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1.
DNA Cell Biol ; 38(11): 1323-1337, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536386

RESUMO

Our previous study has indicated that the parathyroid hormone type 1 receptor (PTHR1) may play important roles in development and progression of osteosarcoma (OS) by regulating Wnt, angiogenesis, and inflammation pathway genes. The goal of this study was to further illuminate the roles of PTHR1 in OS by investigating upstream regulation mechanisms (including microRNA [miRNA] and transcription factors [TFs]) of crucial genes. The microarray dataset GSE46861 was downloaded from the Gene Expression Omnibus database, in which six tumors with short hairpin RNA (shRNA) PTHR1 knockdown (PTHR1.358) and six tumors with shRNA control knockdown (Ren.1309) were collected from mice. Differentially expressed genes (DEGs) between PTHR1.358 and Ren.1309 were identified using the linear models for microarray data (LIMMA) method, and then the miRNA-TF-mRNA regulatory network was constructed using data from corresponding databases, followed by module analysis, to screen crucial regulatory relationships. OS-related human miRNAs were extracted from the curated Osteosarcoma Database. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. As a result, the miRNA-TF-mRNA regulatory network, including 1049 nodes (516 miRNA, 25 TFs, and 508 DEGs) and 15942 edges (interaction relationships, such as Pparg-Abca1 and miR-590-3p-AXIN2), was constructed, from which three significant modules were extracted and modules 2 and 3 contained interactions between miRNAs/TFs and DEGs such as miR-103-3p-AXIN2, miR-124-3p-AR-Tgfb1i1, and miR-27a-3p-PPARG-Abca1. miR-27a-3p was a known miRNA associated with OS. Abca1, AR, and miR-124-3p were hub genes in the miRNA-TF-mRNA network. Tgfb1i1 was involved in cell proliferation, Abca1 participated in the cholesterol metabolic process, and AXIN2 was associated with the canonical Wnt signaling pathway. Furthermore, we also confirmed upregulation of miR-590-3p and downregulation of AXIN2 in the mouse OS cell line K7M2-WT transfected with PTHR1 shRNA. In conclusion, PTHR1 may play important roles in progression of OS by activating miR-124-3p-AR-Tgfb1i1, miR-27a-3p-PPARG-Abca1, and miR-103/590-3p-AXIN2 axes.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Receptor Tipo 1 de Hormônio Paratireóideo/fisiologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Animais , Proteína Axina/genética , Proteína Axina/fisiologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Humanos , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/fisiologia , Osteossarcoma/genética , Osteossarcoma/patologia , PPAR gama/genética , PPAR gama/fisiologia , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptores Androgênicos/genética , Receptores Androgênicos/fisiologia , Transdução de Sinais/genética , Células Tumorais Cultivadas
2.
PLoS Biol ; 17(6): e3000330, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31226122

RESUMO

The repair of white matter damage is of paramount importance for functional recovery after brain injuries. Here, we report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 d after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific peroxisome proliferator-activated receptor gamma (PPARγ) knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the central nervous system (CNS), which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.


Assuntos
Interleucina-4/metabolismo , Oligodendroglia/metabolismo , PPAR gama/metabolismo , Animais , Lesões Encefálicas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Diferenciação Celular/fisiologia , Doenças Desmielinizantes/metabolismo , Interleucina-4/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa , Neurogênese , Oligodendroglia/fisiologia , PPAR gama/fisiologia , Recuperação de Função Fisiológica , Remielinização/fisiologia , Transdução de Sinais , Acidente Vascular Cerebral , Substância Branca
3.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(5): 561-565, 2019 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-31140420

