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1.
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
2.
Int J Mol Sci ; 20(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470514

RESUMO

Tobacco smoking (TS) is one of the most addictive habit sand a main public health hazards, impacting the vascular endothelium through oxidative stress (OS) stimuli, exposure to nicotine, and smoking-induced inflammation in a dose-dependent manner. Increasing evidence also suggested that TS increases glucose intolerance and the risk factor of developing type-2 diabetes mellitus (2DM), which, along with TS, is connected to blood-brain barrier (BBB) injuries, and heightens the risk of cerebrovascular disorders. Although the exact mechanism of rosiglitazone (RSG) is unknown, our previous in vitro work showed how RSG, an oral anti-diabetic drug belonging to the family of thiazolidinedione class, can protect BBB integrity through enhancement of nuclear factor erythroid 2-related factor (Nrf2) activity. Herein, we have validated the protective role of rosiglitazone against TS-induced BBB impairment in vivo. Our results revealed that RSG as a peroxisome proliferator-activated receptor gamma (PPARγ), activates counteractive mechanisms primarily associated with the upregulation of Nrf2 and PPARγ pathways which reduce TS-dependent toxicity at the cerebrovascular level. In line with these findings, our results show that RSG reduces inflammation and protects BBB integrity. In conclusion, RSG offers a novel and promising therapeutic application to reduce TS-induced cerebrovascular dysfunction through activation of the PPARγ-dependent and/or PPARγ-independent Nrf2 pathway.


Assuntos
Transtornos Cerebrovasculares/prevenção & controle , Diabetes Mellitus/prevenção & controle , Hipoglicemiantes/farmacologia , Rosiglitazona/farmacologia , Fumar Tabaco/efeitos adversos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtornos Cerebrovasculares/etiologia , Cotinina/sangue , Cotinina/metabolismo , Diabetes Mellitus/etiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Nicotina/sangue , Nicotina/metabolismo , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Ups J Med Sci ; 124(3): 158-167, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31407948

RESUMO

Background: Tissue factor (TF) combined with its ligand FVII initiates blood coagulation and intracellular signaling. Obese and type 2 diabetic subjects have increased TF expression in their adipose tissue and an increased risk for thrombotic complications. Here we address the role of TF/FVII on adipocyte functions. Materials and methods: Subcutaneous fat was obtained by means of needle aspiration from healthy volunteers, and adipocytes were isolated after collagenase digestion. 3T3-L1 fibroblasts kept in culture were differentiated into adipocytes by addition of IBMX, dexamethasone, rosiglitazone, and insulin to the media. Proteins and mRNA were analyzed by western blot and RT-PCR. Coagulation activity was determined by a colorimetric FX-assay. Lipolysis was measured as free glycerol using a colorimetric method. Glucose uptake was evaluated by scintillation counting of D-[U-14C] glucose. Results: In isolated human primary adipocytes we found expression of TF and FVII. TF expression was confirmed in 3T3-L1 adipocytes, and both cell types were found to be procoagulant in a TF/FVIIa-dependent manner. FXa was generated without FVIIa added to the coagulation assay, and active site-inhibited FVIIa blocked FXa formation, supporting our finding of FVII production by human primary adipocytes. There was no evidence for a role of TF in either lipolysis or glucose uptake in our experimental settings. Conclusion: Human primary adipocytes express active TF and FVII, and the TF/FVIIa complex formed on the adipocyte surface can activate substrate FX. Whether the TF/FVIIa complex conveys signaling pathways leading to biological functions and has any biological activity in adipocytes beyond coagulation remains to be elucidated.


Assuntos
Adipócitos/metabolismo , Regulação da Expressão Gênica , Serina Endopeptidases/genética , Tromboplastina/genética , Adipócitos/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Western Blotting , Células Cultivadas , Meios de Cultivo Condicionados , Dexametasona/farmacologia , Regulação para Baixo , Voluntários Saudáveis , Humanos , Insulina/farmacologia , Lipólise/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Rosiglitazona/farmacologia , Transdução de Sinais , Gordura Subcutânea/citologia , Transfecção
4.
Toxicol In Vitro ; 60: 347-358, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31233785

