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1.
Chem Biol Interact ; 311: 108758, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348919

RESUMO

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in children. It is diagnosed by two main behavioral phenotypes i.e. social-communication impairments and repetitive behavior. ASD is complex disorder with unsolved etiology due to multiple genes involvement, epigenetic mechanism and environmental factors. The clinical and preclinical studies have been indicating the association of propionic acid with autism spectrum disorder. Numerous studies suggest the potential therapeutic effects of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in different brain disorders. This research evaluates the utility of selective agonist of PPAR-γ, pioglitazone in postnatal propionic acid induced ASD related symptomatology in male Wistar rats. PPA (250 mg/kg, p.o.) was administered to male offspring for three consecutive days from postnatal 21st day to 23rd day. PPA induced social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity in rats. Also, postnatal propionic acid-treated rats showed higher levels of oxidative stress (increased in thiobarbituric acid reactive species and decreased in reduced glutathione) as well as inflammation (increased in interleukin-6, tumor necrosis factor-alpha and decreased in interleukin-10) in the cerebellum, brainstem and prefrontal cortex. The rats were treated daily with pioglitazone (10 mg/kg and 20 mg/kg, p.o.) from postnatal 24th day to end of the study. Treatment with pioglitazone, significantly attenuated the postnatal propionic acid-induced social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, pioglitazone also reduced the postnatal propionic acid-induced oxidative stress and neuroinflammation in aforementioned brain regions. Hence, pioglitazone improved the propionic acid-induced neurobehavioral and biochemical impairments in rats.


Assuntos
Transtorno do Espectro Autista/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Pioglitazona/farmacologia , Animais , Ansiedade/prevenção & controle , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Glutationa/metabolismo , Inflamação/prevenção & controle , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Locomoção/efeitos dos fármacos , Masculino , PPAR gama/metabolismo , Fenótipo , Pioglitazona/uso terapêutico , Propionatos/toxicidade , Ratos , Ratos Wistar
2.
Life Sci ; 232: 116609, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254585

RESUMO

Pioglitazone has been demonstrated to exert anti-fibrotic and renoprotective effects. But the detailed pharmacological mechanisms have not been clearly revealed. The present study aimed to investigate the possible mechanisms of pioglitazone in these two effects. TGF-ß1-stimulated HK-2 cells and unilateral ureteral obstruction (UUO) mice were used as in vitro and in vivo models. The results showed that pioglitazone inhibited Smad-2/3 phosphorylation, upregulated Smad-7 expression and downregulated miR-21-5p expression in TGF-ß1-exposed HK-2 cells. In addition, miR-21-5p inhibitors replicated the anti-fibrotic effects of pioglitazone, and miR-21-5p mimics inhibited these effects. In in vivo study, pioglitazone attenuated UUO-induced renal fibrosis and significantly decreased the expressions of pro-fibrotic proteins. Whereas, agomir of miR-21-5p inhibited the renoprotective function of pioglitazone in UUO mice. In conclusion, the present data suggest that modulation of miR-21-5p/Smad-7 signal may be involved in the anti-fibrotic effect of pioglitazone in the kidney of UUO mice.


Assuntos
Rim/efeitos dos fármacos , Rim/patologia , MicroRNAs/metabolismo , Pioglitazona/farmacologia , Animais , Linhagem Celular , Fibrose/induzido quimicamente , Fibrose/genética , Células HEK293 , Humanos , Rim/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/patologia
3.
Gen Physiol Biophys ; 38(3): 259-264, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31184312

RESUMO

The peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor and nutrition factor which takes part in the cellular signaling by several agonists such as pioglitazone. PPARγ can serve as potential target in treatments of metabolic syndrome diseases and/or hypertension. In the present study we investigated the effects of pioglitazone, a PPARγ agonist, on hypertension development in young and adult borderline hypertensive rats (BHR). In renal signaling we observed connections between PPARγ and Nrf2, antioxidant in adult animals and differences between young and adult BHR in Nrf2-activated detoxificant outputs (NQO1, HO-1) and NO-synthases. Blood pressure in animals had been detected by cuff plethysmography, cell signaling in the kidney was studied by gene expression determination using qPCR, and nitric oxide synthase (NOS) activity was measured by radioactive detection. Pioglitazone treatment in adult BHR caused no detectable changes in antioxidant and detoxificant responses. The main effects were observed in blood pressure improvement, endothelial NOS expression and NOS activities in both young and adult BHR.


