population of cardiac-committed progenitor cells, it is crucial to know the mechanisms of cardiac progenitor formation. Previous studies suggested ROS effect on cardiac commitment events to play a key role in the cell signaling and activate cardiac differentiation of pluripotent stem cells. We previously reported that PPARγ activity is essential for cardiac progenitor cell commitment. Although several studies have conducted the involvement of PPARγ-related signaling pathways in cardiac differentiation, so far, the regulatory mechanisms of these signaling pathways have not been discussed and cleared. In this study, we focus on the role of PPARγ agonist in ROS generation and its further effects on the differentiation of cardiac cells from mESCs. The results of this study show that the presence of ROS is necessary for heart differentiation in the precursor stage of cardiac cells, and the coenzyme Q10 antioxidant precludes proper cardiac differentiation. In addition, this antioxidant prevents the action of pioglitazone in increasing oxygen radicals as well as beating cardiomyocyte differentiation properties. In this case, it can be concluded that PPARγ is required to modulate ROS levels during cardiac differentiation.


Assuntos
Miócitos Cardíacos , PPAR gama , Antioxidantes/metabolismo , Miócitos Cardíacos/metabolismo , PPAR gama/metabolismo , Pioglitazona/metabolismo , Pioglitazona/farmacologia , Espécies Reativas de Oxigênio/metabolismo
6.
Front Cell Infect Microbiol ; 12: 884237, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909958

RESUMO

Patients with cutaneous leishmaniasis (CL) due to Leishmania braziliensis infection have an exacerbated inflammatory response associated with tissue damage and ulcer development. An increase in the rate of patients who fail therapy with pentavalent antimony has been documented. An adjuvant therapy with an anti-inflammatory drug with the potential of Leishmania killing would benefit CL patients. The aim of the present study was to investigate the contribution of peroxisome proliferator-activated receptor-γ (PPAR-γ) activation by pioglitazone in the regulation of the inflammatory response and L. braziliensis killing by monocytes. Pioglitazone is an oral drug used in the treatment of diabetes, and its main mechanism of action is through the activation of PPAR-γ, which is expressed in many cell types of the immune response. We found that activation of PPAR-γ by pioglitazone decreases the inflammatory response in CL patients without affecting L. braziliensis killing by monocytes. Our data suggest that pioglitazone may serve as an adjunctive treatment for CL caused by L. braziliensis.


Assuntos
Leishmania braziliensis , Leishmaniose Cutânea , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Monócitos , PPAR gama/uso terapêutico , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico
7.
Sci Rep ; 12(1): 13595, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35948569

RESUMO

The α-glucosidase inhibitor (α-GI) delays the intestinal absorption of glucose, which reduces postprandial hepatic glucose intake. This mechanism is considered to be effective in treating non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of voglibose, an α-glucosidase inhibitor, on high-fat, high-fructose (HFHFr) diet-induced NAFLD models. Seven-week-old male C57BL/6J mice were randomly placed in a chow diet group or an HFHFr diet group. After 10 weeks, mice in the HFHFr group were randomly assigned to one of three groups: HFHFr diet with vehicle, HFHFr with voglibose, or HFHFr with pioglitazone. Each diet and treatment was continued for 10 weeks. The HFHFr diet induced severe NAFLD in terms of steatosis, hepatitis, and fibrosis. Administration of voglibose improved all aspects of NAFLD, comparable to those of pioglitazone, a positive control. In voglibose-treated mice, gene expressions of hepatic lipogenesis markers were significantly downregulated. In the in vitro experiment, reducing the influx of glucose into hepatocytes significantly reduced steatosis and de novo lipogenesis even in the presence of sufficient fructose and fat, demonstrating that the mechanism of voglibose could be effective in treating HFHFr diet-induced NAFLD. These results indicate that voglibose improves HFHFr diet-induced NAFLD by suppressing hepatic de novo lipogenesis.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Frutose/metabolismo , Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Inositol/análogos & derivados , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pioglitazona/metabolismo , Pioglitazona/farmacologia
8.
Int J Biol Macromol ; 219: 779-787, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-35940433

