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1.
Artigo em Chinês | MEDLINE | ID: mdl-34624942

RESUMO

Objective: To investigate the effect and mechanism of PPAR-γ agonist Pioglitazone (PGZ) on the proliferation of malignant mesothelioma (MM) cells. Methods: In December 2019, MM cell lines MSTO-211H and NCI-H2452 were incubated with different final concentrations of PGZ (0, 10, 50, 100, 150, and 200 µmol/L) for different periods of time (24 h, 48 h, and 72 h) , and then the cell proliferation level was detected by CCK8 assay. After given various final concentration of PGZ (0, 10, 50, 100, 150, 200 µmol/L) the for 72 hours, the changes of number and morphology of MM cells were observed under an inverted microscope. The expressions of PPAR-γ and HMGB1 mRNA were determined by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR) after treatment of MM cells with PGZ of 0, 10, 50, 100 µmol/L for 72 h. The MM cells were treated with PGZ at concentration of 0, 100 µmol/L for 72 h, and the protein expressions of HMGB1 were examined using Western blotting and immunofluorescence; the protein expressions of Ki67 were assessed by immunohistochemistry. Results: The cell viability rate of MM cells was decreased after treated with PGZ (P<0.05) . Cell number in PGZ-treated group was significantly less than that in control group and morphology changes were observed under light microscope. QRT-PCR results revealed significantly increased PPAR-γ mRNA expression in the PGZ-treated group compared to the control group (P<0.05) . There was a significant decrease in the mRNA expression level of HMGB1 in the PGZ-treated group (100 µmol/L) as compared to the control group in MSTO-211H (P<0.05) ; however, the expression level of HMGB1 in NCI-H2452 was an increase or no significant differences (P>0.05) . Western blotting and immunofluorescence results showed that the protein expression of HMGB1 was reduced in the PGZ-treated group compared with the control group in MSTO-211H (P<0.05) , but the protein expression of that in NCI-H2452 was no significant differences (P>0.05) . Immunohistochemistry results showed increased expression of proliferation marker Ki-67. Conclusion: Pioglitazone suppresses the proliferation of MM cells through inhibition of HMGB1 by the activation of PPAR-γ.


Assuntos
Proteína HMGB1 , Mesotelioma/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células , Humanos
2.
Biomed Pharmacother ; 139: 111684, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243632

RESUMO

PPARγ regulate the expression of genes involved in peripheral insulin sensitivity, adipogenesis, and glucose homeostasis. Moreover, PPARγ agonists, such as pioglitazone and rosiglitazone, are used in the treatment of various diseases, e.g. diabetes (type II), atherosclerosis, inflammatory skin disease, and some types of cancers. PPARγ agonists have also been found to reduce oxidative-stress (OS) and OS-induced apoptosis. Therefore, the aim of the present study was to evaluate the impact of 4-thiazolidinone-based derivatives Les-2194, Les-3377, and Les-3640 on the expression of antioxidant enzymes in human squamous cell carcinoma (SCC-15), lung carcinoma (A549), colon adenocarcinoma (CACO-2), and skin fibroblast (BJ) cell lines. After 24 h of exposure, Les-2194 caused an increase in ROS production in the SCC-15 and CACO-2 cell lines; however, no changes in caspase-3 activity and metabolic activity were observed. Nevertheless, the Ki67 level was significantly decreased. Les-3377 was able to increase ROS production in all tested cell lines, but no impact on metabolic activity and caspase-3 activity were noticed. In turn, Les-3640 was able to induce ROS overproduction in BJ, SCC-15, and CACO-2 and did not affect metabolic activity. However, an increase in caspase-3 activity was observed at the 10 µM concentration in all tested cell lines. All tested compounds were able to influence CAT and SOD1 expression and decreased (Les-2194 in the BJ cells) or increased (Les-3640 in the SCC-15 and CACO-2 cells) PPARγ expression.