Assuntos
Envelhecimento/fisiologia , Hipertensão , Rim/efeitos dos fármacos , Rim/metabolismo , PPAR gama/agonistas , Pioglitazona/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Hipertensão/fisiopatologia , Ratos
4.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083336

RESUMO

Mesenchymal stem cells (MSCs) are optimal sources of autologous stem cells for cell-based therapy in chronic kidney disease (CKD). However, CKD-associated pathophysiological conditions, such as endoplasmic reticulum (ER) stress and oxidative stress, decrease MSC function. In this work, we study the protective effect of pioglitazone on MSCs isolated from CKD patients (CKD-MSCs) against CKD-induced ER stress. In CKD-MSCs, ER stress is found to induce mitochondrial reactive oxygen species generation and mitochondrial dysfunction. Treatment with pioglitazone reduces the expression of ER stress markers and mitochondrial fusion proteins. Pioglitazone increases the expression of cellular prion protein (PrPC) in CKD-MSCs, which is dependent on the expression levels of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Treatment with pioglitazone is found to protect CKD-MSCs against reactive oxygen species generation, aberrant mitochondrial oxidative phosphorylation of complexes I and IV, and aberrant proliferation capacity through the PGC-1α-PrPC axis. These results indicate that pioglitazone protects the mitochondria of MSCs from CKD-induced ER stress. Pioglitazone treatment of CKD-MSCs may be a potential therapeutic strategy for CKD patients.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Pioglitazona/farmacologia , Insuficiência Renal Crônica/terapia , Adulto , Antioxidantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Biogênese de Organelas , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Priônicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/patologia , Regulação para Cima/efeitos dos fármacos
5.
Molecules ; 24(7)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965670

RESUMO

Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3ß (GSK-3ß) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP⁺-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3ß enzyme inhibition against MPP⁺. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3ß enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3ß along with PPARγ activation may be responsible for neuroprotection.


Assuntos
1-Metil-4-fenilpiridínio/efeitos adversos , Neurônios/citologia , Transdução de Sinais/efeitos dos fármacos , Tiadiazóis/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pioglitazona/farmacologia
6.
J Exp Clin Cancer Res ; 38(1): 178, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027492

RESUMO

BACKGROUND: Pioglitazone, a synthetic peroxisome proliferator activated receptor (PPAR-γ) ligand, is known as an antidiabetic drug included in the thiazolidinediones (TZDs) class. It regulates the lipid and glucose cell metabolism and recently a role in the inhibition of numerous cancer cell processes has been described. METHODS: In our work we investigate the anti-tumor effects of pioglitazone in in vitro models of non small cell lung cancer (NSCLC) and also, we generated ex-vivo three-dimensional (3D) cultures from human lung adenocarcinoma (ADK) as a model to test drug efficacy observed in vitro. The inhibitory effect of pioglitazone on cell proliferation, apoptosis and cell invasion in a panel of human NSCLC cell lines was evaluated by multiple assays. RESULTS: Pioglitazone reduced proliferative and invasive abilities with an IC50 ranging between 5 and 10 µM and induced apoptosis of NSCLC cells. mRNA microarray expression profiling showed a down regulation of MAPK, Myc and Ras genes after treatment with pioglitazone; altered gene expression was confirmed by protein analysis in a dose-related reduction of survivin and phosphorylated proteins levels of MAPK pathway. Interestingly mRNA microarray analysis showed also that pioglitazone affects TGFß pathway, which is important in the epithelial-to-mesenchimal transition (EMT) process, by down-regulating TGFßR1 and SMAD3 mRNA expression. In addition, extracellular acidification rate (ECAR) and a proportional reduction of markers of altered glucose metabolism in treated cells demonstrated also cell bioenergetics modulation by pioglitazone. CONCLUSIONS: Data indicate that PPAR-γ agonists represent an attractive treatment tool and by suppression of cell growth (in vitro and ex vivo models) and of invasion via blockade of MAPK cascade and TGFß/SMADs signaling, respectively, and its role in cancer bioenergetics and metabolism indicate that PPAR-γ agonists represent an attractive treatment tool for NSCLC.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , PPAR gama/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Proteína Smad3/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , PPAR gama/agonistas , Pioglitazona/farmacologia , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética
7.
Mol Med Rep ; 19(4): 2740-2748, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816473