RESUMO

Pregnane & Xenobiotic Receptor (PXR), one of the members of nuclear receptor superfamily, acts as a 'master-regulator' of drug metabolism and disposition machinery (DMD). Activation of PXR enables detoxification and elimination of toxic xenobiotics/endobiotics, and defends our body against chemical insults. On the contrary, PXR activation also imposes a serious concern for drug-drug interactions (DDIs). Such DDIs could either decrease the efficacy or lead to accumulation of co-administered drugs at toxic level. Therefore, it is desirable that during drug development process the small drug molecules are screened on PXR-platform prior to their clinical trial and prevent late stage failures. In view of this, we have selected a group of anti-diabetic drug molecules to examine if the success and potential failure of small molecule modulators can be pre-assessed and judiciously correlated on PXR platform. For this purpose, we have examined the PXR activation potential of the selected anti-diabetic drugs. Subsequent to screening of these anti-diabetic drugs, we elaborated the study further with rosiglitazone and pioglitazone (thiazolidinediones, TZDs) which are oral anti-diabetic formulations and have been in controversy owing to their association with cardiotoxicity and bladder cancer respectively. Our study revealed that some of the selected anti-diabetic drugs possess PXR activation potential, implying that these can up-regulate the expression of CYP3A4, UGT1A1, MDR1 and thereby can be predicted to inflict undesirable consequences.


Assuntos
Hipoglicemiantes/farmacologia , Receptor de Pregnano X/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interações de Medicamentos , Glucuronosiltransferase/genética , Humanos , Pioglitazona/farmacologia , Receptor de Pregnano X/genética , RNA Interferente Pequeno/genética , Rosiglitazona/farmacologia
5.
Mediators Inflamm ; 2019: 7915730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31217747

RESUMO

In this study, we investigated the role of MAP kinase phosphatase-1 (MKP-1) and rosiglitazone (RSG) in glucocorticoid resistance and glucocorticoid sensitivity, respectively, using a guinea pig model of lipopolysaccharide- (LPS-) induced sudden sensorineural hearing loss (SSHL). The pigs were divided into control, LPS, LPS+dexamethasone (DEX), LPS+RSG, and LPS+DEX+RSG groups. Their hearing was screened by auditory brainstem response measurement. Immunofluorescence staining was used to identify the location of MKP-1 in the inner ear. The expression levels of MKP-1 and the related proteins in the inner ear were detected using western blotting. The morphological changes in the cochlea were observed via hematoxylin-eosin staining. Severe hearing loss was observed in the LPS group, as opposed to the protection from hearing loss observed in the LPS+DEX+RSG group. A positive correlation was observed between MKP-1 expression levels and protection from hearing loss. RSG and DEX synergistically influenced inner ear inflammation. In conclusion, resistance of LPS-induced SSHL guinea pig models to glucocorticoids may result from impaired MKP-1 function in inner ear tissues, induced by glucocorticoids, impairing the inhibition of inflammation. Our findings present novel targets to develop potential therapeutics to treat inflammatory diseases of the inner ear.


Assuntos
Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Audição/efeitos dos fármacos , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Animais , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Fosfatase 1 de Especificidade Dupla , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cobaias , Perda Auditiva Neurossensorial/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino
6.
Molecules ; 24(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212694

RESUMO

Recent evidence suggests that PPARγ agonists may promote anti-tumor immunity. We show that immunogenic PDV cutaneous squamous cell carcinoma (CSCC) tumors are rejected when injected intradermally at a low cell number (1 × 106) into immune competent syngeneic hosts, but not immune deficient mice. At higher cell numbers (5 × 106 PDV cells), progressively growing tumors were established in 14 of 15 vehicle treated mice while treatment of mice with the PPARγ agonist rosiglitazone resulted in increased tumor rejection (5 of 14 tumors), a significant decrease in PDV tumor size, and a significant decrease in tumor cell Ki67 labeling. Rosiglitazone treatment had no effect on tumor rejection, tumor volume or PDV tumor cell proliferation in immune deficient NOD.CB17-PrkdcSCID/J mice. Rosiglitazone treatment also promoted an increase in tumor infiltrating CD3+ T-cells at both early and late time points. In contrast, rosiglitazone treatment had no significant effect on myeloid cells expressing either CD11b or Gr-1 but suppressed a late accumulation of myeloid cells expressing both CD11b and Gr-1, suggesting a potential role for CD11b+Gr-1+ myeloid cells in the late anti-tumor immune response. Overall, our data provides evidence that the PPARγ agonist rosiglitazone promotes immune-mediated anti-neoplastic activity against tumors derived from this immunogenic CSCC cell line.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Hipoglicemiantes/farmacologia , Imunomodulação/efeitos dos fármacos , PPAR gama/agonistas , Rosiglitazona/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Isogênico , Carga Tumoral/efeitos dos fármacos
7.
Acta Biochim Biophys Sin (Shanghai) ; 51(7): 715-722, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31168600