RESUMO

Long noncoding RNAs (lncRNAs) as regulatory molecules play important roles in early treatment and diagnosis of cancers. Considering the role of PPARγ in colorectal cancer (CRC) as a tumor suppressor, the GEO database was used to identify candidate genes that affect the activation of PPARγ protein in CRC cell lines. Then were selected 5 genes containing PPARγ response element (PPRE) in up to 4000 bp upstream and were affected by PPARγ protein activation in HT-29 colon cancer cell line using UCSC database. Expression meta-analysis was applied to map the expression network between candidate genes and all known lncRNAs through expression correlation and lncRNAs that correlated with a greater number of candidate genes (R > 0.5, P.value < 0.001). Moreover, were selected 3 lncRNAs as lncRNAs affected by PPARγ protein activation. Next, the expression levels of candidate genes and lncRNAs were evaluated using RT-qPCR in HT-29 cell line. Results showed a significant increase (FDR <0.05) in the expression level of 5 candidate genes and lncRNAs LINC01133, MBNL1-AS, LOC100288911 after treatment with pioglitazone as PPARγ ligand compared to the untreated group in HT-29 cells. Although additional tests are needed to confirm bioinformatics predictions, it can be concluded that increased expression of PPARγ may increase genes and lncRNAs expression. In summary, this study could be suggested identifying lncRNAs affected by PPARγ activation could be a new strategy in understanding the function and activity of PPARγ in colon cancer.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , RNA Longo não Codificante , Neoplasias do Colo/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , PPAR gama/genética , PPAR gama/metabolismo , Pioglitazona , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
9.
Eur J Neurosci ; 56(6): 4948-4961, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35945686

RESUMO

Diabetes can cause vascular remodelling and is associated with worse outcome after ischaemic stroke. Pioglitazone is a commonly used anti-diabetic agent. However, it is not known whether pioglitazone use before ischaemia could reduce brain ischaemic injury. Pioglitazone was administered to 5-week-old db+ or db/db mice. Cerebral vascular remodelling was examined at the age of 9 weeks. Expression of peroxisome proliferator-activated receptor-γ (PPARγ), p-PPARγ (S112 and S273), nucleotide-binding domain (NOD)-like receptor protein 3 (Nlrp3), interleukin-1ß (IL-1ß) and tumour necrosis factor-α (TNF-α) was evaluated in the somatosensory cortex of mice. Neurological outcome was evaluated 24 h after brain ischaemia. Results showed that early pioglitazone treatment provided a long-lasting effect of euglycaemia but enhanced hyperlipidaemia in the db/db mice. Diabetic mice exhibited increased vascular tortuosity, narrower middle cerebral artery (MCA) width and IgG leakage in the brain. These changes were blocked by early pioglitazone treatment. In diabetic animals, PPARγ expression was reduced, and p-PPARγ at S273 but not S112, Nlrp3, IL-1ß and TNF-α were increased in the somatosensory cortex. PPARγ decrease and Nlrp3 increase were mainly in the neurons of the diabetic brain, which was reversed by early pioglitazone treatment. Pioglitazone attenuated the aggravated neurological outcome after stroke in diabetic mice. But this protective effect was abolished through restoring cerebral inflammation by intracerebroventricular administration of IL-1ß and TNF-α in pioglitazone-treated diabetic mice before MCAO. In summary, early pioglitazone treatment attenuates cerebral vascular remodelling and ischaemic brain injury possibly via blocking chronic neuroinflammation in the db/db mice.


Assuntos
Isquemia Encefálica , Diabetes Mellitus Experimental , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Inflamação/complicações , Inflamação/tratamento farmacológico , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , PPAR gama/metabolismo , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Acidente Vascular Cerebral/complicações , Fator de Necrose Tumoral alfa , Remodelação Vascular
10.
J Immunol Res ; 2022: 2651790, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36033393

RESUMO

Diabetes and cancer are common diseases and are frequently diagnosed in the same individual. These patients need to take antidiabetic drugs while receiving antitumor drugs therapy. Recently, immunotherapy offers significant advances for cancer treatment. However, it is unclear whether antidiabetic drugs affect immunotherapy. Here, by employing syngeneic mouse colon cancer model and melanoma model, we studied the effects of 6 common antidiabetic drugs on anti-PD1 immune checkpoint inhibitor in tumor treatment, including acarbose, sitagliptin, metformin, glimepiride, pioglitazone, and insulin. We found that acarbose and sitagliptin enhanced the tumor inhibition of anti-PD1, and metformin had no effect on the tumor inhibition of anti-PD1, whereas glimepiride, pioglitazone, and insulin weakened the tumor inhibition of anti-PD1. Our study suggests that cancer patients receiving anti-PD1 antibody therapy need serious consideration when choosing antidiabetic drugs. In particular, acarbose significantly inhibited tumor growth and further enhanced the therapeutic effect of anti-PD1, which can be widely used in tumor therapy. Based on this study, further clinical trials are expected.