RESUMO

The peroxisome proliferator­activated receptor γ (PPARγ) agonist pioglitazone has been widely used in previous studies to ameliorate diabetes mellitus and regulate inflammation. However, the present study aimed to investigate the effect of pioglitazone on macrophages and determine its impact on renal fibrosis in vivo. Firstly, bone marrow­derived macrophages (BMDM) were used to detect the effects of pioglitazone on macrophages in vitro. It was demonstrated that pioglitazone promoted M2 macrophage activation and induced vascular endothelial growth factor receptor 3 (VEGFR3) upregulation in a PPARγ­dependent manner. Furthermore, pioglitazone increased macrophage proliferation and macrophage VEGFR3 expression in a murine unilateral ureteral obstruction (UUO) model; however, it had no therapeutic effect on renal fibrosis in vivo. Therefore, the results in the present study implied that presence of M2 macrophages may inhibit pioglitazone's ability to attenuate UUO­induced renal fibrosis. In addition, the results demonstrated that macrophage­associated VEGFR3 could be induced by pioglitazone, although it is still unclear what role VEGFR3+ M2 macrophages have in renal fibrosis.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , PPAR gama/metabolismo , Pioglitazona/farmacologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Masculino , Camundongos
8.
J Diabetes Res ; 2019: 5245063, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863781

RESUMO

Increasing evidence shows that statins increase the risk of new-onset diabetes mellitus, but the exact mechanism is not clearly known. Free fatty acid receptor 1 (FFA1) has been recognized to mediate insulin secretion, and pioglitazone has direct effects on glucose-stimulated insulin secretion in addition to the reversion of insulin resistance. In this study, we found that atorvastatin decreased potassium-stimulated insulin secretion and inhibited the expression of FFA1, PDX-1, and BETA2/NeuroD in INS-1 cells. Further study demonstrated that pioglitazone prevented the impairment of insulin secretion induced by atorvastatin and enhanced the expression of FFA1, PDX-1, and BETA2/NeuroD reduced by atorvastatin in INS-1 cells. In addition, the preventive effect of pioglitazone on atorvastatin-induced impairment of insulin secretion and the enhancement of the expression of PDX-1 and BETA2/NeuroD was abolished by knockdown of FFA1 using siRNA or the PLC inhibitor, U-73122, respectively. Ultimately, FFA1 may mediate the atorvastatin-induced pancreatic ß-cell dysfunction and pioglitazone may ameliorate this deleterious effect through the upregulation of FFA1 expression.


Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Pioglitazona/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Proteínas de Homeodomínio/metabolismo , Insulina/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ratos , Transativadores/metabolismo
9.
Mol Med Rep ; 19(5): 3815-3822, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896803

RESUMO

Post­operative cognitive dysfunction is a common complication after anesthesia and surgery. Sevoflurane (SEV), a widely used inhalational anesthetic, can exaggerate neuroinflammation and cause cognitive dysfunction under chronic intermittent hypoxia (CIH) conditions by downregulating hippocampal peroxisome proliferator­activated receptor­Î³ (PPAR­Î³). In the present study, it was examined whether treatment with PPAR­Î³ agonist pioglitazone (PIO) is beneficial in counteracting SEV­induced neuroinflammation and cognitive decline in a rat model of CIH. Rats were exposed to CIH for 4 weeks. After 2 weeks of CIH, these animals underwent either 2.6% SEV or control (CON) exposure for 4 h. PIO (60 mg/kg) or vehicle (VEH) was administered orally twice daily for 2 weeks, starting one day prior to SEV or CON exposure. Compared with CIH­CON+VEH rats, CIH­SEV+VEH rats exhibited significant cognitive decline as indicated by increased latency to locate the hidden platform and shorter dwell­time in the goal quadrant in the Morris Water Maze task. Molecular studies revealed that CIH­SEV+VEH rats had increased proinflammatory cytokine expression and microglial activation in the hippocampus, which were associated with decreased PPAR­Î³ activity. Notably, SEV­induced cognitive decline and increases in proinflammatory cytokine expression and microglial activation were prevented by PIO, which increased hippocampal PPAR­Î³ activity. PIO also increased hippocampal PPAR­Î³ activity in CIH­CON rats but did not alter proinflammatory cytokine expression and microglial activation as well as cognitive function. Additionally, expression of hippocampal PPAR­α and PPAR­ß, two other PPAR isotypes, were comparable among the groups. These data suggest that PIO prevents SEV­induced exaggeration of neuroinflammation and cognitive decline under CIH conditions by upregulating hippocampal PPAR­Î³. PIO may have the potential to prevent anesthetic SEV­induced cognitive decline in surgical patients with obstructive sleep apnea.