RESUMO

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is expressed in pancreatic ß cells and is involved in insulin secretion. However, the precise mechanisms remain unclear. Calcium/calmodulin-dependent serine protein kinase (CASK), which plays a vital role in the anchoring of insulin granules on pancreatic ß cell membrane, is probably a downstream of the transcription factor PPAR-γ. The aim of the present study was to investigate the correlation among PPAR-γ, CASK and insulin secretion. We found that rosiglitazone (RSG) had a positive effect on the expression of CASK and PPAR-γ in INS-1 cells as shown by real-time polymerase chain reaction (PCR) and western blot analysis, but did not change the cellular location of CASK as shown by immunofluorescence assay. Knockdown of PPAR-γ significantly attenuated the mRNA and protein expression levels of CASK. ChIP-qPCR and luciferase assays showed that PPAR-γ bound with the Cask promoter, and promoter activity of Cask was elevated by RSG. RSG significantly enhanced the insulin secretion with potassium stimulation, but did not alter the insulin content as shown by potassium-stimulated insulin secretion assay. In addition, with RSG pretreatment, knockdown of Cask did not significantly affect the PPAR-γ activation-mediated insulin secretion. Moreover, electron microscopy demonstrated that with RSG pretreatment, silence of Cask did not change the number of vesicles anchored on the cell membranes compared with those in siCask-treated cells. Overall, the present study identifies that CASK is one of the PPAR-γ downstream targets and PPAR-γ exerts a positive effect on the expression of CASK in INS-1 cells. PPAR-γ activation increases insulin secretion independent of the upregulation of CASK.


Assuntos
Guanilato Quinases/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , PPAR gama/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Guanilato Quinases/genética , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos Endogâmicos C57BL , PPAR gama/agonistas , PPAR gama/genética , Interferência de RNA , Ratos , Rosiglitazona/farmacologia , Fatores de Tempo
8.
Cell Mol Biol Lett ; 24: 35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31160894

RESUMO

Background: Pulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this. Methods: Our ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1ß in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 µM) with or without GW9662 (10 µM). The expressions of αENaC and SGK1 were determined 24 h later. Results: A mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1ß levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662. Conclusions: Rosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Líquido da Lavagem Broncoalveolar/química , Canais Epiteliais de Sódio/metabolismo , PPAR gama/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Rosiglitazona/farmacologia , Transdução de Sinais , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
Methods Mol Biol ; 1966: 261-289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041755

RESUMO

The chapter is focused on methods relevant for predictive toxicology and computer-aided drug design (adverse outcome pathway development, pharmacophore modeling, docking, and 3D QSAR analysis) and applied to study interactions between peroxisome proliferator-activated receptor γ (PPARγ) and its ligands. The methods have been combined to develop an integrated in silico approach allowing both to predict potential PPARγ-mediated hepatotoxicity of receptor's full agonists, thus supporting hazard characterization, and to identify naturally derived antidiabetic triterpenoids potentially acting through PPARγ partial agonism.