RESUMO

OBJECTIVE: To investigate the inhibitory effect of genistein on activation of hepatic stellate cells (HSCs) in vitro and the role of the autophagy pathway regulated by PPAR-γ in mediating this effect. METHODS: Cultured HSC-T6 cells were exposed to different concentrations of genistein for 48 h, and HSC activation was verified by detecting the expressions of -SMA and 1(I) collagen; autophagy activation in the cells was determined by detecting the expressions of LC3-II and p62 using Western blotting. The autophagy inhibitor 3-MA was used to confirm the role of autophagy in genistein-induced inhibition of HSC activation. A PPAR-γ inhibitor was used to explore the role of PPAR-γ in activating autophagy in the HSCs. RESULTS: Genistein at concentrations of 5 and 50 µmol/L significantly inhibited the expressions of -SMA and 1(I) collagen (P < 0.05), markedly upregulated the expressions of PPAR-γ and the autophagy-related protein LC3-II (P < 0.05) and significantly down-regulated the expression of the ubiqutin-binding protein p62 (P < 0.05) in HSC-T6 cells. The cells pretreated with 3-MA prior to genistein treatment showed significantly increased protein expressions of -SMA and 1(I) collagen compared with the cells treated with genistein only (P < 0.05). Treatment with the PPAR-γ inhibitor obviously lowered the expression of LC3-II and enhanced the expression p62 in genistein-treated HSC-T6 cells, suggesting the activation of the autophagy pathway. CONCLUSIONS: PPAR-γ- regulated autophagy plays an important role in mediating genistein-induced inhibition of HSC activation in vitro.


Assuntos
Anticarcinógenos , Autofagia , Genisteína , Células Estreladas do Fígado , PPAR gama , Anticarcinógenos/farmacologia , Colágeno Tipo I , Genisteína/farmacologia , Humanos , PPAR gama/fisiologia
4.
Genet Test Mol Biomarkers ; 23(3): 166-175, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30793973

RESUMO

AIMS: Nonalcoholic fatty liver disease (NAFLD) is an important public health issue worldwide. Several recent studies have reported that peroxisome proliferator-activated receptor-γ (PPARγ) and angiotensin II type 1 receptor (AGTR1) variants are associated with NAFLD occurrence, but the results have been inconsistent. The aim of this study was to analyze the interactions between PPARγ and AGTR1 polymorphisms and their associations with NAFLD in Chinese adults. METHODS: Seven single nucleotide polymorphisms (SNPs) of the PPARγ gene and 5 SNPs of the AGTR1 gene were selected and genotyped in 1591 unrelated Chinese adults. The SNPAssoc package of R was used to examine the relationships between the selected SNPs and NAFLD. RESULTS: After adjusting the covariance, the results from the overdominant model showed that participants carrying the T/C genotype of rs2638360 in AGTR1 have a decreased risk of NAFLD compared with those with T/T-C/C genotypes (odds ratio: 0.70, 95% confidence interval: 0.49-1.00). However, our results showed that none of the selected PPARγ variants were significantly associated with the risk of NAFLD after applying a false discovery rate correction. Among the 12 selected SNPs from PPARγ and AGTR1, model-based multifactor dimensionality reduction (MB-MDR) analyses for gene-gene interactions revealed that all the models were significantly associated with the increased risk of NAFLD (p < 0.05) except the 2-, 10-, 11-, and 12-locus models. Further, among the 10 SNPs negatively associated with NAFLD, the four-locus model (rs13431696 and rs3856806 in PPARγ, and rs5182, rs1492100 in ATGR1) and the five-locus model (rs9817428, rs1175543, rs13433696, and rs2920502 in PPARγ, and rs1492100 in ATGR1) were closely related with NAFLD susceptibility (p = 0.019 and p = 0.048, respectively). CONCLUSION: Our present study suggests that interactions among multiple AGTR1 and PPARγ polymorphisms are associated with the risk of NAFLD in the Chinese population.


Assuntos
Hepatopatia Gordurosa não Alcoólica/genética , PPAR gama/genética , Receptor Tipo 1 de Angiotensina/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Epistasia Genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Razão de Chances , PPAR gama/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 1 de Angiotensina/fisiologia , Fatores de Risco
5.
J Pharmacol Sci ; 139(1): 46-49, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30522964

RESUMO

Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment.


Assuntos
Colo/efeitos dos fármacos , Hiperalgesia , Hipoglicemiantes/farmacologia , Síndrome do Intestino Irritável , PPAR gama/agonistas , Pioglitazona/farmacologia , Animais , Colo/metabolismo , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Lipopolissacarídeos , Masculino , PPAR gama/fisiologia , Permeabilidade/efeitos dos fármacos , Ratos Sprague-Dawley , Estresse Fisiológico
6.
Appl Physiol Nutr Metab ; 44(3): 229-238, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30189147