Assuntos
Disfunção Cognitiva/prevenção & controle , Hipóxia/fisiopatologia , Inflamação/prevenção & controle , Neuroimunomodulação/efeitos dos fármacos , PPAR gama/metabolismo , Pioglitazona/farmacologia , Sevoflurano/toxicidade , Animais , Doença Crônica , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hipoglicemiantes/farmacologia , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Inibidores da Agregação de Plaquetas/toxicidade , Ratos , Ratos Sprague-Dawley
10.
Cardiovasc Diabetol ; 18(1): 39, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902059

RESUMO

BACKGROUND: The efficacy of cell transplantation in heart failure is reportedly modest, but adjuvant drugs combined with cell therapy may improve this efficacy. Peroxisome proliferator-activated receptor (PPAR)γ, one of the hypoglycemic medicine for diabetes mellitus, reportedly enhances cytokine production in adipose tissue-derived regenerative cells (ADRCs). We hypothesized that combined administration of PPARγ agonists and ADRCs may enhance the paracrine effects of adiponectin (APN), leading to functional recovery in a chronic myocardial infarction (MI) model. METHODS: ADRCs were isolated from adipose tissues of adult rats by gradient centrifugation and embedded in bio-compatible fibrin-glue to produce ADRCs grafts. In the in vitro study, the ADRCs grafts released APN, which was significantly enhanced by the PPARγ agonist (PGZ, pioglitazone). Transplantation of ADRCs grafts (group A), ADRCs mixed with PGZ (group AP), APN knockdown-ADRCs (group Si) or PGZ (group P) onto the epicardium or a sham operation (group C) was performed (n = 10-20 per group). RESULTS: The AP group showed significant improvement in ejection fraction compared to that in the other groups. In the AP group, a significantly larger number of M2-polarized macrophages was detected and existed for a significantly longer duration in the infarct area. Furthermore, comparing Si group and P group, western blotting of T-cadherin revealed that exogenous APN and local expression of T-cadherin were essential to this histological change and recovery of cardiac function. CONCLUSIONS: Combined administration of PPARγ agonist and ADRSCs activated M2-polarized macrophages with enhancement of APN paracrine effects and lead to better cardiac function in a rat infarction model.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/transplante , Cardiomiopatias/terapia , Transplante de Células/métodos , Macrófagos/efeitos dos fármacos , Infarto do Miocárdio/terapia , PPAR gama/agonistas , Pioglitazona/farmacologia , Regeneração/efeitos dos fármacos , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Caderinas/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , PPAR gama/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Fenótipo , Ratos Endogâmicos Lew , Recuperação de Função Fisiológica , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
11.
Med Sci Monit ; 25: 1582-1589, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30820023

