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1.
Int J Nanomedicine ; 16: 2373-2388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790555

RESUMO

Aim: The metastasis of breast cancer is an important cause of tumor recurrence. This study highlights that tyrosine kinase inhibitors dasatinib (DAS) and rosiglitazone (ROZ) inhibit tumor growth and reduce the occurrence of tumor cell metastasis. Due to the poor water solubility, short half-time in the body of DAS and ROZ, which increases the difficulty of tumor treatment, as well as the demand for nano-drug delivery systems for organ-specific therapies. Methods: Hyaluronic acid (HA) and DAS are bonded by a pH-sensitive ester bond to form an HA-DAS polymer. Then, ROZ was added as the core, D-A-tocopherol polydiethylene glycol isosuccinate (TPGS) and HA-DAS were used as carriers to form HA-DAS and TPGS mixed micelle system loaded with ROZ (THDR-NPs). The size and structure of THDR-NPs were characterized, the drug release, stability and biosafety of THDR-NPs were studied. In vitro, the cytotoxicity, targeting effect and tumor metastasis inhibition of THDR-NPs were evaluated in human breast cancer cell lines. In addition, the selective potency of designed THDR-NPs in depleting was further verified in vivo in the tumor-bearing nude mice model. Results: The designed THDR-NPs have a particle size of less than 100 nm, good stability, biological safety and sustained release, and showed strong therapeutic effects on breast cancer models in vitro and in vivo. Moreover, it has been proved that THDR-NPs have the ability to inhibit tumor metastasis. Conclusion: DAS and ROZ were designed into micelles, the efficacy of THDR-NPs was higher than that of free drugs. These results indicate that nanoparticles have a good application prospect in the treatment of tumor metastasis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dasatinibe/administração & dosagem , Dasatinibe/farmacocinética , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Rosiglitazona/farmacocinética , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
2.
Life Sci ; 269: 119013, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33417950

RESUMO

OBJECTIVE: To investigate the protective efficacies and potent mechanisms of combination therapy with semaglutide and rosiglitazone (RSG) on the high-glucose incubated human ARPE-19 cells and diabetic retinopathy (DR) model rats. MAIN METHODS: The CCK-8 methods were used to evaluate the protective effects of semaglutide and RSG alone or combination on the cell viability of high-glucose treated ARPE-19 cells. After the DR rat model was established, the effects of combined treatment on general indexes, retinal morphological changes, retinal Müller cells as well as PI3K/Akt/MTOR related factors of DR model rats were investigated. RESULTS: The CCK-8 assay showed obviously enhanced protective efficacies of combination therapy with semaglutide and RSG on the ARPE-19 with oxidative stress induced by high-glucose with combination index all below 1.5 demonstrating obvious synergistic effects. Combined incubation could also effectively decrease the expression of inflammatory factors, including TNF-α, IL-1ß, IL-6, and the increase of ROS content in ARPE cell culture supernatant induced by high-glucose. Combined use of the antioxidant, PI3K/Akt and mTOR inhibitors, we further demonstrated that combined incubation of semaglutide and RSG could effectively by reduce high glucose-induced inflammatory injury inhibiting ROS/PI3K/Akt/mTOR signaling. Furthermore, chronic combination treatment effectively improved the histopathological characteristics and down-regulated the GFAP expression in Müller cells as well as PI3K/Akt/MTOR signaling pathway-related factors in retina which was better than any monomer treatment group. CONCLUSIONS: Combined semaglutide with RSG exhibited synergistically protective efficacies on retinal cells by decreasing the GFAP expression, inhibiting oxidative stress and PI3K/Akt/MTOR signaling-transduction in DR model rats.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Rosiglitazona/uso terapêutico , Animais , Antioxidantes/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Inflamação/patologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
3.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339154