Assuntos
Antioxidantes/metabolismo , Pioglitazona/farmacologia , Rosiglitazona/farmacologia , Tiazolidinas/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Células CACO-2 , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo
3.
J Immunol ; 207(2): 483-492, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34193599

RESUMO

Alcohol use disorders (AUD) increase susceptibility to respiratory infections by 2- to 4-fold in part because of impaired alveolar macrophage (AM) immune function. Alcohol causes AM oxidative stress, diminishing AM phagocytic capacity and clearance of microbes from the alveolar space. Alcohol increases AM NADPH oxidases (Noxes), primary sources of AM oxidative stress, and reduces peroxisome proliferator-activated receptor γ (PPARγ) expression, a critical regulator of AM immune function. To investigate the underlying mechanisms of these alcohol-induced AM derangements, we hypothesized that alcohol stimulates CCAAT/enhancer-binding protein ß (C/EBPß) to suppress Nox-related microRNAs (miRs), thereby enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. Furthermore, we postulated that pharmacologic PPARγ activation with pioglitazone would inhibit C/EBPß and attenuate alcohol-induced AM dysfunction. AM isolated from human AUD subjects or otherwise healthy control subjects were examined. Compared with control AM, alcohol activated AM C/EBPß, decreased Nox1-related miR-1264 and Nox2-related miR-107, and increased Nox1, Nox2, and Nox4 expression and activity. These alcohol-induced AM derangements were abrogated by inhibition of C/EBPß, overexpression of miR-1264 or miR-107, or pioglitazone treatment. These findings define novel molecular mechanisms of alcohol-induced AM dysfunction mediated by C/EBPß and Nox-related miRs that are amenable to therapeutic targeting with PPARγ ligands. These results demonstrate that PPARγ ligands provide a novel and rapidly translatable strategy to mitigate susceptibility to respiratory infections and related morbidity in individuals with AUD.


Assuntos
Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Etanol/efeitos adversos , Macrófagos Alveolares/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Pioglitazona/farmacologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Masculino , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Fagócitos/metabolismo
4.
Exp Cell Res ; 406(1): 112736, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273404

RESUMO

Electric field (EF) directed cell migration (electrotaxis) is known to occur in glioblastoma multiforme (GBM) and neural stem cells, with key signalling pathways frequently dysregulated in GBM. One such pathway is EGFR/PI3K/Akt, which is down-regulated by peroxisome proliferator activated receptor gamma (PPARγ) agonists. We investigated the effect of electric fields on primary differentiated and glioma stem cell (GSCs) migration, finding opposing preferences for anodal and cathodal migration, respectively. We next sought to determine whether chemically disrupting Akt through PTEN upregulation with the PPARγ agonist, pioglitazone, would modulate electrotaxis of these cells. We found that directed cell migration was significantly inhibited with the addition of pioglitazone in both differentiated GBM and GSCs subtypes. Western blot analysis did not demonstrate any change in PPARγ expression with and without exposure to EF. In summary we demonstrate opposing EF responses in primary GBM differentiated cells and GSCs can be inhibited chemically by pioglitazone, implicating GBM EF modulation as a potential target in preventing tumour recurrence.


Assuntos
Movimento Celular/genética , Células-Tronco Neoplásicas/metabolismo , Neuroglia/metabolismo , PPAR gama/genética , Resposta Táctica , Anilidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Eletricidade , Eletrodos , Campos Eletromagnéticos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , PPAR gama/agonistas , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Pioglitazona/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
5.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208374

RESUMO

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague-Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1ß (IL-1ß) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1ß levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1ß induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity.


Assuntos
Comportamento Animal , Encefalite/tratamento farmacológico , Mitocôndrias/patologia , Pioglitazona/uso terapêutico , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Encefalite/patologia , Feminino , Hipotermia Induzida , Lipopolissacarídeos , Microglia/efeitos dos fármacos , Microglia/patologia , Mitocôndrias/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Pioglitazona/farmacologia , Gravidez , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Perda de Peso/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
6.
Pharmacology ; 106(7-8): 409-417, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34082428

RESUMO

INTRODUCTION: Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on ß-arrestin2 signaling in classical insulin target tissues. METHODS: Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. RESULTS: The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the ß-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased ß-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. CONCLUSION: To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases ß-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.