RESUMO

BACKGROUND This study investigated the therapeutic effects of the peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone in ob/ob mice with obesity-related glomerulopathy (ORG). MATERIAL AND METHODS A total of 24 mice were divided into 3 groups: wild-type C57BL/6 mice (n=8), ob/ob mice (n=8), and ob/ob mice receiving pioglitazone treatment (n=8). Body mass, blood glucose, serum adiponectin (ADP), and urine microalbumin (mALB) levels were determined. Renal histology was examined using light and electron microscopy. Wilms tumor 1 (WT1), Zonula occludens-1 (ZO-1), AMP activated protein kinase (AMPK), and NADPH oxidase-4 (NOX-4) expression were evaluated by immunohistochemistry and Western blot. RESULTS Serum ADP did not alter between weeks 0 and 12 in the control group, while the ob/ob mice showed a time-dependent decrease that was prevented by pioglitazone. Urinary mALB did not alter between week 0 and 12 in the control group, but was higher in week 0 and week 12 in the ob/ob group. Pioglitazone prevented the rise in urinary mALB in week 12. Histology revealed glomerulomegaly, mesangial proliferation, focal segmental glomerulosclerosis, and foot processes fusion in the ob/ob group, which were ameliorated by pioglitazone treatment. Compared to the control group, ob/ob mice had a higher kidney index and glomerular diameter, which were reduced by pioglitazone treatment. Immunohistochemical and Western blot experiments revealed lower expression levels of WT1, ZO-1, and AMPK and higher NOX-4 expression level in the ob/ob group, which was prevented by pioglitazone treatment. CONCLUSIONS Pioglitazone, a PPARγ agonist, can prevent ORG, probably by reducing oxidative stress.


Assuntos
Glomerulonefrite Membranosa/metabolismo , PPAR gama/agonistas , Pioglitazona/farmacologia , Adiponectina/análise , Adiponectina/sangue , Animais , Glicemia , Hipoglicemiantes , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Estresse Oxidativo , PPAR gama/metabolismo , Pioglitazona/metabolismo , Albumina Sérica/análise , Tiazolidinedionas
12.
Drug Dev Ind Pharm ; 45(7): 1061-1072, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30922126

RESUMO

Growing evidence suggest that Alzheimer's disease (AD), the most common cause of dementia among the elderly is a metabolic disorder associated with impaired brain insulin signaling. Hence, the diabetic drug can be a therapeutic option for the management AD. The researches in this area are ongoing and Pioglitazone (PIO) is one of the most investigated diabetic drug in AD. Eventhough PIO treatment was found to improve AD significantly in the preclinical models, the poor blood-brain barrier (BBB) permeability and serious peripheral side effects limited its success in the clinical trials. The objective of the present study was to formulate and optimize intranasal (IN) nano lipid carriers (NLC) of PIO for its targeted delivery to the brain. A Box-Behnken design was employed to optimize the effect of three independent variables on two dependent variables. The optimized formulation had a particle size (PS) of 211.4 ± 3.54 nm and zeta potential of (ZP) of 14.9 ± 1.09 mv. The polydispersibility index (PDI) and entrapment efficiency (EE) was found to be 0.257 ± 0.108 and 70.18 ± 4.5% respectively. Storage stability studies performed has confirmed the stability of NLCs at 4 °C and 25 °C. The in-vitro drug release study has exhibited a sustained release of drug from the NLC. The formulation was observed to improve the nasal permeability of PIO ex-vivo significantly. Toxicity studies were performed to confirm the safety of formulation for the in-vivo administration. In-vivo biodistribution study in rats has shown a direct transport of drug from the nose to brain from the IN-NLC.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Pioglitazona/química , Pioglitazona/farmacologia , Administração Intranasal , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Nanoestruturas/química , Mucosa Nasal/metabolismo , Tamanho da Partícula , Ratos , Ratos Wistar , Ovinos , Distribuição Tecidual/efeitos dos fármacos
13.
Biomed Pharmacother ; 111: 926-933, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841472

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies. METHODS: Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 µg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria. RESULTS: HFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation. CONCLUSION: Similar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Liraglutida/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/efeitos dos fármacos , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Ratos Sprague-Dawley , Roedores/sangue , Roedores/metabolismo , Triglicerídeos/sangue
14.
J Clin Pharm Ther ; 44(3): 337-348, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30738020