Assuntos
Melanoma , Metformina , Acarbose , Animais , Hipoglicemiantes , Inibidores de Checkpoint Imunológico , Insulina , Camundongos , Pioglitazona , Fosfato de Sitagliptina
11.
Neuroscience ; 500: 52-62, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35934252

RESUMO

Overactivated microglia in the spinal cord leads to neuropathic pain sensitivity. The FGF 10, a Fibroblast Growth Factor (FGFs) that is prevalent in neurons, has been demonstrated to suppress microglial polarization. The objective of this study was to investigate the role of FGF 10 in neuropathic pain and the underlying regulatory mechanisms. Immunofluorescence staining and western blot detection revealed that FGF 10 expression was upregulated in the ipsilateral spinal dorsal horn of Spared Nerve Injury (SNI) rat models and was mainly detected in neurons and microglia. To test the anti-microgliosis actions of FGF 10, SNI rats were intrathecally administered with different concentrations of recombinant FGF 10. Behavioral tests and immunostaining results showed that FGF 10 relieved hyperalgesia in SNI rats and inhibited microglial activity in the ipsilateral spinal dorsal horn in a dose-dependent manner. Besides, BV2 cells were cultured and treated with LPS to activate microglia to explore the underlying mechanisms of FGF 10-induced analgesic effects in vitro. As a result, FGF 10 administration suppressed the LPS-induced microglial augmentation in a dose-dependent manner, followed by increased PPAR-γ and decreased NFκB phosphorylation (p-NFκB) levels. Moreover, PPAR-γ agonist (pioglitazone) and antagonist (GW9662) were administrated into spinal cords of SNI rats, revealing that pioglitazone had similar anti-nociceptive and anti-microglial effects to FGF 10. Conversely, GW9662 reversed all beneficial effects of FGF 10 on SNI rats. In addition, phosphorylated levels of NFκB were reduced by pioglitazone or FGF 10 treatment but raised by GW9662 administration in FGF 10-treated SNI rats. Our findings show that FGF 10 has analgesic effects in rats after peripheral nerve injury and justify the role of PPAR-γ/NFκB signaling in FGF 10-regulated anti-microgliosis.


Assuntos
NF-kappa B , Neuralgia , Analgésicos/farmacologia , Animais , Fator 10 de Crescimento de Fibroblastos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , PPAR gama/metabolismo , Pioglitazona/metabolismo , Pioglitazona/farmacologia , Ratos , Medula Espinal/metabolismo
13.
Orv Hetil ; 163(22): 855-862, 2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35895614

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. Non-alcoholic steatohepatitis (NASH), the aggressive form of NAFLD can progress to cirrhosis, and is becoming the leading cause of end-stage liver disease. NAFLD and NASH are prevalent in obese individuals and frequently coexist with type 2 diabetes mellitus as well as cardiovascular and renal complications. There is no approved therapy for the treatment of NAFLD and NASH. Their current management focuses on controlling risk factors, and lifestyle modification, weight reduction, caloric restriction, diet and exercise, but these can be difficult to achieve and maintain. Thus, there is an urgent need for effective pharmacotherapy. This review summarizes pharmacological agents available to treat diabetes mellitus, the main risk factor of NAFLD, drugs that could potentially be useful also for the therapy of NASH. Furthermore, we describe novel therapies targeting different pathogenic pathways of NAFLD, several agents that are under development specifically for the treatment of NASH. These new classes of medications may target hepatic fat accumulation, de novo lipogenesis, farnesoid X receptor-bile acid axis, oxidative stress, inflammation, gut microbiome and fibrogenesis. Until now, the use of pioglitazone and vitamin E has only been recommended by guidelines for selected patient groups with biopsy-proven NASH. It is likely that in the future, the combination of different types of targeted pharmacotherapies will provide an effective treatment for NASH. Since NAFLD is a systemic metabolic disease, cooperation between diabetologists, nephrologists, cardiologists and hepatologists is also highly advised in the management of these patients. Orv Hetil. 2022; 163(22): 855-862.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pioglitazona/uso terapêutico
14.
Physiol Rep ; 10(14): e15357, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35851836