Assuntos
Resistência à Insulina , Insulina/metabolismo , Pioglitazona/farmacologia , beta-Arrestina 2/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Am J Physiol Lung Cell Mol Physiol ; 321(1): L236-L247, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009030

RESUMO

Obesity-related asthma often presents with more severe symptoms than non-obesity-related asthma and responds poorly to current treatments. Both insulin resistance and hyperinsulinemia are common in obesity. We have shown that increased insulin mediates airway hyperreactivity in diet-induced obese rats by causing neuronal M2 muscarinic receptor dysfunction, which normally inhibits acetylcholine release from parasympathetic nerves. Decreasing insulin with streptozotocin prevented airway hyperreactivity and M2 receptor dysfunction. The objective of the present study was to investigate whether pioglitazone, a hypoglycemic drug, prevents airway hyperreactivity and M2 receptor dysfunction in obese rats. Male rats fed a low- or high-fat diet were treated with pioglitazone or PBS by daily gavage. Body weight, body fat, fasting insulin, and bronchoconstriction and bradycardia in response to electrical stimulation of vagus nerves and to aerosolized methacholine were recorded. Pilocarpine, a muscarinic receptor agonist, was used to measure M2 receptor function. Rats on a high-fat diet had potentiated airway responsiveness to vagal stimulation and dysfunctional neuronal M2 receptors, whereas airway responsiveness to methacholine was unaffected. Pioglitazone reduced fasting insulin and prevented airway hyperresponsiveness and M2 receptor dysfunction but did not change inflammatory cytokine mRNA expression in alveolar macrophages. High-fat diet, with and without pioglitazone, had tissue-specific effects on insulin receptor mRNA expression. In conclusion, pioglitazone prevents vagally mediated airway hyperreactivity and protects neuronal M2 muscarinic receptor function in obese rats.


Assuntos
Hiper-Reatividade Brônquica/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Insulina/metabolismo , Neurônios/efeitos dos fármacos , Obesidade/complicações , Pioglitazona/farmacologia , Receptor Muscarínico M2/metabolismo , Animais , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Dieta Hiperlipídica/efeitos adversos , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Hipoglicemiantes/farmacologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M2/genética
8.
Future Med Chem ; 13(14): 1175-1183, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34013764

RESUMO

Background: PPARγ is known to be a key regulator of metabolism and storage of lipids and glucose and to be implicated in the pathology of severe syndromes like obesity, diabetes, atherosclerosis and cancer. Methods: As a continuation of the authors' studies on oxyprenylated secondary metabolites as effective PPARγ agonists, the authors describe herein the chemical synthesis of natural O-prenyl cinnamaldehydes and cinnamyl alcohols and preliminary data on their in vitro effects on PPARγ transcription. Results: Among the panel of eight compounds tested, three - namely, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)acrylaldehyde, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)prop-2-en-1-ol and boropinal A - exerted activity in a dose-dependent manner. Conclusion: O-prenyl cinnamaldehydes and cinnamyl alcohols have the potential to effectively interact with PPARγ receptor.


Assuntos
Acroleína/análogos & derivados , Neopreno/química , PPAR gama/metabolismo , Propanóis/química , Acroleína/química , Acroleína/farmacologia , Genes Reporter , Células HEK293 , Humanos , PPAR gama/agonistas , PPAR gama/genética , Pioglitazona/química , Pioglitazona/farmacologia , Propanóis/farmacologia , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos
9.
PLoS One ; 16(5): e0251069, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983968