RESUMO

Neuroinflammation is a key process of many neurodegenerative diseases and other brain disturbances, and astrocytes play an essential role in neuroinflammation. Therefore, the regulation of astrocyte responses for inflammatory stimuli, using small molecules, is a potential therapeutic strategy. We investigated the potency of peroxisome proliferator-activated receptor (PPAR) ligands to modulate the stimulating effect of lipopolysaccharide (LPS) in the primary rat astrocytes on (1) polyunsaturated fatty acid (PUFAs) derivative (oxylipins) synthesis; (2) cytokines TNFα and interleukin-10 (IL-10) release; (3) p38, JNK, ERK mitogen-activated protein kinase (MAPKs) phosphorylation. Astrocytes were exposed to LPS alone or in combination with the PPAR ligands: PPARα (fenofibrate, GW6471); PPARß (GW501516, GSK0660); PPARγ (rosiglitazone, GW9662). We detected 28 oxylipins with mass spectrometry (UPLC-MS/MS), classified according to their metabolic pathways: cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), lipoxygenase (LOX) and PUFAs: arachidonic (AA), docosahexaenoic (DHA), eicosapentaenoic (EPA). All tested PPAR ligands decrease COX-derived oxylipins; both PPARß ligands possessed the strongest effect. The PPARß agonist, GW501516 is a strong inducer of pro-resolution substances, derivatives of DHA: 4-HDoHE, 11-HDoHE, 17-HDoHE. All tested PPAR ligands decreased the release of the proinflammatory cytokine, TNFα. The PPARß agonist GW501516 and the PPARγ agonist, rosiglitazone induced the IL-10 release of the anti-inflammatory cytokine, IL-10; the cytokine index, (IL-10/TNFα) was more for GW501516. The PPARß ligands, GW501516 and GSK0660, are also the strongest inhibitors of LPS-induced phosphorylation of p38, JNK, ERK MAPKs. Overall, our data revealed that the PPARß ligands are a potential pro-resolution and anti-inflammatory drug for targeting glia-mediated neuroinflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Astrócitos/metabolismo , Interleucina-10/metabolismo , Oxilipinas/metabolismo , PPAR gama/agonistas , PPAR beta/agonistas , Fator de Necrose Tumoral alfa/metabolismo , Anilidas/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fenofibrato/farmacologia , Lipopolissacarídeos/toxicidade , MAP Quinase Quinase 4/metabolismo , Oxazóis/farmacologia , PPAR gama/antagonistas & inibidores , PPAR beta/antagonistas & inibidores , Ratos , Ratos Wistar , Rosiglitazona/farmacologia , Tiazóis/farmacologia , Tirosina/análogos & derivados , Tirosina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Life Sci ; 259: 118270, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32814067

RESUMO

AIMS: Partial PPARγ agonists attracted substantially heightened interest as safer thiazolidinediones alternatives. On the other hand, Wnt/ß-catenin antagonists have been highlighted as promising strategy for type 2 diabetes management via up-regulating PPARγ gene expression. We aimed at synthesizing novel partial PPARγ agonists with ß-catenin inhibitory activity which could enhance insulin sensitivity and avoid the side effects of full PPARγ agonists. MAIN METHODS: We synthesized novel series of α-phthlimido-o-toluoyl-2-aminothiazoles hybrids for evaluating their antidiabetic activity and discovering its mechanistic pathway. We assessed effect of the new hybrids on PPARγ activation using a luciferase reporter assay system. Moreover, intracellular triglyceride levels, gene levels of c/EBPα, PPARγ and PPARγ targets including GLUT4, adiponectin, aP2 were measured in 3T3-L1 cells. Uptake of 2-DOG together with PPARγ and ß-catenin protein levels were evaluated in 3T3-L1cells. In addition, molecular docking studies with PPARγ LBD, physicochemical properties and structure activity relationship of the novel hybrids were also studied. KEY FINDINGS: Three of the synthesized hybrids showed partial PPARγ agonistic activity and distinct PPARγ binding pattern. These compounds modulated PPARγ gene expression and PPARγ target genes; and increased glucose uptake in 3T3-L1 and slightly induced adipogenesis compared to rosiglitazone. Moreover, these compounds reduced ß-catenin protein level which reflected in increased both PPARγ gene and protein levels that leads to improved insulin sensitivity and increased GLUT4 and adiponectin gene expression. SIGNIFICANCE: Our synthesized compounds act as novel partial PPARγ agonists and ß-catenin inhibitors that have potent insulin sensitizing activity and mitigate the lipogenic side effects of TZDs.