RESUMO

Ob/ob mice have recently emerged as a model for obesity-related hyperoxaluria as they are obese and excrete more urine oxalate compared to wild type mice. Ob/ob mice are deficient of leptin and develop obesity with hyperphagia and hyperinsulinemia. We hypothesized that insulin resistance and the gut microbiome contribute to hyperoxaluria in ob/ob mice. We developed a new liquid chromatography-mass spectrometry assay for urine oxalate and first compared urine oxalate excretion in ob/ob mice before and after ablation of intestinal bacteria with a standard antibiotic cocktail. We then compared urine oxalate excretion in ob/ob mice before and after leptin replacement or pioglitazone treatment, two maneuvers that reduce insulin resistance in ob/ob mice. Ob/ob mice excreted more oxalate into the urine in a 24-h period compared to wild type mice, but antibiotic, leptin, or pioglitazone treatment did not change urine oxalate excretion in ob/ob mice. Unexpectedly, we found that when food intake was carefully matched between ob/ob and wild type mice, the amount of 24-h urine oxalate excretion did not differ between the two mouse strains, suggesting that ob/ob mice excrete more urine oxalate because of hyperphagia. Since the level of urine oxalate excretion in wild type mice in our study was higher than those reported in prior studies, future work will be needed to standardize the measurement of urine oxalate and to define the range of urine oxalate excretion in wild type mice so that accurate and valid comparisons can be made between wild type mice and ob/ob mice or other mouse models.


Assuntos
Microbioma Gastrointestinal , Hiperoxalúria , Resistência à Insulina , Oxalatos , Animais , Antibacterianos/farmacologia , Hiperoxalúria/etiologia , Hiperoxalúria/urina , Hiperfagia/urina , Leptina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Obesos , Obesidade/microbiologia , Obesidade/urina , Oxalatos/urina , Pioglitazona/farmacologia
15.
J Stroke Cerebrovasc Dis ; 31(9): 106667, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35901589

RESUMO

BACKGROUND: Central adjudication of outcome events is the standard in clinical trial research. We examine the benefit of central adjudication in the Insulin Resistance Intervention after Stroke (IRIS) trial and show how the benefit is influenced by outcome definition and features of the adjudicated events. METHODS: IRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke. We compared the hazard ratios for study outcomes classified by site and central adjudication. We repeated the analysis for an updated stroke definition. RESULTS: The hazard ratios for the primary outcome were identical (0.76) and statistically significant regardless of adjudicator. The hazard ratios for stroke alone were nearly identical with site and central adjudication, but only reached significance with site adjudication (HR, 0.80; p = 0.049 vs. HR, 0.82; p = 0.09). Using the updated stroke definition, all hazard ratios were lower than with the original IRIS definition and statistically significant regardless of adjudication method. Agreement was higher when stroke type was certain, subtype was large vessel or cardioembolic, signs or symptoms lasted > 24 h, imaging showed a stroke, and when NIHSS was ≥3. DISCUSSION: Central stroke adjudication caused the hazard ratio for a main secondary outcome in IRIS (stroke alone) to be higher and lose statistical significant compared with site review. The estimate of treatment effects were larger with the updated stroke definition. There may be benefit of central adjudication for events with specific features, such as shorter symptom duration or normal brain imaging.


Assuntos
Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Método Duplo-Cego , Humanos , Hipoglicemiantes/uso terapêutico , Ataque Isquêmico Transitório/diagnóstico , Pioglitazona , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento
16.
Indian J Pharmacol ; 54(3): 194-197, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35848690

RESUMO

BACKGROUND: These days, poly pharmacy is very common for the treatment of multiple diseases and majority of drugs were metabolized with CYP 450 enzymes. Diabetes mellitus is such a disorder, which requires continuous therapy for the control of blood glucose concentration. Depression was quite common in diabetic patients. Therefore, multiple drugs required to treat diabetes mellitus and depression. Simultaneous administration of these drugs leads to drug interaction. Pioglitazone and trazodone metabolized by CYP3A4 enzymes which may lead to potential drug interaction. OBJECTIVES: This study aimed to find the influence of trazodone on the pharmacokinetics & pharmacodynamics of pioglitazone in normal & diabetic rats, also on rabbits and subsequently effectiveness and safety of the combination was evaluated. METHODS AND MATERIAL: Blood glucose concentration was determined by Glucose oxidase/peroxidase method in normal and diabetic rats. Diabetes was induced with Streptozotocin at a dose of 55 mg/kg body weight. Serum pioglitazone concentration was estimated by high performance liquid chromatography method for pharmacokinetic data. The values were expressed as Mean ± Standard Error Mean (SEM), GraphPad Prism 3.0 (San Diego, California, USA) software was used to express the data. Student's paired 't' test was used to determine the significance. RESULTS: Pioglitazone produces hypoglycaemia in normal rats with a maximum decrease of 36.78 % ± 0.81 at 3 hours interval and anti-hyperglycaemic activity in diabetic rats with maximum reduction of 45.13 % ± 1.52 at 2 hours interval. Trazodone altered the pharmacokinetics of pioglitazone and improved the pioglitazone hypoglycaemic effect. CONCLUSION: Trazodone apparently produced pharmacokinetic interaction with pioglitazone which might be by attenuating the metabolism of pioglitazone. Therefore, care should be taken in simultaneous therapy with pioglitazone and trazodone.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Tiazolidinedionas , Trazodona , Animais , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Coelhos , Ratos , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Trazodona/farmacocinética , Trazodona/uso terapêutico
17.
BMC Complement Med Ther ; 22(1): 176, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35778706