Assuntos
Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular/métodos , PPAR gama/metabolismo , Humanos , Ligantes , Oxazóis/farmacologia , PPAR gama/agonistas , PPAR gama/química , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Rosiglitazona/farmacologia , Tirosina/análogos & derivados , Tirosina/farmacologia
10.
Reprod Domest Anim ; 54(8): 1069-1077, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31099063

RESUMO

Spermatozoa are highly specialized cells, and energy metabolism plays an important role in modulating sperm viability and function. Rosiglitazone is an antidiabetic drug in the thiazolidinedione class that regulates metabolic flexibility and glucose uptake in various cell types, but its effects on boar sperm metabolism are unknown. In this study, we investigated the potential effect of rosiglitazone against time-dependent deterioration of boar spermatozoa during liquid preservation at 17°C. Freshly ejaculated semen was diluted with Beltsville Thawing Solution (BTS) containing different concentrations of rosiglitazone, and the motility, membrane and acrosome integrity of sperm were detected. Besides, we measured glucose uptake capacity, l-lactate production level, mitochondrial membrane potential, adenosine triphosphate (ATP) content and mitochondrial reactive oxygen species (mROS) production of sperm after boar semen had been incubated with or without rosiglitazone, iodoacetate (glycolysis inhibitor) and rotenone (electron transport chain inhibitor) for 5 days. The addition of rosiglitazone significantly enhanced sperm quality and had a strong protective effect on the sperm membrane and acrosome integrity during storage. BTS containing 50 µM rosiglitazone maintained the total motility of liquid-preserved sperm above 60% for 7 days. Rosiglitazone improved sperm quality by regulating energy metabolism manner of preserved sperm, protected the sperm mitochondrial membrane potential, enhanced sperm ATP production and in the meanwhile reduced mROS through enhancing glycolysis but not oxidative phosphorylation. The data suggested the practical feasibility of using rosiglitazone for improving boar spermatozoa quality during semen preservation.


Assuntos
Hipoglicemiantes/farmacologia , Rosiglitazona/farmacologia , Preservação do Sêmen/veterinária , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Suínos , Animais , Crioprotetores/farmacologia , Metabolismo Energético , Masculino , Motilidade Espermática
11.
Can J Cardiol ; 35(4): 480-489, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30935639

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as important mediators of cardiac pathophysiology. The aim of the present study is to investigate the effects of lncR-30245, an lncRNA, on cardiac fibrogenesis and the underlying mechanism. METHODS: Myocardial infarction (MI) and transforming growth factor (TGF)-ß1 were used to induce fibrotic phenotypes. Cardiac fibrosis was detected by Masson's trichrome staining. Cardiac function was evaluated by echocardiography. Western blot, quantitative reverse transcription-polymerase chain reaction, and pharmacological approaches were used to investigate the role of lncR-30245 in cardiac fibrogenesis. RESULTS: Expression of lncR-30245 was significantly increased in MI hearts and TGF-ß1-treated cardiac fibroblasts (CFs). LncR-30245 was mainly located in the cytoplasm. Overexpression of lncR-30245 promoted collagen production and CF proliferation. Knockdown of lncR-30245 significantly inhibited TGF-ß1-induced collagen production and CF proliferation. LncR-30245 overexpression inhibited the antifibrotic role of peroxisome proliferator-activated receptor (PPAR)-γ and increased connective tissue growth factor (CTGF) expression, whereas lncR-30245 knockdown exerted the opposite effects. Rosiglitazone, a PPAR-γ agonist, significantly inhibited lncR-30245-induced CTGF upregulation and collagen production in CFs. In contrast, T0070907, a PPAR-γ antagonist, attenuated the inhibitory effects of lncR-30245 small interfering RNA (siRNA) on TGF-ß1-induced CTGF expression and collagen production. LncR-30245 knockdown significantly enhanced ejection fraction and fractional shortening and attenuated cardiac fibrosis in MI mice. CONCLUSION: Our study indicates that the lncR-30245/PPAR-γ/CTGF pathway mediates MI-induced cardiac fibrosis and might be a therapeutic target for various cardiac diseases associated with fibrosis.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Cardiopatias/metabolismo , PPAR gama/metabolismo , RNA Longo não Codificante , Animais , Benzamidas/farmacologia , Proliferação de Células , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Fibroblastos/metabolismo , Fibrose , Camundongos Endogâmicos C57BL , Modelos Animais , Infarto do Miocárdio/metabolismo , Piridinas/farmacologia , Rosiglitazona/farmacologia , Volume Sistólico , Fator de Crescimento Transformador beta1/farmacologia , Regulação para Cima/efeitos dos fármacos
12.
BMC Neurosci ; 20(1): 15, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947684