Assuntos
Resistência à Insulina/fisiologia , Ftalimidas/farmacologia , Tiazóis/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Insulina/metabolismo , Camundongos , Simulação de Acoplamento Molecular , PPAR gama/agonistas , PPAR gama/metabolismo , Rosiglitazona/farmacologia , Tiazolidinedionas/farmacologia , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
5.
Zhonghua Gan Zang Bing Za Zhi ; 28(5): 410-415, 2020 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-32536057

RESUMO

Objective: To investigate the effect of rosiglitazone (RGZ) on the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and heme oxygenase-1 (HO-1) in hepatic stellate cells (HSCs). Methods: In vitro activated hepatic stellate cell-T6 (HSC-T6) as research subjects were divided into blank control group, RGZ intervention group, and RGZ + ZnPP-IX mutual intervention group. MTT colorimetry method was used to measure the condition of cell proliferation. ELISA was used to detect the content of hyaluronic acid (HA) and type III procollagen peptide (PIIIP) in the cell supernatant. Real-time quantative PCR, western blot and immunocytochemistry were used to detect the relative expression levels of PPARγ, HO-1 mRNA and protein. One-way analysis of variance was used to compare the sample mean between multiple groups, and LSD test was used for comparison between two groups. Results: The proliferation activity of HSC-T6 and the expressions of HA and PIIIP in the RGZ intervention group were significantly lower than those in the blank control group (P ​​< 0.01), but the relative expression levels of PPARγ and HO-1 mRNA and protein were significantly increased compared with the blank control group (PPARγ : 2.97 ± 0.22 vs. 1.07 ± 0.05, 0.96 ± 0.08 vs. 0.31 ± 0.03; HO-1: 4.28 ± 0.73 vs. 1.80 ± 0.36, 1.83 ± 0.26 vs. 0.61 ± 0.09), and the difference was statistically significant (P < 0.01). The proliferation activity of HSC-T6 and the expression of HA and PIIIP was higher in RGZ + ZnPP-IX mutual intervention group as compared with RGZ group (P < 0.05). HO-1 mRNA (3.16 ± 0.38 vs. 4.28 ± 0.73) and protein (1.31 ± 0.17 vs. 1.83 ± 0.26) relative expression levels was decreased, and the difference was statistically significant (P < 0.05). There was no statistically significant difference in the relative expression of PPARγ mRNA and protein (P > 0.05), however, there was a decreasing trend. HO-1 mRNA (1.80 ± 0.36) and protein (0.61 ± 0.09) relative expression was significantly increased in RGZ + ZnPP-IX group as compared to blank control group (P < 0.05). Immunocytochemical staining had consistency with the above results. Conclusion: The effect of rosiglitazone on inducing increased expression of PPARγ, and then inhibiting HSC proliferation activity and collagen production may be realized by regulating its downstream HO-1 expression.


Assuntos
Hipoglicemiantes , PPAR gama , Rosiglitazona , Proliferação de Células , Heme Oxigenase-1/genética , Células Estreladas do Fígado , Hipoglicemiantes/farmacologia , PPAR gama/genética , Rosiglitazona/farmacologia
6.
Am J Physiol Lung Cell Mol Physiol ; 319(3): L435-L443, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32579381

RESUMO

Antenatal steroids (ANS) accelerate fetal lung maturation and reduce the incidence of respiratory distress syndrome. However, sex specificity, i.e., being less effective in males, and potential long-term neurodevelopmental sequelae, particularly with repeated courses, remain significant limitations. The differential sex response to ANS is likely mediated via the inhibitory effect of fetal androgens on steroid's stimulatory effect on alveolar epithelial-mesenchymal interactions. Since peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists accelerate lung maturation by stimulating alveolar epithelial-mesenchymal interactions, independent of fetal sex, we hypothesized that the effect of PPAR-γ agonist pioglitazone (PGZ) would be sex-independent. Pregnant Sprague-Dawley rat dams were intraperitoneally administered dexamethasone (DEX) or PGZ on embryonic day (e) 18 and e19. At e20, pups were delivered by cesarean section, and fetal lungs and brains were examined for markers of lung maturation and apoptosis, respectively. Mixed epithelial-fibroblast cell cultures were examined to gain mechanistic insights. Antenatal PGZ increased alveolar epithelial and mesenchymal maturation markers equally in males and females; in contrast, antenatal DEX had sex-specific effects. Additionally, unlike DEX, antenatal PGZ did not increase hippocampal apoptosis. We conclude that PPAR-γ agonist administration is an effective, and probably even a superior, alternative to ANS for accelerating fetal lung maturity equally in both males and females.