RESUMO

Interleukin (IL)-15 is a cytokine with important immunological functions. It is highly expressed in skeletal muscle and is believed to be a myokine, a hypothesis supported by the rapid increase in circulating levels of IL-15 in response to exercise. Treatment with high doses of IL-15 results in metabolic adaptations such as improved insulin sensitivity and whole-body fatty acid oxidation and protection from high-fat-diet-induced obesity and insulin resistance. IL-15 secreted by contracting muscle may therefore act as an endocrine factor to improve adiposity and energy metabolism in different tissues. Most studies have used supraphysiological doses of IL-15 that do not represent circulating IL-15 in response to exercise. However, evidence shows that IL-15 levels are higher in muscle interstitium and that IL-15 might improve muscle glucose homeostasis and oxidative metabolism in an autocrine/paracrine manner. Nevertheless, how IL-15 signals in skeletal muscle to improve muscle energy metabolism is not understood completely, especially because the absence of the α subunit of the IL-15 receptor (IL-15Rα) results in a phenotype similar to that of overexpressing/oversecreting IL-15 in mice. In this article, we review the literature to propose a model for the regulation of IL-15 by the soluble form of IL-15Rα to explain why some findings in the literature seem, at first glance, to be contradictory.


Assuntos
Subunidade alfa de Receptor de Interleucina-15/fisiologia , Interleucina-15/fisiologia , Músculo Esquelético/metabolismo , Adiposidade , Animais , Metabolismo Energético , Exercício , Glucose/metabolismo , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Camundongos , PPAR gama/fisiologia
7.
Eur Rev Med Pharmacol Sci ; 22(24): 8839-8848, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30575926

RESUMO

OBJECTIVE: Intestinal fibrosis is a process characterized by an excessive deposition of Extracellular Matrix (ECM) proteins by activated myofibroblasts and represents a consequence of a chronic inflammation that usually occurs during Inflammatory Bowel Disease (IBD). The relationship between inflammation and fibrosis in IBD remains still unclear and nevertheless the recent pharmacological progresses, currently the only resolutive therapeutic strategy is surgery, especially when complications (stricture, stenosis and obstruction of intestinal tracts) appear. As many different cellular types and molecular mechanisms are implicated in the pathogenesis of IBD, the identification of molecules able to counteract this process could be crucial. MATERIALS AND METHODS: This is a literature review of several articles published on PubMed databases. RESULTS: A number of researches suggest that Proliferator-Activated Receptor-gamma (PPAR-γ) has both anti-inflammatory and anti-fibrotic effects in many organs. PPAR-γ has been demonstrated to be able to downregulate pro-inflammatory cytokines production such as Interleukin (IL)-4,-5,-6 but also to interfere with profibrotic molecules as Platelet-Derived Growth Factor (PDGF), IL-1 and Transforming Growth Factor Beta (TGF-ß), the main promoter of fibrosis. In preliminary clinical trials and in experimental models of intestinal fibrosis, natural and chemical PPAR-γ ligands have ameliorated the fibrotic process. CONCLUSIONS: Since PPAR-γ could play a crucial role in the development of the disease, the research of new molecules, capable of ameliorating both inflammation and fibrosis lesions, as PPAR-γ agonists, could represent a valid and effective therapeutic approach for the prevention and treatment of IBD and intestinal fibrosis.


Assuntos
Fibrose/prevenção & controle , Inflamação/prevenção & controle , Doenças Inflamatórias Intestinais/tratamento farmacológico , PPAR gama/fisiologia , Humanos , NF-kappa B/fisiologia , PPAR gama/agonistas
8.
Biochem Biophys Res Commun ; 505(3): 951-957, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30309656

RESUMO

Obesity is characterized by an expansion of white adipose tissue (WAT) mass, which mainly consists of adipocytes. During the commitment and differentiation of adipocytes, PPARγ functions as a key transcriptional factor for adipogenesis, and is associated with its suppressive coregulator, TAZ. Previous studies have shown the importance of TAZ in adipogenesis using an in vitro model; however, the understanding of its role in adipogenesis in vivo remains limited. Here, we report a unique obese mouse model that is associated with TAZ downregulation, which arose from the overexpression of Yap, a Taz paralog. YAP activation facilitated Hippo signaling feedback, which induced a compensatory reduction in YAP, subsequently neutralizing its functional activity. This feedback also induced TAZ suppression and exclusion from the nucleus. In Yap transgenic mice, TAZ downregulation in adipose stem cells activated PPARγ, leading to their differentiation into mature adipocytes and consequently increased adipose tissue. These results highlight the in vivo necessity of TAZ for adipocyte commitment and differentiation, which could provide insight into anti-obesity therapeutics.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Obesidade/metabolismo , Fosfoproteínas/genética , Fatores de Transcrição/genética , Adipogenia , Animais , Proteínas de Ciclo Celular , Diferenciação Celular , Regulação para Baixo , Camundongos , Camundongos Transgênicos , PPAR gama/fisiologia , Células-Tronco/citologia
9.
Life Sci ; 213: 269-278, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30189217