RESUMO

BACKGROUND: Smoking (TS) and recently e-cigarettes (EC) vaping, have been associated with vascular endothelial dysfunction primarily relevant to oxidative stress, exposure to nicotine, and smoking-induced inflammation. It is accepted that both EC and TS enhance glucose intolerance and the risk of developing type-2 diabetes mellitus which is also one of the causes of blood-brain barrier (BBB) damage and the higher risk of cerebrovascular diseases. Recent studies have shown how Metformin, the first common antidiabetic drug, can protect the BBB integrity through enhancement of nuclear factor erythroid 2-related factor (Nrf2) activity. Herein, we investigated the role of rosiglitazone (RSG; family of thiazolidinedione class used oral anti-diabetic drug) in TS/EC-induced BBB impairment. RESULTS: Although the exact mechanism of RSG is not fully understood, previous studies have revealed that RSG can promote counteractive protective mechanisms primarily associated with the enhancement of Nrf2 activity through activation of the peroxisome proliferator-activated receptor gamma. In line with these findings, our results show an increased expression of PPARy by RSG, enhancement of Nrf2 activity and BBB protection against TS/EC exposure including reduced inflammation, oxidative stress, tight junction downregulation and loss of BBB integrity. CONCLUSIONS: RSG could be considered as a promising therapeutic potential to prevent TS/EC induced cerebrovascular dysfunction and possibly other xenobiotic substances which may impact the BBB via oxidative stress-mediated effects. However, additional in vivo studies and clinical setting will be needed to validate our results and assess the full extent of RSG protective effects.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina , Fármacos Neuroprotetores/farmacologia , Rosiglitazona/farmacologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Permeabilidade Capilar/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Camundongos Endogâmicos C57BL , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/patologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , PPAR gama/metabolismo , Dados Preliminares , Espécies Reativas de Oxigênio/metabolismo
13.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939750

RESUMO

Obesity is a major risk for diabetes. Brown adipose tissue (BAT) mediates production of heat while white adipose tissue (WAT) function in the storage of fat. Roles of BAT in the treatment of obesity and related disorders warrants more investigation. Peroxisome proliferator activator receptor gamma (PPAR-γ) is the master regulator of both BAT and WAT adipogenesis and has roles in glucose and fatty acid metabolism. Adipose tissue is the major expression site for PPAR-γ. In this study, the effects of rosiglitazone on the brown adipogenesis and the association of MAPK and PI3K pathways was investigated during the in vitro adipogenic differentiation of telomerase transformed mesenchymal stromal cells (iMSCs). Our data indicate that 2 µM rosiglitazone enhanced adipogenesis by over-expression of PPAR-γ and C/EBP-α. More specifically, brown adipogenesis was enhanced by the upregulation of EBF2 and UCP-1 and evidenced by multilocular fatty droplets morphology of the differentiated adipocytes. We also found that rosiglitazone significantly activated MAPK and PI3K pathways at the maturation stage of differentiation. Overall, the results indicate that rosiglitazone induced overexpression of PPAR-γ that in turn enhanced adipogenesis, particularly browning adipogenesis. This study reports the browning effects of rosiglitazone during the differentiation of iMSCs into adipocytes in association with the activation of MAPK and PI3K signaling pathways.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipogenia , Hipoglicemiantes/farmacologia , Sistema de Sinalização das MAP Quinases , Rosiglitazona/farmacologia , Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
14.
Am J Physiol Endocrinol Metab ; 317(1): E65-E73, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30964707