Assuntos
Pulmão/efeitos dos fármacos , PPAR gama/agonistas , Pioglitazona/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Maturidade Sexual , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Feminino , Masculino , Ratos Sprague-Dawley , Rosiglitazona/farmacologia , Caracteres Sexuais
7.
Sci Rep ; 10(1): 3775, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111895

RESUMO

Brown adipocytes coordinate systemic energy metabolism associated with the pathogenesis of obesity and related metabolic diseases including type 2 diabetes. We have previously reported chemical compound-induced brown adipocytes (ciBAs) converted from human dermal fibroblasts without using transgenes. In this study, to reveal a precise molecular mechanism underlying the direct conversion and human adipocyte browning, we developed serum-free brown adipogenic medium (SFBAM) with an optimized chemical cocktail consisting of Rosiglitazone, Forskolin, and BMP7. During the direct conversion, treatment with BMP7 enhanced Ucp1 expression rather than the conversion efficiency in the absence of BMP signalling inhibitors. Moreover, treatment with a TGF-ß signalling pathway inhibitor was no longer required in the serum-free medium, likely because the TGF-ß pathway was already suppressed. SFBAM and the chemical cocktail efficiently converted human dermal fibroblasts into ciBAs within four weeks. The ciBAs exhibited increased mitochondrial levels, elevated oxygen consumption rate, and a response to ß-adrenergic receptor agonists. Thus the ciBAs converted by the serum-free medium and the chemical cocktail provide a novel model of human brown (beige) adipocytes applicable for basic research, drug screening, and clinical applications.


Assuntos
Adipócitos Marrons/metabolismo , Diferenciação Celular , Derme/metabolismo , Fibroblastos/metabolismo , Transdução de Sinais , Adipócitos Marrons/citologia , Proteína Morfogenética Óssea 7/química , Proteína Morfogenética Óssea 7/farmacologia , Colforsina/química , Colforsina/farmacologia , Meios de Cultura Livres de Soro/química , Meios de Cultura Livres de Soro/farmacologia , Derme/citologia , Fibroblastos/citologia , Humanos , Rosiglitazona/química , Rosiglitazona/farmacologia
8.
Curr Med Sci ; 40(1): 55-62, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166665

RESUMO

The present study aimed to explore the molecular mechanisms underlying the increase of nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in brain tissues after intracerebral hemorrhage (ICH). The microglial cells obtained from newborn rats were cultured and then randomly divided into the normal control group (NC group), model control group (MC group), rosiglitazone (RSG) intervention group (RSG group), retinoic-acid intervention group (RSG+RA group), and sulforaphane group (RSG+SF group). The expression levels of NQO1, γ-GCS, and nuclear factor E2-related factor 2 (Nrf2) were measured by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. The results showed that the levels of NQO1, γ-GCS and Nrf2 were significantly increased in the MC group and the RSG group as compared with those in the NC group (P<0.01). They were found to be markedly decreased in the RSG+RA group and increased in the RSG+SF group when compared with those in the MC group or the RSG group (P<0.01). The RSG+SF group displayed the highest levels of NQO1, γ-GCS, and Nrf2 among the five groups. In conclusion, a medium dose of RSG increased the anti-oxidative ability of thrombin-activated microglia by increasing the expression of NQO1 and γ-GCS. The molecular mechanisms underlying the increase of NQO1 and γ-GCS in thrombin-activated microglia may be associated with the activation of Nrf2.


Assuntos
Hemorragia Cerebral/genética , Glutamato-Cisteína Ligase/genética , Microglia/citologia , NAD(P)H Desidrogenase (Quinona)/genética , Fator 2 Relacionado a NF-E2/genética , PPAR gama/genética , Trombina/farmacologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Glutamato-Cisteína Ligase/metabolismo , Isotiocianatos/administração & dosagem , Isotiocianatos/farmacologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , PPAR gama/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Rosiglitazona/administração & dosagem , Rosiglitazona/farmacologia , Tretinoína/administração & dosagem , Tretinoína/farmacologia
9.
BMJ ; 368: l7078, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024657

RESUMO

OBJECTIVES: To conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing. DESIGN: Systematic review and meta-analysis of randomized controlled trials. DATA SOURCES: GlaxoSmithKline's (GSK's) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK's Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults. DATA EXTRACTION AND SYNTHESIS: For analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals. RESULTS: 33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK's summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used. CONCLUSIONS: The results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety. SYSTEMATIC REVIEW REGISTRATION: OSF Home https://osf.io/4yvp2/.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Rosiglitazona/efeitos adversos , Doenças Cardiovasculares/mortalidade , Humanos , Hipoglicemiantes/farmacologia , Disseminação de Informação , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Rosiglitazona/farmacologia
10.
Mol Med Rep ; 21(3): 1552-1560, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016452