RESUMO

Diabetic cardiomyopathy (DCM) is a kind of disease caused by metabolic disorders and microangiopathy. The main pathophysiological changes of DCM include fibrosis, myocardial cell apoptosis and autonomic neuropathy. Therefore, treatment aimed at these processes may benefit patients with DCM. We designed an experiment with the peroxisome proliferator-activated receptor-gamma (PPARγ) agonist GW 1929 to detect whether the activation of PPARγ could alleviate the degree of DCM. To further detect the mechanism of PPARγ in DCM, we used the PPARγ antagonist GW 9662 and ERK antagonist PD 098059 both in vitro and in vivo and found that PPARγ functioned by inhibiting ERK. We also performed Western blot, PCR, ELISA, immunohistochemistry, TUNEL assay, Sirius red staining and gelatin zymography to investigate inflammation, apoptosis, MMP activity and epithelial-to-mesenchymal transition (EMT). The results showed that the activation of PPARγ inhibited these reactions and inhibiting ERK also simulated this phenomenon. In conclusion, these results demonstrated that PPARγ activation in the diabetic myocardium of mice reduces myocardial fibrosis via regulation of the TGF-ß/ERK pathway and EMT.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , PPAR gama/metabolismo , Animais , Benzofenonas , Transição Epitelial-Mesenquimal/fisiologia , Fibrose/metabolismo , Inflamação/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , PPAR gama/agonistas , PPAR gama/fisiologia , Receptores Ativados por Proliferador de Peroxissomo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Tirosina/análogos & derivados
10.
Int Immunopharmacol ; 64: 110-115, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30172103

RESUMO

Abietic acid has been reported to have anti-inflammatory activity. However, whether abietic acid has anti-inflammatory effects against osteoarthritis (OA) remains unclear. The present study aimed to measure the anti-inflammatory effects of abietic acid on OA in vitro. Human osteoarthritis chondrocytes were pretreated with abietic acid 1 h before IL-1ß treatment. The results showed that treatment of abietic acid significantly inhibited IL-1ß-induced TNF-α, NO, PGE2 production, and COX-2 expression. Abietic acid also concentration-dependently suppressed MMP1, MMP3, and MMP13 production induced by IL-1ß. Moreover, the increased phosphorylation levels of NF-κB p65 and IκBα were inhibited by the treatment of abietic acid. We also found that the expression of PPAR-γ was increased by abietic acid. The inhibition of abietic acid on TNF-α, NO, and PGE2 production were reversed by GW9662, the inhibitor of PPAR-γ. In conclusion, the study elucidated abietic acid suppressed IL-1ß-induced inflammation in human osteoarthritis chondrocytes by activating PPAR-γ.


Assuntos
/farmacologia , Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/fisiologia , Dinoprostona/biossíntese , Humanos , Mediadores da Inflamação/metabolismo , Metaloproteases/biossíntese , NF-kappa B/fisiologia , PPAR gama/fisiologia
11.
Biomed Res Int ; 2018: 7475626, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30105244

RESUMO

To investigate the role of the peroxisome proliferator-activated receptor-γ (PPARγ) in the progression of cholesterol gallstone disease (CGD), C57bl/6J mice were randomized to the following groups (n=7/group): L (lithogenic diet, LGD), LM (LGD+pioglitazone), CM (chow diet+pioglitazone), and NC (normal control, chow diet). Gallbladder stones were observed by microscopy. Histological gallbladder changes were assessed. Bile acids (BA) and cholesterol were measured in the serum, bile, and feces. Proteins and mRNA expression of genes involved in BA metabolism and enterohepatic circulation were assessed by western blotting and real-time RT-PCR. PPARγ activation was performed in LO2 cell by lentivirus transfection and in Caco2 cell by PPARγ agonist treatment. Downregulation of farnesoid X receptor (FXR) by small interference RNA (siRNA) was performed in L02 cells and Caco2 cells, respectively. Results showed that pharmacological activation of PPARγ by pioglitazone prevents cholesterol gallstone formation by increasing biliary BA synthesis and enterohepatic circulation. Activated PPARγ induced the expression of genes involved in enterohepatic circulation and bile acid synthesis (like PCG1α, BSEP, MRP2, MRP3, MRP4, NTCP, CYP7A1, CYP27A1, ASBT, OSTα, and OSTß). Downregulation of FXR repressed expression of partial genes involved in BA enterohepatic circulation. These findings suggest a new function of PPARγ in preventing CGD by handling BA synthesis and transport through a FXR dependent or independent pathway.