RESUMO

BACKGROUND: Luteolin, a flavonoid compound with anti-inflammatory activity, has been reported to alleviate cerebral ischemia/reperfusion (I/R) injury. However, its potential mechanism remains unclear. METHODS: The binding activity of luteolin to peroxisome proliferator-activated receptor gamma (PPARγ) was calculated via molecular docking analysis. Rats were subjected to middle cerebral artery occlusion and reperfusion (MCAO/R). After reperfusion, vehicle, 25 mg/kg/d luteolin, 50 mg/kg/d luteolin, 10 mg/kg/d pioglitazone, 50 mg/kg/d luteolin combined with 10 mg/kg/d T0070907 (PPARγ inhibitor) were immediately orally treatment for 7 days. ELISA, TTC staining, H&E staining, immunohistochemistry, immunofluorescence and transmission electron microscope methods were performed to evaluate the inflammation and autophagy in damaged hippocampal region. The PPARγ, light chain 3 (LC3) B-II/LC3B-I and p-nuclear factor-κB (NF-κB) p65 proteins expression levels in damaged hippocampal region were analyzed. RESULTS: Luteolin showed good PPARγ activity according to docking score (score = - 8.2). Luteolin treatment downregulated the infarct area and the pro-inflammatory cytokines levels caused by MCAO/R injury. Moreover, luteolin administration ameliorated neuroinflammation and autophagy in damaged hippocampal region. Pioglitazone plays protective roles similar to luteolin. T0070907 concealed the neuroprotective roles of 50 mg/kg/d luteolin. CONCLUSIONS: Luteolin exerts neuroprotective roles against inflammation and autophagy of hippocampus induced by cerebral I/R by activating PPARγ in rats.


Assuntos
Isquemia Encefálica , Luteolina , Traumatismo por Reperfusão , Animais , Autofagia/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Luteolina/farmacologia , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Pioglitazona/farmacologia , Ratos , Reperfusão , Traumatismo por Reperfusão/tratamento farmacológico
18.
Hepatol Commun ; 6(10): 2623-2633, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35903833

RESUMO

Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease that is associated with a spectrum of liver fibrosis and can lead to cirrhosis. Patients with NASH report lower health-related quality of life (HRQoL) than the general population. It remains uncertain how changes in histologic severity are associated with changes in HRQoL. This is a secondary analysis of the Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) and Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis (PIVENS) randomized controlled trials in patients with biopsy-proven NASH. HRQoL was assessed using short form-36 at baseline and at follow-up biopsy (at 72 and 96 weeks, respectively). Adjusted linear regression models were used to examine the association between changes in liver fibrosis (primary analysis), nonalcoholic fatty liver disease (NAFLD) activity score (secondary analysis), and changes in HRQoL scores. Compared with stable fibrosis, improvement of fibrosis by at least one stage was significantly associated with improvements only in the physical function component by 1.8 points (95% confidence interval, 0.1, 3.5). Worsening of fibrosis by at least one stage was not associated with statistically significant changes in any HRQoL domain compared with stable fibrosis. Associations between HRQoL and NAFLD disease activity score in the secondary analysis were of similar magnitude. Weight loss was associated with small improvements in physical function, general health, and energy levels. Conclusion: Improvements in fibrosis stage were associated with improvements in the physical component of HRQoL, but the clinical impact was modest. As improving fibrosis may not meaningfully improve well-being, treatment for NASH will be cost effective only if it prevents long-term hepatic and cardiovascular disease.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Fibrose , Humanos , Ligantes , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Pioglitazona/uso terapêutico , Qualidade de Vida , Vitamina E/uso terapêutico
19.
Diabetologia ; 65(10): 1587-1600, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35908083