RESUMO

The peroxisome proliferator­activated receptor Î³ (PPARγ) plays an important role in insulin sensitivity and adipocyte differentiation. It is known as ligand­receptor that improves insulin sensitivity in type 2 diabetes mellitus. Several kinds of indigo plant have been already used to treat diabetes in oriental traditional medicine, but its mechanism has not been clarified yet. To investigate the effect of indirubin, which is a component of Polygonum tinctorium on the cell differentiation and adipprocess in 3T3­L1 cells, 3T3­L1 cells were cultured to determine the effect of cell differentiation and glucose uptake with indirubin. As a result, Indirubin compound enhanced adipocyte differentiation in 3T3­L1 cells similar to rosiglitazone. This effect was terminated by cotreatment with GW9662, a PPARγ antagonist. In mature 3T3­L1 adipocytes, the lipid droplet size and accumulation were reduced by this compound. The basal and insulin­stimulated glucose uptakes were also significantly increased. In addition, indirubin treatment significantly enhanced estrogen level by 1.64­fold with mature adipocytes which can be attributed to its aromatase activity. Conclutionaly, this finding suggested that indirubin is a potential anti­diabetic compound for type 2 diabetes mellitus by promoting adipocyte differentiation and glucose uptake via PPARγ.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR gama/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Animais , Biomarcadores , Proliferação de Células , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Indóis/farmacologia , Insulina/metabolismo , Ligantes , Camundongos , Rosiglitazona/farmacologia
11.
Cancer Chemother Pharmacol ; 85(2): 273-284, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31907647

RESUMO

OBJECTIVE: Senescence mechanisms are vital to resistance to long-term olaparib maintenance treatment. Recently, peroxisome proliferator-activated receptor-γ agonists (e.g., rosiglitazone) have been reported to ameliorate the senescence-like phenotype by modulating inflammatory mediator production. This study examined synergistic effects on the anti-tumor activity of rosiglitazone combined with olaparib in ovarian cancer treatment. METHODS: A2780 and SKOV3 mouse subcutaneous xenograft models were established for observing anti-tumor effects in living organisms and were randomly split into combination (both olaparib and rosiglitazone), rosiglitazone (10 mg/kg), olaparib (10 mg/kg), control (solvent) groups that received treatment once every 2 or 3 days (n = 6 per group). Cell counting kit-8 (CCK-8) assays were used to test the influences of rosiglitazone and olaparib on cell proliferation. PI and Annexin-V-FITC staining was used with flow cytometry to assess the cell cycle distribution and cell apoptosis. Senescence-associated ß-galactosidase (SA-ß-Gal) staining was used to observe cellular senescence. We performed quantitative real-time polymerase chain reaction assays to study the senescence-related secretory phenotype (SASP). RESULTS: Olaparib and rosiglitazone were observed to synergistically retard subcutaneous ovarian cancer growth in vivo, and synergistically suppress ovarian cancer cell proliferation in vitro. Compared with olaparib alone, the percentage of positive cells expressed SA-ß-gal and SASP were significantly decreased in the treatment of combination of olaparib and rosiglitazone. Furthermore, olaparib plus rosiglitazone increased the percentage of apoptosis in ovarian cancer cell compared with olaparib alone. In A2780 cells, it showed lower expression of P53, phospho-p53 (Ser15), P21, and P18 protein in combination treatment compared with olaparib alone. While, in SKOV3 cells, it showed lower expression of phosphor-retinoblastoma protein (Rb) (Ser807/811), and higher expression of cyclin D1, P21, and P16 protein in combination treatment compared with olaparib alone. CONCLUSIONS: Rosiglitazone combined with olaparib can help manage ovarian cancer by ameliorating olaparib-induced senescence and improving anti-tumor effects.


Assuntos
Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Neoplasias Ovarianas/induzido quimicamente , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Rosiglitazona/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Proteína Supressora de Tumor p53/metabolismo
12.
Biochem Pharmacol ; 171: 113693, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706843

RESUMO

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.