RESUMO

Targeting metabolic determinants of exercise performance with pharmacological agents that would mimic/potentiate the effects of exercise represents an attractive clinical alternative to counterbalance the poor exercise capacity in patients with type 2 diabetes mellitus (T2DM). We examined the effect of 1-yr treatment with the insulin sensitizer peroxisome proliferator-activated receptor (PPAR)γ agonist rosiglitazone on aerobic exercise capacity and body fat composition/distribution in men with T2DM and stable coronary artery disease (CAD). One-hundred four men (age: 64 ± 7 yr; body mass index: 30.0 ± 4.4 kg/m2) with T2DM and CAD were randomized to receive rosiglitazone or placebo for 1 yr. Aerobic exercise capacity (exercise duration) was assessed with a maximal treadmill test, and body composition/distribution were assessed by dual-energy X-ray absorptiometry/computed tomography scans. At 1 yr, patients with T2DM under PPARγ agonist treatment showed a reduction in aerobic exercise capacity compared with the control group (exercise duration change, -31 ± 8 versus 7 ± 11 s, P = 0.009). Significant increases in body fat mass (3.1 ± 0.4 kg, 12%), abdominal and mid-thigh subcutaneous adipose tissue (AT) levels, and mid-thigh skeletal muscle fat were found (all P < 0.01), whereas no effect on visceral AT levels was observed (P > 0.05) under treatment. Subcutaneous fat mass gained under PPARγ agonist was the strongest predictor of the worsening in aerobic exercise capacity (P > 0.0001); no association was found with skeletal muscle fat infiltration nor visceral AT. Treatment with the insulin sensitizer PPARγ agonist rosiglitazone in patients with T2DM and CAD is associated with a worsening in aerobic exercise capacity, which seems to be mainly attributable to weight gain and subcutaneous fat mass expansion.


Assuntos
Distribuição da Gordura Corporal , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Tolerância ao Exercício/efeitos dos fármacos , Rosiglitazona/farmacologia , Idoso , Composição Corporal/efeitos dos fármacos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/terapia , Exercício/fisiologia , Humanos , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , PPAR gama/agonistas , Rosiglitazona/uso terapêutico , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo
15.
Lipids ; 54(2-3): 141-148, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30891789

RESUMO

In the current investigation, the effect of epigallocatechin gallate (EGCG) on the phosphorylation of IRS1S307 and AktS473 molecules in insulin-resistant C2C12 muscle cells induced with palmitate was studied and compared with the effect of the antidiabetic drug, rosiglitazone. C2C12 myoblasts were cultured in Dulbecco's modified Eagle's medium and differentiated into myotubes using horse serum and the creatine kinase test was used to confirm their differentiation. The treatment of C2C12 myotubes was carried out with palmitate, where albumin was used as the conjugator. The Western blot technique was used to check the useful phosphorylation of IRS1S307 and AktS473 in C2C12 myotubes, in the presence or absence of palmitate. There was a significant (p < 0.00) and linear increase in the activity of creatine kinase over time (0 to 96 h after differentiation) with everyday myoblast formation. While neither EGCG nor rosiglitazone showed a significant (p > 0.05) effect on palmitate content during 96 h of incubation of IRS1S307 , EGCG alone or combined with rosiglitazone increased the phosphorylation of AktS473 , leading to the increase of glucose uptake into C2C12 cells. Thus, it can be concluded that EGCG alone or in combination with rosiglitazone may show some therapeutic effects for the prevention or treatment of Type 2 diabetes owing to its substantial effect on increasing the phosphorylation of AktS473 and the subsequent glucose uptake into the cells.


Assuntos
Catequina/análogos & derivados , Proteínas Substratos do Receptor de Insulina/metabolismo , Palmitatos/farmacologia , Chá/química , Animais , Catequina/farmacologia , Linhagem Celular , Hipoglicemiantes/farmacologia , Resistência à Insulina/fisiologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt , Rosiglitazona/farmacologia
16.
BMC Cancer ; 19(1): 204, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845932

RESUMO

BACKGROUND: Heterogeneity in bladder cancer results in variable clinical outcomes, posing challenges for clinical management of this malignancy. Recent studies suggest both tumor suppressive and oncogenic role of PPARγ in bladder cancer. The fuction of PPARγ signaling pathway in modulating carcinogenesis is controversial. METHODS: The expression of PPARγ and association with overall survival were analyzed in patients from two cohorts. The effect of PPARγ activation on cell proliferation, cell cycle, and cell apoptosis were determined with the agonists (rosiglitazone and pioglitazone), the inverse agonist (T0070907), and the antagonist (GW9662) in Umuc-3 and 5637 bladder cancer cells. The correlation of PPARγ activation with PI3K-Akt pathway was evaluated with RNA sequencing data from the TCGA cases and 30 human bladder cancer cell lines. The effect of PPARγ activation on tumor growth was validated with subcutaneous tumor models in vivo. The effect of PPARγ activation on PI3K-Akt signaling transduction was determined with multiple assays including immunohistochemistry, flow cytometry, proteomic array, and western blotting. RESULTS: We showed that PPARγ was a favorable prognostic factor in patients with bladder cancer. PPARγ activation by rosiglitazone and pioglitazone markedly induced cell cycle G2 arrest and apoptosis in bladder cancer cells, which resulted in inhibition of cell proliferation in vitro and suppression of tumor growth in vivo. The underlying mechanism involved marked inhibition of PI3K-Akt pathway. CONCLUSIONS: This study reported the tumor-suppressive effect of PPARγ agonists in bladder cancer, suggesting that transactivation of PPARγ could be served as a potential strategy for the chemoprevention and therapeutic treatment of bladder cancer.