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Alzheimer's disease (AD) is the most common cause of dementia among the elderly. The exact cause of the disease is not clearly known, and no existing therapies are able to prevent disease progression. Identification of the possible "impaired brain insulin signalling in AD" enriched the scope for "the repurposing of diabetic drugs in AD management." Among the different classes of diabetic drugs, pioglitazone (PIO), a PPARγ agonist classed as an insulin sensitizer, is of the highest interest for AD management. The drug is reported to have direct action on multiple targets involved in AD, independent of insulin signalling. Even though PIO has appeared to be a potent molecule in preclinical trials, limited success was observed in the clinical stage. The tentative reasons for the limited therapeutic success in the clinical stage are not clear. The main focus of the review is to discuss various factors that might limit the therapeutic success of PIO in clinical trials and possible approaches to overcome those limitations. METHOD: The research articles, review articles, and patents containing information regarding the clinical and preclinical trials of PIO in AD have been reviewed thoroughly using the keywords related to diabetic drugs in AD, PIO for AD management and mechanism of PIO in AD. Literature search was conducted on PubMed, SCOPUS and EMBASE. RESULTS AND DISCUSSION: Previous studies have indicated that the blood-brain barrier (BBB) is the biggest challenge to delivering PIO to the brain. Therefore, to attain a therapeutic concentration in the brain, a higher dose is needed, which is also supported by preclinical investigations in AD; however, in clinical studies, scientists have used the usual diabetic doses. This dose is inadequate to attain a therapeutic concentration in the brain and appears to be the primary reason for the limited success of PIO in clinical trials. The stage of drug intervention and the nature of the study population are also influential factors for the therapeutic response. WHAT IS NEW AND CONCLUSION: The insufficient concentration of the drug reaching the brain appears to be the crucial factor that limits the therapeutic success of PIO in AD management. Since the administration of higher doses cannot be recommended due to safety issues, the current situation demands the use of novel tools to ensure a therapeutic concentration reaches the brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Química Farmacêutica/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Insulina/metabolismo
15.
J Diabetes Res ; 2019: 2376512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729133

RESUMO

Metformin and pioglitazone are two commonly prescribed oral hypoglycemic agents for diabetes. Recent evidence suggests that these drugs may contribute to bladder cancer. This study investigated molecular mechanism underlying effects of metformin and pioglitazone in bladder epithelial carcinogenesis in type 2 diabetes. The cells derived from human bladder epithelial cells (HBlEpCs) were treated with metformin or pioglitazone with high glucose and insulin. Cell viability and proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a bromodeoxyuridine incorporation assay, respectively, while cell cycle regulatory factors and oncogene expression were analyzed using western blotting. Metformin or pioglitazone suppressed cell viability concentration and time dependently, which was reversed by exposure to high glucose with or without insulin. Prolonged exposure to high glucose and insulin enhanced cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression and suppressed cyclin-dependent kinase inhibitors p21 and p15/16 in HBlEpC cotreated with pioglitazone and metformin. Levels of tumor suppressor proteins p53 and cav-1 were downregulated while those of the oncogenic protein as c-Myc were upregulated under high glucose and insulin supplementation in HBlEpC cotreated with pioglitazone and metformin. Prolonged exposure to high glucose with or without insulin downregulated B cell lymphoma 2-associated X (Bax) and failed to enhance the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) in drug-treated cells. These results suggest that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells and uncontrolled hyperglycemia and hyperinsulinemia are probably greater cancer risk factors than diabetes drugs.


Assuntos
Ciclo Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Glucose/farmacologia , Insulina/farmacologia , Metformina/farmacologia , Pioglitazona/farmacologia , Bexiga Urinária/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/citologia , Humanos , Hipoglicemiantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bexiga Urinária/citologia
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(1): 23-29, 2019 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-30692062

RESUMO

OBJECTIVE: To study the protective effect of enhanced peroxisome proliferator activated receptor γ (PPARγ) pathway against apoptosis of long-term cultured primary nerve cells. METHODS: A natural aging model was established in primary rat nerve cells by long-term culture for 22 days. The cells were divided into control group, 0.1, 1.0, 5.0, and 10 µmol/L GW9662 intervention groups, and 0.1, 1.0, 5.0, and 10 µmol/L pioglitazone intervention groups. The cell viability was assessed using MTT assay and the cell morphological changes were observed after the treatments to determine the optimal concentrations of GW9662 and pioglitazone. Double immunofluorescence labeling and flow cytometry were used to observe the changes in the number of viable cells and cell apoptosis following the treatments; immunocytochemical staining was used to assess the changes in the anti-oxidation ability of the treated cells. RESULTS: The optimal concentrations of GW9662 and pioglitazone determined based on the cell viability and morphological changes were both 1 µmol/L. Compared with the control group, GW9662 treatment significantly lowered while pioglitazone significantly increased the total cell number and nerve cell counts (P < 0.05), and nerve cells in the cell cultures maintained a constant ratio at about 80% in all the groups (P > 0.05). GW9662 significantly enhanced while pioglitazone significantly lowered the cell apoptosis rates compared with the control group (P < 0.05). GW9662 obviously lowered SOD activity and GSH content in G group (P < 0.05) and increased MDA content in the cells (P < 0.05), and pioglitazone resulted in reverse changes in SOD, GSH and MDA contents in the cells (P < 0.05). CONCLUSIONS: Activation of PPARγ pathway protects long-term cultured primary nerve cells by enhancing cellular anti-oxidant capacity and reducing cell apoptosis, suggesting a potential strategy for anti-aging treatment of the nervous system through intervention of the PPARγ pathway.