Assuntos
Ácidos e Sais Biliares/metabolismo , Circulação Êntero-Hepática , Cálculos Biliares/prevenção & controle , PPAR gama/fisiologia , Animais , Células CACO-2 , Colesterol , Humanos , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Receptores Citoplasmáticos e Nucleares
12.
Behav Neurol ; 2018: 7646104, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123388

RESUMO

Background and Purpose: PPAR-γ is a transcriptional factor which is associated with promoting hematoma clearance and reducing neurological dysfunction after intracerebral hemorrhage (ICH). Haptoglobin- (Hp-) hemoglobin- (Hb-) CD163 acts as a main pathway to Hb scavenging after ICH. The effect of PPAR-γ on the Hp-Hb-CD163 signaling pathway has not been reported. We hypothesized that PPAR-γ might protect against ICH-induced neuronal injury via activating the Hp-Hb-CD163 pathway in a rat ICH model. Methods: 107 Sprague-Dawley rats were used in this research. They were randomly allocated to 4 groups as follows: sham group, vehicle group, monascin-treated group, and Glivec-treated group. Animals were euthanized at 3 days after the model was established successfully. We observed the effects of PPAR-γ on the brain water content, hemoglobin levels, and the expressions of CD163 and Hp in Western blot and real-ime PCR; meanwhile, we measured hematoma volumes and edema areas by MRI scanning. Result: The results showed that PPAR-γ agonist significantly reduced hematoma volume, brain edema, and hemoglobin after ICH. It also enhanced CD163 and Hp expression while PPAR-γ antagonist had the opposite effects. Conclusions: PPAR-γ promotes hematoma clearance and plays a protective role through the Hp-Hb-CD163 pathway in a rat collagenase infusion ICH model.


Assuntos
Hemorragia Cerebral/fisiopatologia , PPAR gama/metabolismo , PPAR gama/fisiologia , Animais , Antígenos CD/fisiologia , Antígenos de Diferenciação Mielomonocítica/fisiologia , Encéfalo/metabolismo , Lesões Encefálicas/complicações , Modelos Animais de Doenças , Haptoglobinas/fisiologia , Hematoma/patologia , Hemoglobinas/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/fisiologia
13.
Ocul Surf ; 16(4): 463-469, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29990545

RESUMO

PURPOSE: To evaluate the role of PPARγ in regulating meibocyte differentiation and lipid synthesis in a human meibomian gland epithelial cell line (hMGEC). METHODS: HMGEC were exposed to the PPARγ agonist, Rosiglitazone, from 10-50 µM. Cultures were also exposed to specific PPARγ antagonist, T0070907, to block PPARγ receptor signaling. Cells were then stained with Ki-67 and LipidTox to determine the effects on cell cycling and lipid synthesis, respectively. Expression of meibocyte differentiation related proteins, ADFP, PPARγ, ELOVL4, and FABP4, were evaluated by quantitative PCR and western blotting. A human corneal epithelial cell line (hTCEpi) was used as a control. RESULT: Rosiglitazone significantly decreased Ki-67 staining within 2 days in a dose-dependent manner (P = 0.003) and increased lipid accumulation in hMGEC in a dose dependent manner. T0070907 suppressed both lipid droplet synthesis and cell cycle exit. Rosiglitazone significantly upregulated expression of ADFP, PPARγ, ELOVL4, and FABP4 by 9.6, 2.7, 2.6, and 3.3 fold on average (all P < 0.05 except for FABP4, P = 0.057) in hMGEC. T0070907 significantly abrogated rosiglitazone-induced upregulation of these genes when treated prior to rosiglitazone treatment (all P < 0.05). The observed lipogenic differentiation response was not duplicated in hTCEpi after exposure to rosiglitazone. CONCLUSION: Rosiglitazone induced cell cycle exit and upregulation of lipogenic gene expression leading to lipid accumulation in hMGEC. These effects were suppressed by PPARγ antagonist indicating that PPARγ signaling specifically directs lipogenesis in hMGEC. These findings suggest that PPARγ plays a critical role in meibocyte differentiation.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Lipogênese/fisiologia , Glândulas Tarsais/citologia , PPAR gama/fisiologia , Células Cultivadas , Humanos , Lipídeos/biossíntese , Lipogênese/efeitos dos fármacos , PPAR gama/antagonistas & inibidores , Rosiglitazona/farmacologia
14.
Med Sci Monit ; 24: 5168-5177, 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30044769