RESUMO

Oral therapeutics used to treat type 2 diabetes and cardiovascular disease often fail to prevent the progression of disease and their comorbidities. Rooibos (Aspalathus linearis), an endemic South African plant used as an herbal tea, has demonstrated positive effects on glycemia and hypercholesterolemia. However, the treatment efficacy of rooibos extract in combination with conventional hypoglycemic and hypolipidemic medications on blood glucose and lipid profiles has not been established. This study aimed to investigate the effects of combining an aspalathin-rich green rooibos extract (Afriplex GRT™) with pioglitazone and atorvastatin, on blood glucose and lipid levels in obese diabetic (db/db) mice. Six-week-old male db/db mice and their nondiabetic lean littermate controls (db+) were divided into 8 experimental groups (n = 6/group). Db/db mice were treated daily either with pioglitazone (25 mg/kg), atorvastatin (80 mg/kg) and GRT (100 mg/kg), a combination of either drug with GRT or a combination of GRT-pioglitazone and atorvastatin for 5 weeks. Untreated vehicle controls were given dimethyl sulfoxide (0.1%) and phosphate buffered saline solution. At termination, serum and liver tissue were collected for lipid and gene expression analysis. Treatment with GRT, pioglitazone and atorvastatin combination effectively lowered fasting plasma glucose (FPG) levels in db/db mice (p = 0.02), whilst increasing body weight, liver weight, and reducing retroperitoneal fat weight. Atorvastatin monotherapy was effective at reducing cholesterol (from 4.00 ± 0.12 to 2.93 ± 0.13, p = 0.0003), LDL-C (from 0.58 ± 0.04 to 0.50 ± 0.00, p = 0.04), HDL-C (from 2.86 ± 0.05 to 2.50 ± 0.04, p = 0.0003) and TG (from 2.77 ± 0.50 to 1.48 ± 0.23, p = 0.04), compared to the untreated diabetic control. The hypotriglyceridemic effect of atorvastatin was enhanced when used in combination with both GRT and pioglitazone. The addition of pioglitazone to GRT significantly lowered FPG and TG. In db/db mice, Apoa1 was significantly downregulated in the liver, whilst Pparγ was significantly upregulated compared to their db+ counterparts. GRT monotherapy downregulated Apoa1 expression (p = 0.02). Atorvastatin combined with GRT significantly downregulated mRNA expression of Apoa1 (p = 0.03), whilst upregulating the expression of Pparγ (p = 0.03), Pparα (p = 0.002), Srebp1 (p = 0.002), and Fasn (p = 0.04). The GRT-pioglitazone-atorvastatin combination therapy downregulated Apoa1 (p = 0.006), whilst upregulating Fasn (p = 0.005), Pparα (p = 0.041), and Srebp1 (p = 0.03). Natural products can improve the efficacy of current drugs to prevent diabetes-associated complications. GRT in combination with pioglitazone enhanced the reduction of FPG, whilst the addition of atorvastatin to the combination, significantly lowered triglyceride levels. However, when GRT was used in combination with atorvastatin only cholesterol levels were affected. Although these results confirm both glucose- and lipoprotein-lowering biological effects of GRT in combination with pioglitazone and atorvastatin, increased expression of genes involved in lipogenesis, cholesterol, and fatty acid transport, ß-oxidation, and synthesis and storage of fatty acids, may exacerbate the hepatotoxic effects of atorvastatin.


Assuntos
Atorvastatina/farmacologia , Chalconas/farmacologia , Pioglitazona/farmacologia , Animais , Aspalathus/química , Aspalathus/metabolismo , Atorvastatina/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada/métodos , Glucose/metabolismo , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipolipemiantes , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Fitoterapia , Pioglitazona/metabolismo , Extratos Vegetais/farmacologia
10.
Biol Pharm Bull ; 44(5): 659-668, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952822

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) modulators are expected to exert anti-diabetic effects without PPARγ-related adverse effects, such as fluid retention, weight gain, and bone loss. The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. These effects were similar to those of pioglitazone. Pioglitazone, but not KY-903, increased adipose tissue and heart weights. In pre-adipocytes (3T3-L1), KY-903, in contrast to pioglitazone, increased adiponectin mRNA levels without adipocyte differentiation, indicating anti-diabetic effects via adiponectin without adipogenesis. In ovariectomized rats fed a high-fat diet (OVX/HFD), KY-903 and pioglitazone decreased plasma triglyceride and non-esterified fatty acid levels and increased adiponectin levels, indicating insulin sensitization via adiponectin. KY-903 reduced body weight gain and adipose tissue weight, while pioglitazone increased heart weight and markedly reduced bone mineral density. In mesenchymal stem cell-like ST2 cells, KY-903 slightly reduced osteoblast differentiation without adipocyte differentiation, while pioglitazone markedly reduced it with adipocyte differentiation. In conclusion, KY-903 is a novel PPARγ modulator that exerts anti-diabetic effects without body weight gain or cardiac hypertrophy in diabetic mice and anti-obesity effects with minor bone loss in OVX/HFD, possibly due to increases in adiponectin levels without adipogenesis.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , PPAR gama/agonistas , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Adiponectina/análise , Adiponectina/metabolismo , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Hipoglicemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/sangue , Obesidade/etiologia , PPAR gama/metabolismo , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Ratos , Tetrazóis/química , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Ganho de Peso/efeitos dos fármacos
11.
J Nanobiotechnology ; 19(1): 150, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020670

RESUMO

BACKGROUND: Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing. RESULTS: We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing. CONCLUSIONS: PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing.