Assuntos
PPAR gama/agonistas , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Modelos Biológicos , Prognóstico , Rosiglitazona/farmacologia , Transcriptoma , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Gene ; 696: 54-62, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30772521

RESUMO

Intramuscular fat (IMF), which is modulated by the number and size of intramuscular preadipocytes, plays a key role in pork quality. DNA (cytosine-5)-methyltransferase 3A (DNMT3A), an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, is involved in the management of diverse intracellular processes. However, the physiological functions of DNMT3A in proliferation and differentiation of porcine intramuscular preadipocytes have not been clearly established. Here, we found that DNMT3A significantly promoted the proliferation, while inhibited the differentiation of intramuscular preadipocytes. We demonstrated that overexpression of DNMT3A promoted the expression of cell proliferation markers but significantly decreased the expression of p21 to repress cell proliferation by the methylation of p21 promoter. Moreover, overexpression of DNMT3A decreased lipid accumulation and significantly down-regulated the levels of adipogenic marker genes including PPARg (Peroxisome proliferator-activated receptor gamma), SREBP-1c (Sterol regulatory element-binding protein 1c), and aP2 (FABP4, fatty acid binding protein 4) through the methylation of PPARg promoter. The blocking effect of DNMT3A on adipogenesis can be rescued by rosiglitazone treatment. Collectively, these findings illustrated the essential role of DNMT3A in the proliferation and differentiation of porcine intramuscular preadipocytes, and provide a potential target to improve pork quality.


Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , PPAR gama/metabolismo , Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Adipogenia/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Metilação de DNA/fisiologia , Regulação para Baixo , Masculino , Músculo Esquelético/citologia , Regiões Promotoras Genéticas/genética , Rosiglitazona/farmacologia , Suínos
18.
Eur J Pharmacol ; 848: 30-38, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30710547

RESUMO

The activation of peroxisome proliferator-activated receptor γ (PPAR-γ) has been shown to attenuate allergic airway inflammation (AAI). To gain better understanding of mechanisms underlying this effect, the impact of rosiglitazone (RSG), a PPAR-γ agonist, on CD4+ effector (Teff) and Foxp3-expressing regulatory (Treg) T cells in a mouse model of allergic asthma was studied. Furthermore, we investigated whether the activation of PPAR-γ may directly affect IL-4, IL-10 and IL-17 production by CD4+ T cells. RSG attenuated but did not prevent ovalbumin (OVA)-induced AAI, and this effect was PPAR-γ-dependent. RSG reduced but did not abolish the OVA-induced increase in the count of CD4+ Teff cells in the mediastinal lymph nodes (MLNs) and lungs, and this effect was PPAR-γ-dependent. RSG did not affect the absolute number of Treg cells in the MLNs and lungs of OVA-immunized mice. In vitro exposure of lung lymphocytes to RSG did not influence the percentage of IL-4-, IL-10- and IL-17-producing CD4+ T cells. Our results indicate that the impairment of clonal expansion of CD4+ Teff cells in the MLNs is involved in the anti-asthmatic properties of PPAR-γ agonists. Activation of PPAR-γ did not affect the recruitment of Treg cells to the MLNs and lungs nor did it induce their local generation. This indicates that Treg cells are not involved in producing the anti-asthmatic effect of PPAR-γ agonists. The results suggest that beneficial effects of PPAR-γ agonists in asthma treatment are not mediated through a direct inhibitory effect on IL-4, IL-10 and IL-17 production by CD4+ Teff cells.