Assuntos
Adiposidade/efeitos dos fármacos , Dronabinol/análogos & derivados , Doenças Metabólicas/prevenção & controle , Obesidade/prevenção & controle , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Dronabinol/metabolismo , Dronabinol/farmacologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Células HEK293 , Humanos , Masculino , Doenças Metabólicas/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , PPAR gama/agonistas , PPAR gama/metabolismo , Rosiglitazona/metabolismo , Rosiglitazona/farmacologia
13.
Syst Rev ; 8(1): 295, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783920

RESUMO

BACKGROUND: Fatty liver is associated with obesity, type 2 diabetes, hyperlipidemia, hypertension, and metabolic syndrome. While there are no approved drugs for the treatment of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis, strategies to ameliorate fatty liver often target these related diseases. We sought to determine if any medications approved by the US Food and Drug Administration to treat diabetes are helpful in reducing weight and improving steatohepatitis in patients with NAFLD. METHODS: We conducted a systematic review of published and unpublished studies evaluating the comparative effectiveness and harms of diabetes medications for the treatment of NAFLD. We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials through 3rd quarter, 2019 using terms for included drugs and indications. RESULTS: We screened 1591 citations and included 18 trials of diabetes drugs to treat NAFLD. Studies of metformin found no difference from placebo in steatosis, fibrosis, NAFLD activity score, or resolution of NASH. While weight and glucose control were improved with metformin, it did not substantially impact liver disease. Studies of pioglitazone in NASH patients found benefits in liver function, liver fat, and NASH resolution, though significant increases in weight may be cause for concern. Evidence for other thiazolinediones was more limited and had somewhat mixed results, but findings were generally consistent with those for pioglitazone: liver fat and function and glucose measures improved, but weight also increased. We found some evidence that liraglutide improves liver fat, liver function, and HbA1c and is effective at resolving NASH and reducing weight. Exenatide performed less well but also resulted in significant reductions in liver fat and weight. CONCLUSIONS: Consistent with existing clinical practice guidelines, which recommend lifestyle intervention and treatment for comorbidities related to fatty liver disease as first-line treatment, trial evidence supports the efficacy of some diabetes drugs (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with some diabetes drugs may warrant caution. Larger trials are needed to better characterize the efficacy and harms of diabetes pharmacotherapy in these patients.


Assuntos
Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Metformina/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona/uso terapêutico , Rosiglitazona/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Exenatida/farmacologia , Exenatida/uso terapêutico , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Metformina/farmacologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Pioglitazona/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Rosiglitazona/farmacologia
14.
PLoS One ; 14(12): e0226069, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31805132

RESUMO

INTRODUCTION: Peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of one-carbon metabolism. Previously we have reported effects on plasma concentrations of metabolites along these pathways as well as markers of B-vitamin status in rats following treatment with a pan-PPAR agonist. Here we aimed to investigate the effect on these metabolites after specific activation of the PPARα and PPARγ subtypes. METHODS: For a period of 12 days, Male Wistar rats (n = 20) were randomly allocated to receive treatment with the PPARα agonist WY-14.643 (n = 6), the PPARγ agonist rosiglitazone (n = 6) or placebo (n = 8). The animals were sacrificed under fasting conditions, and plasma concentration of metabolites were determined. Group differences were assessed by one-way ANOVA, and planned comparisons were performed for both active treatment groups towards the control group. RESULTS: Treatment with a PPARα agonist was associated with increased plasma concentrations of most biomarkers, with the most pronounced differences observed for betaine, dimethylglycine, glycine, nicotinamide, methylnicotinamide, pyridoxal and methylmalonic acid. Lower levels were observed for flavin mononucleotide. Fewer associations were observed after treatment with a PPARγ agonist, and the most notable was increased plasma serine. CONCLUSION: Treatment with a PPARα agonist influenced plasma concentration of one-carbon metabolites and markers of B-vitamin status. This confirms previous findings, suggesting specific involvement of PPARα in the regulation of these metabolic pathways as well as the status of closely related B-vitamins.