RESUMO

Postprandial hyperlipidaemia is an important feature of diabetic dyslipidaemia and plays an important role in the development of cardiovascular disease in individuals with type 2 diabetes. Postprandial hyperlipidaemia in type 2 diabetes is secondary to increased chylomicron production by the enterocytes and delayed catabolism of chylomicrons and chylomicron remnants. Insulin and some intestinal hormones (e.g. glucagon-like peptide-1 [GLP-1]) influence intestinal lipid metabolism. In individuals with type 2 diabetes, insulin resistance and possibly reduced GLP-1 secretion are involved in the pathophysiology of postprandial hyperlipidaemia. Several factors are involved in the overproduction of chylomicrons: (1) increased expression of microsomal triglyceride transfer protein, which is a key enzyme in chylomicron synthesis; (2) higher stability and availability of apolipoprotein B-48; and (3) increased de novo lipogenesis. Individuals with type 2 diabetes present with disorders of cholesterol metabolism in the enterocytes with reduced absorption and increased synthesis. The increased production of chylomicrons in type 2 diabetes is also associated with a reduction in their catabolism, mostly because of a reduction in activity of lipoprotein lipase. Modification of the microbiota, which is observed in type 2 diabetes, may also generate disorders of intestinal lipid metabolism, but human data remain limited. Some glucose-lowering treatments significantly influence intestinal lipid absorption and transport. Postprandial hyperlipidaemia is reduced by metformin, pioglitazone, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors and GLP-1 agonists. The most pronounced effect is observed with GLP-1 agonists, which reduce chylomicron production significantly in individuals with type 2 diabetes and have a direct effect on the intestine by reducing the expression of genes involved in intestinal lipoprotein metabolism. The effect of sodium-glucose cotransporter 2 inhibitors on intestinal lipid metabolism needs to be clarified.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Hiperlipidemias , Metformina , Apolipoproteína B-48/metabolismo , Apolipoproteína B-48/farmacologia , Colesterol , Remanescentes de Quilomícrons/metabolismo , Remanescentes de Quilomícrons/farmacologia , Quilomícrons/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/farmacologia , Inibidores de Glicosídeo Hidrolases , Humanos , Insulina/metabolismo , Absorção Intestinal , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Lipoproteínas , Metformina/farmacologia , Pioglitazona , Período Pós-Prandial , Sódio , Triglicerídeos/metabolismo
20.
Pharmacoepidemiol Drug Saf ; 31(10): 1039-1045, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35790047

RESUMO

PURPOSE: National regulators in Australia and the United Kingdom issued safety advisories on the association between pioglitazone use and bladder cancer in July 2011. The Australian advisory noted that males were at higher risk of bladder cancer than females, while the UK advisory highlighted a new recommendation, suggest careful consideration in the elderly due to increasing risk with age. This study examined whether these differences in the advisories had different age- and sex-based impacts in each country. METHODS: Interrupted time series analysis was used to compare pioglitazone use (prescriptions/100000 population) in Australia and the United Kingdom for the 24 months before and 11 months after the July 2011 safety advisories (study period July 2009-June 2012). Separate models were used to compare use by sex and age group (≥65 years vs. <65 years) in each country. RESULTS: Pioglitazone use fell in Australia (17%) and the United Kingdom (24%) following the safety advisories. Use of pioglitazone fell more for males (18%) than females (16%) in Australia, and more for females (25%) than males (23%) in the United Kingdom; however, neither difference was statistically significant (Australia p = 0.445, United Kingdom p = 0.462). Pioglitazone use fell to a similar extent among older people than younger people in the United Kingdom (23% vs. 26%, p = 0.354), and did not differ between age groups in Australia (both 18%, p = 0.772). CONCLUSIONS: The results indicate that differences in the Australian and UK safety advisories resulted in substantial reductions in pioglitazone use at the population level in both countries, however, differences by sub-groups were not observed.


Assuntos
Diabetes Mellitus Tipo 2 , Tiazolidinedionas , Neoplasias da Bexiga Urinária , Idoso , Austrália/epidemiologia , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Análise de Séries Temporais Interrompida , Masculino , Pioglitazona/efeitos adversos , Tiazolidinedionas/efeitos adversos , Reino Unido/epidemiologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia
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