Assuntos
Asma/tratamento farmacológico , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/biossíntese , PPAR gama/agonistas , Rosiglitazona/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Asma/metabolismo , Contagem de Linfócito CD4 , Fatores de Transcrição Forkhead/genética , Expressão Gênica , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Rosiglitazona/farmacologia , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento
19.
J Immunol ; 202(6): 1798-1806, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30700583

RESUMO

Infection of mice with Borrelia burgdorferi causes an inflammatory arthritis that peaks 3-4 wk postinfection and then spontaneously resolves. Although the recruitment of neutrophils is known to drive the development of arthritis, mechanisms of disease resolution remain unclear. Efficient clearance of apoptotic cells (AC) is likely an important component of arthritis resolution. In this article, we show the number of AC increases in the joints of B. burgdorferi-infected mice around day 21 postinfection and peaks around day 28. Injection of AC directly into the ankles of B. burgdorferi-infected mice limited ankle swelling but had no effect on spirochete clearance or arthritis severity scores. In vitro, addition of AC to bone marrow macrophage cultures decreased B. burgdorferi-induced TNF-α and KC and increased IL-10. In addition, phagocytosis of B. burgdorferi and neutrophil migration to LTB4 were inhibited by AC. Exogenous AC caused an increase in peroxisome proliferator-activated receptor-γ (PPAR-γ) expression both in vitro and in vivo during B. burgdorferi infection. The PPAR-γ agonist rosiglitazone elicited similar changes in macrophage cytokine production and neutrophil migration as exogenous AC. Addition of the PPAR-γ antagonist GW 9662 abrogated the effects of AC in vitro. Injection of rosiglitazone directly into the tibiotarsal joints of B. burgdorferi-infected mice decreased ankle swelling and immune cell recruitment, similar to the injection of AC. These results suggest that clearance of AC plays a role in the resolution of inflammation during experimental Lyme arthritis through the activation of PPAR-γ. PPAR-γ agonists, such as rosiglitazone, may therefore be effective treatments for inducing arthritis resolution.


Assuntos
Apoptose , Doença de Lyme/imunologia , PPAR gama/imunologia , Animais , Borrelia burgdorferi/imunologia , Feminino , Doença de Lyme/complicações , Doença de Lyme/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Rosiglitazona/farmacologia
20.
Eur J Pharmacol ; 851: 133-143, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30797787

RESUMO

Rosiglitazone, a PPAR-γ agonist, possesses anti-fibritic effect; however, its inhibitory effect on paraquat (PQ)-induced pulmonary fibrosis is not completely understood. Here, we investigated the inhibitory effect of rosiglitazone on PQ-induced acute pulmonary fibrosis in rats and its underlying mechanism. Male Sprague-Dawly rats were administered a single intraperitoneal injection of 30 mg/kg PQ and euthanised 7, 14, 21, and 28 days after PQ poisoning. PQ-induced pulmonary fibrosis was most obvious on day 28. Male Sprague-Dawly rats were exposed either against distilled water as control groups or PQ (30 mg/kg, i.p.) as test groups. The control groups were nominated as NC group (without treatment), RSG group (only treatment with rosiglitazone, 10 mg/kg/d), and GW group (only treatment with GW9662, a PPAR-γ antagonist, 1 mg/kg/d). The test groups were nominated as PQ group (PQ exposed without treatment), PQ + RSG group (treatment with rosiglitazone), and PQ + RSG + GW group (treatment with rosiglitazone and GW9662). Rosiglitazone was able to recover the PQ-induced decrease in arterial oxygen partial pressure (PaO2), increase in the wet-to-dry (W/D) lung tissue weight ratio and lung fibrosis score. Rosiglitazone inhibited the PQ-induced reduction in protein and mRNA levels of PPAR-γ and PTEN and elevation in protein and mRNA levels of TGF-ß1 and α-SMA. GW9662 administration antagonized the effect of rosiglitazone. These data suggest that rosiglitazone attenuated PQ-induced pulmonary fibrosis by upregulateing PTEN and downregulating TGF-ß1 expression in a PPAR-γ dependent manner.


Assuntos
PPAR gama/metabolismo , Paraquat/envenenamento , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Rosiglitazona/farmacologia , Actinas/genética , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxiprolina/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Oxigênio/metabolismo , PPAR gama/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Rosiglitazona/uso terapêutico , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
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