Assuntos
Diabetes Mellitus/metabolismo , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Pioglitazona/metabolismo , Pioglitazona/farmacologia , Cicatrização/efeitos dos fármacos , Indutores da Angiogênese/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno/metabolismo , Diabetes Mellitus Experimental , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos
12.
Braz J Med Biol Res ; 54(8): e10782, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34037093

RESUMO

We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Carboidratos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Insulina/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Pioglitazona/metabolismo , Pioglitazona/farmacologia , Ratos
13.
Am J Physiol Heart Circ Physiol ; 320(6): H2222-H2239, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33834866

RESUMO

Extracellular matrix (ECM) exerts a series of biological functions and contributes to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the role of periostin in vascular calcification has yet to be fully investigated. As found in this study, recombinant periostin accelerated the thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS) ex vivo, which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition and suppressed PPARγ expression. Mechanistically, periostin caused overactivation of glycolysis and mitochondrial dysfunction in VSMCs as assessed by extracellular acidification rate, oxygen consumption rate, and mitochondrial respiratory chain complex activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients undergoing computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score in patients with coronary artery calcification (CAC). There was also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.NEW & NOTEWORTHY Periostin caused arterial calcification, overactivated glycolysis, and damaged OXPHOS. PPARγ agonists alleviated periostin-promoted arterial calcification and corrected abnormal glycolysis and unbalanced mitochondrial homeostasis. There exists a relationship between periostin and lactate in patients with CAC.


Assuntos
Aorta Torácica/metabolismo , Moléculas de Adesão Celular/metabolismo , Doença da Artéria Coronariana/metabolismo , Glucose/metabolismo , Mitocôndrias/metabolismo , Miócitos de Músculo Liso/metabolismo , PPAR gama/metabolismo , Calcificação Vascular/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Apoptose/efeitos dos fármacos , Moléculas de Adesão Celular/farmacologia , Angiografia por Tomografia Computadorizada , Regulação para Baixo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ácido Láctico/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio , PPAR gama/agonistas , Pioglitazona/farmacologia , Ratos
14.
Food Chem Toxicol ; 152: 112183, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33836209

RESUMO

T-2 toxin, the most virulent toxin produced by the Fusarium genus, is thought to be the main cause of fatal cardiomyopathy known as Keshan disease. However, the mechanisms of T-2 toxin-induced cardiac toxicity and possible targets for its treatment remain unclear. In the present study, male Wistar rats were administered with 2 mg/kg b. w. T-2 toxin (i.g.) and sacrificed on day 7 after exposure. The hematological indices (CK, LDH) and electrocardiogram were significantly abnormal, the ultrastructure of mitochondria in the heart was changed, and the percentage of collagen area was significantly increased in the T-2 toxin-treated group. Meanwhile, T-2 toxin activated the TGF-ß1/Smad2/3 signalling pathway, and also activated PPAR-γ expression in rats and H9C2 cells. Further application of PPAR-γ agonist (pioglitazone) and antagonist (GW9662) in H9C2 cells revealed that the up-regulation of PPAR-γ expression induced by T-2 toxin is a self-preservation phenomenon, and increasing exogenous PPAR-γ can alleviate the increase in TGF-ß1 caused by T-2 toxin, thereby playing a role in relieving cardiac fibrosis. These findings for the first time demonstrate that T-2 toxin can regulate the expression of PPAR-γ and that PPAR-γ has the potential to serve as an effective therapeutic target in T-2 toxin-induced cardiac fibrosis of rats.