Assuntos
Carbono/metabolismo , PPAR alfa/agonistas , Pirimidinas/farmacologia , Complexo Vitamínico B/sangue , Animais , Masculino , PPAR gama/agonistas , Ratos , Ratos Wistar , Rosiglitazona/farmacologia , Fatores de Tempo
15.
Molecules ; 25(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878261

RESUMO

In this study, for the purpose of elucidation for antidiabetic components, we isolated and identified compounds that could become lead compounds for the development of antidiabetic agents from the herbal medicine Vitex trifolia, which is used for liver protection in Myanmar. Three kinds of lignan, (-)-O-methylcubebin (MC), (-)-hinokinin, and (-)-cubebin, were isolated from the ethyl acetate extract of the leaves of V. trifolia, using various chromatography. Among the three isolated compounds, MC showed the strongest effects to increase intracellular lipid accumulation in 3T3-L1 cells. From the results of the elucidation of the MC's effects on the adipogenesis of 3T3-L1 cells, the downsizing of adipocytes and the promotion of the expression of adipogenesis-related proteins, as well as adiponectin, were observed. On the other hand, since the activity of MC was inhibited by antagonists of PPARγ and improved by inhibitors of the classical mitogen-activated protein kinase (MAPK) pathway and p38MAPK pathway, MC was considered to be an agonist of PPARγ, and furthermore promoted adipogenesis via the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38MAPK phosphorylation. Although MC showed similar effects to those of rosiglitazone (RO) used as a positive control, RO promoted the migration of GLUT4 from the cytoplasm to the cell membrane, whereas MC did not show such an effect. From the abovementioned results, it was considered that MC could be a lead compound for the development of antidiabetic drugs that does not show weight gain, which is a side effect of RO.


Assuntos
Adipogenia/efeitos dos fármacos , Lignanas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Vitex/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células 3T3-L1 , Adiponectina/metabolismo , Animais , Berberina/farmacologia , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
16.
Nat Commun ; 10(1): 5825, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862968

RESUMO

The repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor.


Assuntos
Proteínas Correpressoras/metabolismo , PPAR gama/metabolismo , Peptídeos/metabolismo , Anilidas/farmacologia , Benzamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Espectrometria de Massa com Troca Hidrogênio-Deutério , Ligantes , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , PPAR gama/ultraestrutura , Conformação Proteica em alfa-Hélice/efeitos dos fármacos , Conformação Proteica em alfa-Hélice/genética , Piridinas/farmacologia , Rosiglitazona/farmacologia
17.
Oxid Med Cell Longev ; 2019: 4826525, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781338

RESUMO

Peroxisome proliferator-activated receptor- (PPAR-) γ is a ligand-dependent transcription factor, and it has become evident that PPAR-γ agonists have renoprotective effects, but their influence and mechanism during the development of calcium oxalate (CaOx) nephrolithiasis remain unknown. Rosiglitazone (RSG) was used as a representative PPAR-γ agonist in our experiments. The expression of transforming growth factor-ß1 (TGF-ß1), hepatocyte growth factor (HGF), c-Met, p-Met, PPAR-γ, p-PPAR-γ (Ser112), Smad2, Smad3, pSmad2/3, and Smad7 was examined in oxalate-treated Madin-Darby canine kidney (MDCK) cells and a stone-forming rat model. A CCK-8 assay was used to evaluate the effects of RSG on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were monitored, and lipid peroxidation in renal tissue was detected according to superoxide dismutase and malondialdehyde levels. Moreover, the location and extent of CaOx crystal deposition were evaluated by Pizzolato staining. Our results showed that, both in vitro and in vivo, oxalate impaired PPAR-γ expression and phosphorylation, and then accumulative ROS production was observed, accompanied by enhanced TGF-ß1 and reduced HGF. These phenomena could be reversed by the addition of RSG. RSG also promoted cell viability and proliferation and decreased oxidative stress damage and CaOx crystal deposition. However, these protective effects of RSG were abrogated by the PPAR-γ-specific inhibitor GW9662. Our results revealed that the reduction of PPAR-γ activity played a critical role in oxalate-induced ROS damage and CaOx stone formation. RSG can regulate TGF-ß1 and HGF/c-Met through PPAR-γ to exert antioxidant effects against hyperoxaluria and alleviate crystal deposition. Therefore, PPAR-γ agonists may be expected to be a novel therapy for nephrolithiasis, and this effect is related to PPAR-γ-dependent suppression of oxidative stress.