Assuntos
Anilidas/administração & dosagem , Apoptose , Neurônios/citologia , PPAR gama/metabolismo , Pioglitazona/administração & dosagem , Anilidas/farmacologia , Animais , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Senescência Celular/fisiologia , Pioglitazona/farmacologia , Ratos
17.
Int J Mol Sci ; 20(3)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678291

RESUMO

Various therapeutic effects of mesenchymal stem cells (MSCs) have been reported. However, the rapid clearance of these cells in vivo, difficulties in identifying their therapeutic mechanism of action, and insufficient production levels remain to be resolved. We investigated whether a pioglitazone pre-treatment of MSCs (Pio-MSCs) would stimulate the proliferation of co-cultured tenocytes. Pioglitazone increased the proliferation of MSCs and enhanced the secretion of VEGF (vascular endothelial growth factor) and collagen in these cells. We then examined the effects of Pio-MSCs on tenocytes using an indirect transwell culture system. A significant increase in tenocyte proliferation and cell cycle progression was observed in these co-cultures. Significant increases were observed in wound scratch closure by tenocytes from a Pio-MSC co-culture. Pio-MSCs also enhanced the secretion of collagen from tenocytes. A higher mRNA level of collagen type 1 (Col 1) and type 3 (Col 3), scleraxis (Scx), and tenascin C (TnC) was found in the tenocytes in Pio-MSC co-cultures compared with monocultured cells or tenocytes cultured with non-treated MSCs. Our results indicate that pioglitazone enhances the therapeutic effects of MSCs on tendon repair.


Assuntos
Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Pioglitazona/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Citometria de Fluxo , Immunoblotting , Masculino , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Tenócitos/efeitos dos fármacos , Tenócitos/metabolismo
18.
Toxicol Appl Pharmacol ; 362: 86-94, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393147

RESUMO

Remote organ damage is the major cause of death in patients with acute kidney injury (AKI) due to renal ischemia reperfusion (IR). Liver is one of the vital organs which are profoundly affected by AKI. The present study aims to investigate the role of peroxisome proliferator activator receptor gamma (PPARγ) in liver damage induced by IR injury in rats. Renal IR was induced by right nephrectomy, occlusion of left renal pedicle for 45 min to induce ischemia, and then reperfusion for 6 or 24 h. The PPARγ agonist, pioglitazone, was given orally for 7 days before renal IR procedure. Animals receiving pioglitazone showed improvement in renal and hepatic functions when compared to IR groups. Renal IR increased renal, hepatic and serum levels of tumor necrosis factor-α (TNF-α) and induced apoptotic cell death in liver. These effects were diminished with pioglitazone. In addition, pioglitazone reduced renal IR-induced oxidative stress in liver. Pioglitazone reduced malondialdehyde (MDA) content and NADPH oxidase mRNA expression and induced further increase in nuclear factor erythroid 2-related factor 2 (Nrf2) expression when compared to IR groups. Furthermore, pioglitazone increased the expression of PPARγ target genes such as renal and hepatic PPARγ1 (Pparg1), hepatic hemoxygenase-1 (Hmox1), and hepatic thioredoxin (TRx). Histological profiles for kidney and liver were also ameliorated with pioglitazone. Hence, PPARγ is a potential target to protect liver in patients with renal IR injury.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Hepatopatias/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Caspase 3/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Pioglitazona/farmacologia , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fator de Necrose Tumoral alfa/metabolismo
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