Assuntos
Cardiomiopatias/metabolismo , Fibrose/metabolismo , PPAR gama/metabolismo , Toxina T-2/toxicidade , Anilidas/farmacologia , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Linhagem Celular , Colágeno/metabolismo , Fibrose/induzido quimicamente , Fibrose/complicações , Fibrose/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Pioglitazona/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos
15.
Eur J Pharmacol ; 901: 174076, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33798599

RESUMO

Several antidiabetic agents, including thiazolidinediones and sodium-glucose cotransporter (SGLT) 2 inhibitors, attenuate the symptoms of nonalcoholic steatohepatitis (NASH). However, thiazolidinediones have serious side effects such as fluid retention and increased risk of congestive heart failure. We examined the effects of SGLT2 inhibitor ipragliflozin, pioglitazone, and ipragliflozin + pioglitazone on fluid retention in type 2 diabetic mice with NASH. Four-week repeated administration of pioglitazone caused significant increases in heart weight (31% increase in 30 mg/kg pioglitazone-treated group compared to vehicle-treated group) concomitant with fluid retention, as estimated by a decrease in plasma osmolality and increase in water intake/urine volume ratio. In addition, pioglitazone significantly increased (by 1.5 to 2-fold) mRNA expression of α, ß, and γ subtypes of ENaC and AQP2 and 3 subtypes in the renal medulla. Thus, pioglitazone-induced fluid retention may arise from enhanced reabsorption of sodium and water associated with increased expression of these channels in the kidney. In contrast, ipragliflozin alone did not induce these symptoms and did not affect ENaC or AQP expression. Combination treatment with ipragliflozin + pioglitazone attenuated these symptoms by ipragliflozin-induced osmotic diuresis. These findings demonstrate that treatment with ipragliflozin monotherapy or coadministered with pioglitazone may be a potential therapeutic option for the treatment of type 2 diabetes with NASH without fluid retention as a side effect.


Assuntos
Líquidos Corporais/metabolismo , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Tiofenos/farmacologia , Animais , Aquaporina 2/biossíntese , Aquaporina 2/genética , Diabetes Mellitus Tipo 2/complicações , Diurese/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Tamanho do Órgão/efeitos dos fármacos , Concentração Osmolar , Sódio/metabolismo
16.
Clin Hemorheol Microcirc ; 79(2): 311-325, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33867357

RESUMO

BACKGROUND: Ischemia-reperfusion injury (IRI) can cause insufficient microcirculation of the transplanted organ and results in a diminished and inferior graft survival rate. OBJECTIVE: This study aimed to investigate the effect of different doses of an anti-diabetic drug, Pioglitazone (Pio), on endoplasmic reticulum stress and histopathological changes, using an in situ perfusion rat model. METHODS: Sixty male Wistar rats were used and were divided into six groups, consisting of the control group, vehicle-treated group and four Pio-treated groups (10, 20, 30 and 40 mg/kg Pio was administered). The rats were perfused through vena cava and an outflow on the abdominal aorta occurred. Following the experiment, kidneys and livers were collected. The level of the endoplasmic reticulum stress markers (XBP1 and Caspase 12) was analyzed using Western blot and histopathological changes were evaluated. RESULTS: Histopathological findings were correlated with the Western blot results and depict a protective effect corresponding to the elevated dosage of Pioglitazone regarding in situ perfusion rat model. CONCLUSIONS: In our study, Pioglitazone can reduce the endoplasmic reticulum stress, and the most effective dosage proved to be the 40 mg/kg Pio referencing the kidney and liver samples.


Assuntos
Estresse do Retículo Endoplasmático , Traumatismo por Reperfusão , Animais , Masculino , Perfusão , Pioglitazona/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico
17.
Sci Rep ; 11(1): 8129, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854134

RESUMO

Exposed rats to normal saline and paraquat (PQ) aerosol as control and PQ group, rats exposed to PQ and treated with 20 and 80 mg/kg/day carvacrol, 5 and 10 mg/kg/day pioglitazone, low dose of pioglitazone + carvacrol and 0.03 mg/kg/day dexamethasone (Dexa) for 16 days after the end of PQ exposure were studied (n = 6 in each group). Lung pathological changes, tracheal responsiveness to methacholine and ovalbumin (OVA) as well as transforming growth factor beta (TGF-ß) and interleukin (IL)-6 level in the lung tissue homogenize as well as TGF-ß, IL-6, oxidant and antioxidant levels oxidant and antioxidants were increased in PQ group (p < 0.01 to p < 0.001). Lung pathological changes, tracheal responsiveness to methacholine and OVA as well as TGF-ß, IL-6 oxidant and antioxidant levels were improved in all treated groups except lung pathological changes in treated group with low dose of pioglitazone (p < 0.05 to p < 0.001). The effects of low dose of pioglitazone and carvacrol alone were significantly lower than in the combination group of low dose of pioglitazone + carvacrol (p < 0.05 to p < 0.001). Carvacrol treatment improved inhaled PQ-induced lug injury similar to the effects of dexamethasone. The synergic effect of carvacrol and pioglitazone suggests PPAR-γ receptor mediated effects of carvacrol on inhaled PQ-induced lung injury.