Assuntos
Oxalato de Cálcio/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento de Hepatócito/biossíntese , Rim/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Animais , Cães , Células Epiteliais/patologia , Hiperoxalúria/tratamento farmacológico , Hiperoxalúria/metabolismo , Hiperoxalúria/patologia , Rim/patologia , Células Madin Darby de Rim Canino , Masculino , Nefrolitíase/tratamento farmacológico , Nefrolitíase/metabolismo , Nefrolitíase/patologia , Ratos Sprague-Dawley
18.
Biofabrication ; 12(1): 015018, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31715591

RESUMO

Adipose models have been applied to mechanistic studies of metabolic diseases (such as diabetes) and the subsequent discovery of new therapeutics. However, typical models are either insufficiently complex (2D cell cultures) or expensive and labor intensive (mice/in vivo). To bridge the gap between these models and in order to better inform pre-clinical studies we have developed a drug-responsive 3D model of white adipose tissue (WAT). Here, spheroids (680 ± 60 µm) comprising adipogenic 3T3-L1 cells encapsulated in 3D matrix were fabricated manually on a 96 well scale. Spheroids were highly characterised for lipid morphology, selected metabolite and adipokine secretion, and gene expression; displaying significant upregulation of certain adipogenic-specific genes compared with a 2D model. Furthermore, induction of lipolysis and promotion of lipogenesis in spheroids could be triggered by exposure to 8-br-cAMP and oleic-acid respectively. Metabolic and high content imaging data of spheroids exposed to an adipose-targeting drug, rosiglitazone, resulted in dose-responsive behavior. Thus, our 3D WAT model has potential as a powerful scalable tool for compound screening and for investigating adipose biology.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipocinas/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/instrumentação , Camundongos , Rosiglitazona/farmacologia , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo
19.
CNS Neurosci Ther ; 25(12): 1363-1372, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31729170

RESUMO

AIMS: Activated microglia have been found in the forebrains and hippocampi of temporal lobe epilepsy (TLE) patients and status epileptic (SE) animal models. The peroxisome proliferator-activated receptor γ (PPAR γ) agonist rosiglitazone has been shown to prevent microglial activation. However, its role in pilocarpine-induced status epilepticus remains unknown. We aimed to examine the effect of the PPAR γ agonist rosiglitazone in protecting against pilocarpine-induced status epileptic resulting from over-activation and to explore phenotypic changes in microglia as the underlying mechanism. METHODS: Male C57BL/6 mice were assigned to three groups: the control group, pilocarpine-induced (SE) group, and rosiglitazone-treated (SE+Rosi) group. Status epileptic mice were administered 300 mg/kg pilocarpine via intraperitoneal injection. SE+Rosi mice were administered rosiglitazone (0.1 mg/kg, i.p.) after SE. Flow cytometry, immunofluorescence staining, and quantitative real-time PCR were used to examine the activation of and phenotypic changes in microglia in the brain and to evaluate neuroinflammation. RESULTS: We found that the expression of proinflammatory CD86 and iNOS was increased and that the expression of antiinflammatory CD206 and Arg-1 was decreased in the brains of pilocarpine-induced SE mice compared to control mice. The mRNA levels of proinflammatory and antiinflammatory cytokines were not significantly changed in the brain. Rosiglitazone treatment significantly inhibited the proinflammatory polarization of microglia and rescued neuron loss in the temporal lobe and hippocampi of the brain after SE. CONCLUSION: Rosiglitazone reverses microglial polarization in the brains of SE mice and also affords neuroprotection against pilocarpine-induced status epilepticus without inducing significant changes in brain inflammation.


Assuntos
Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , PPAR gama/agonistas , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Estado Epiléptico/prevenção & controle , Animais , Antígeno B7-2/biossíntese , Química Encefálica/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Convulsivantes , Citocinas/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Pilocarpina , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia
20.
Pharmacogenomics ; 20(16): 1125-1141, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31755367

RESUMO

Aim: The objective was to determine via high-throughput RNA sequencing the temporal effects of rosiglitazone (Avandia®) on the neonatal rat ventricular myocyte transcriptome. Materials & methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to rosiglitazone in vitro. Meta analyses utilized temporal comparisons of 0.5 h control versus 0.5 h treatment, 0.5 h treatment versus 24 h treatment and 24 h treatment versus 48 h treatment. Results: Time dependent responses were observed. At 0.5 h, the PI3K-AKT signaling pathway was impacted. At 24 h endoplasmic reticulum activity and protein degradation were altered. At 48 h, oxytocin signaling was perturbed. Conclusion: The effects of rosiglitazone occured early and increased in magnitude over time. A protective molecular response was triggered at 24 h and maintained until 48 h. In parallel, a response that can cause cardiac damage was activated. Our findings suggest that rosiglitazone has deleterious effects.


Assuntos
Ventrículos do Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Rosiglitazona/farmacologia , Transcriptoma/genética , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Ventrículos do Coração/patologia , Humanos , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
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