Assuntos
Cimenos/administração & dosagem , Dexametasona/administração & dosagem , Lesão Pulmonar/tratamento farmacológico , Paraquat/efeitos adversos , Pioglitazona/administração & dosagem , Animais , Estudos de Casos e Controles , Cimenos/farmacologia , Dexametasona/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/imunologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona/farmacologia , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
18.
FEBS Open Bio ; 11(5): 1452-1464, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33822489

RESUMO

Human pathogenic RNA viruses are threats to public health because they are prone to escaping the human immune system through mutations of genomic RNA, thereby causing local outbreaks and global pandemics of emerging or re-emerging viral diseases. While specific therapeutics and vaccines are being developed, a broad-spectrum therapeutic agent for RNA viruses would be beneficial for targeting newly emerging and mutated RNA viruses. In this study, we conducted a screen of repurposed drugs using Sendai virus (an RNA virus of the family Paramyxoviridae), with human-induced pluripotent stem cells (iPSCs) to explore existing drugs that may present anti-RNA viral activity. Selected hit compounds were evaluated for their efficacy against two important human pathogens: Ebola virus (EBOV) using Huh7 cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using Vero E6 cells. Selective estrogen receptor modulators (SERMs), including raloxifene, exhibited antiviral activities against EBOV and SARS-CoV-2. Pioglitazone, a PPARγ agonist, also exhibited antiviral activities against SARS-CoV-2, and both raloxifene and pioglitazone presented a synergistic antiviral effect. Finally, we demonstrated that SERMs blocked entry steps of SARS-CoV-2 into host cells. These findings suggest that the identified FDA-approved drugs can modulate host cell susceptibility against RNA viruses.


Assuntos
Antivirais/farmacologia , Reposicionamento de Medicamentos , Vírus de RNA/efeitos dos fármacos , RNA Viral/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/tratamento farmacológico , Linhagem Celular , Chlorocebus aethiops , Reposicionamento de Medicamentos/métodos , Ebolavirus/efeitos dos fármacos , Ebolavirus/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/virologia , Testes de Sensibilidade Microbiana/métodos , Pioglitazona/farmacologia , Vírus de RNA/fisiologia , Cloridrato de Raloxifeno/farmacologia , SARS-CoV-2/fisiologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Vírus Sendai/efeitos dos fármacos , Vírus Sendai/fisiologia , Células Vero
19.
Theranostics ; 11(9): 4531-4548, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754076

RESUMO

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to elucidate this process in view of cellular metabolism, especially glutaminolysis. Methods: MTT, CCK-8, Annexin V-FITC/PI staining or trypan blue exclusion assays were used to analyze cytotoxicity. Flow cytometry and Q-PCR assays were applied to determine Th17 responses. The detection of metabolite levels using commercial kits and rate-limiting enzyme expression using western blotting assays was performed to illustrate the metabolic activity. ChIP assays were used to examine H3K4me3 modifications. Mouse models of dextran sulfate sodium (DSS)-induced colitis and house dust mite (HDM)/lipopolysaccharide (LPS)-induced asthma were established to confirm the mechanisms studied in vitro. Results: The PPARγ agonists rosiglitazone and pioglitazone blocked glutaminolysis but not glycolysis under Th17-skewing conditions, as indicated by the detection of intracellular lactate and α-KG and the fluorescence ratios of BCECF-AM. The PPARγ agonists prevented the utilization of glutamine and thus directly limited Th17 responses even when Foxp3 was deficient. The mechanisms were ascribed to restricted conversion of glutamine to glutamate by reducing the expression of the rate-limiting enzyme GLS1, which was confirmed by GLS1 overexpression. Replenishment of α-KG and 2-HG but not succinate weakened the effects of PPARγ agonists, and α-KG-promoted Th17 responses were dampened by siIDH1/2. Inhibition of KDM5 but not KDM4/6 restrained the inhibitory effect of PPARγ agonists on IL-17A expression, and the H3K4me3 level in the promoter and CNS2 region of the il-17 gene locus down-regulated by PPARγ agonists was rescued by 2-HG and GLS1 overexpression. However, the limitation of PPARγ agonists on the mRNA expression of RORγt was unable to be stopped by 2-HG but was attributed to GSH/ROS signals subsequent to GLS1. The exact role of PPARγ was proved by GW9662 or PPARγ knockout, and the mechanisms for PPARγ-inhibited Th17 responses were further confirmed by GLS1 overexpression in vivo. Conclusion: PPARγ agonists repressed Th17 responses by counteracting GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals, which is beneficial for Th17 cell-related immune dysregulation.


Assuntos
Glutaminase/metabolismo , Glutamina/metabolismo , Glutationa/metabolismo , Histonas/metabolismo , PPAR gama/agonistas , Espécies Reativas de Oxigênio/metabolismo , Células Th17/efeitos dos fármacos , Animais , Colite/tratamento farmacológico , Colite/metabolismo , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pioglitazona/farmacologia , RNA Mensageiro/metabolismo , Rosiglitazona/farmacologia , Células Th17/metabolismo
20.
J Biomed Sci ; 28(1): 22, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33781257

RESUMO

BACKGROUND: Obesity-related cardiovascular risk, end points, and mortality are strongly related to arterial stiffening. Current therapeutic approaches for arterial stiffening are not focused on direct targeting within the vessel. Perivascular adipose tissue (PVAT) surrounding the artery has been shown to modulate vascular function and inflammation. Peroxisome proliferator-activated receptor γ (PPARγ) activation significantly decreases arterial stiffness and inflammation in diabetic patients with coronary artery disease. Thus, we hypothesized that PPARγ activation alters the PVAT microenvironment, thereby creating a favorable environment for the attenuation of arterial stiffening in obesity. METHODS: Obese ob/ob mice were used to investigate the effect of PPARγ activation on the attenuation of arterial stiffening. Various cell types, including macrophages, fibroblasts, adipocytes, and vascular smooth muscle cells, were used to test the inhibitory effect of pioglitazone, a PPARγ agonist, on the expression of elastolytic enzymes. RESULTS: PPARγ activation by pioglitazone effectively attenuated arterial stiffening in ob/ob mice. This beneficial effect was not associated with the repartitioning of fat from or changes in the browning of the PVAT depot but was strongly related to improvement of the PVAT microenvironment, as evidenced by reduction in the expression of pro-inflammatory and pro-oxidative factors. Pioglitazone treatment attenuated obesity-induced elastin fiber fragmentation and elastolytic activity and ameliorated the obesity-induced upregulation of cathepsin S and metalloproteinase 12, predominantly in the PVAT. In vitro, pioglitazone downregulated Ctss and Mmp12 in macrophages, fibroblasts, and adipocytes-cell types residing within the adventitia and PVAT. Ultimately, several PPARγ binding sites were found in Ctss and Mmp12 in Raw 264.7 and 3T3-L1 cells, suggesting a direct regulatory mechanism by which PPARγ activation repressed the expression of Ctss and Mmp-12 in macrophages and fibroblasts. CONCLUSIONS: PPARγ activation attenuated obesity-induced arterial stiffening and reduced the inflammatory and oxidative status of PVAT. The improvement of the PVAT microenvironment further contributed to the amelioration of elastin fiber fragmentation, elastolytic activity, and upregulated expression of Ctss and Mmp12. Our data highlight the PVAT microenvironment as an important target against arterial stiffening in obesity and provide a novel strategy for the potential clinical use of PPARγ agonists as a therapeutic against arterial stiffness through modulation of PVAT function.


Assuntos
Tecido Adiposo/fisiopatologia , Hipoglicemiantes/farmacologia , Obesidade/fisiopatologia , PPAR gama/agonistas , Pioglitazona/farmacologia , Rigidez Vascular/fisiologia , Células 3T3 , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células RAW 264.7
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