RESUMO

BACKGROUND Cigarette smoking is a well-known risk factor in multiple chronic pulmonary diseases. This study aims to investigate the role of peroxisome proliferator-activated receptor (PPAR) g in cigarette smoking-induced inflammation. MATERIAL AND METHODS Cigarette smoking extract (CSE) was employed to induce inflammation in bronchial epithelial cells (BECs). After CSE administration, several autophagy-related proteins (Beclin1, autophagy-related gene (ATG)5, ATG7, p62, and LC3) and PPARg levels were examined by western blot. Subsequently, PPARg agonists and antagonist were used to treat CSE-induced BECs, several inflammatory factors (interleukin (IL)-6, IL-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2) and autophagy-related proteins were detected to measure the inflammatory and autophagy levels. Then LC3 knockdown was performed to verify the role of autophagy in CSE-induced inflammation. Finally, the AMP-activated protein kinase (AMPK) and its downstream S6 kinase (S6K) were detected in CSE-stimulated BECs. RESULTS CSE administration caused insufficient autophagy and the decrease of PPARγ in BECs. The PPARγ agonists ameliorate the CSE-induced inflammation and promote the autophagy development, evidenced by the changes of inflammatory factors and autophagy-related proteins. Loss-of-function experiments demonstrated that the PPARγ played an anti-inflammatory role in an autophagy-dependent manner. In addition, CSE administration inactivated the AMPK signaling, which was restored by PPARγ agonists. The effects of PPARγ agonists on inflammation and autophagy could be abolished by AMPK inhibitor. CONCLUSIONS We demonstrated that PPARγ played a protective role in CSE-induced inflammation and autophagy by activating AMPK signaling in BECs, which may provide investigation basis for clinical therapy of chronic pulmonary diseases.


Assuntos
Inflamação/tratamento farmacológico , PPAR gama/metabolismo , PPAR gama/fisiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Anti-Inflamatórios/uso terapêutico , Autofagia/efeitos dos fármacos , Brônquios/metabolismo , Linhagem Celular , Células Cultivadas , Fumar Cigarros/efeitos adversos , Células Epiteliais/metabolismo , Humanos , Inflamação/prevenção & controle , Pulmão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fumaça , Fumar
15.
Ann Otol Rhinol Laryngol ; 127(10): 677-686, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30047791

RESUMO

INTRODUCTION: Oral leukoplakia is defined as a mucous membrane disorder characterized by white patches that cannot be scraped off. Leukoplakia is the most frequent, potentially premalignant oral mucosa disorder and a good candidate for chemopreventive therapies. Pioglitazone activates peroxisome proliferator-activated receptor gamma (PPARγ), which forms a complex with nuclear cofactors and regulates gene expression of a variety of cell-cycle proteins and is currently being tested preclinically and clinically in aerodigestive cancer prevention. METHODS: In the present study, we hypothesized that pioglitazone would decrease proliferation of human leukoplakia cells (MSK Leuk1) and transformed bronchial epithelial cells (BEAS-2B) through regulatory changes of G1 checkpoint protein regulators, p21 and cyclin-D1. MSK Leuk1 and BEAS-2B cells were treated with pioglitazone and assayed for cell proliferation and p21 transcriptional activity. RESULTS: We discovered pioglitazone significantly inhibited cell proliferation in a dose-dependent fashion. We also observed p21 protein induction after treatment with pioglitazone, which was preceded by measurable increases in p21 mRNA induction. CONCLUSIONS: We conclude the PPARγ activator, pioglitazone, can activate p21, which is associated with decreased proliferation in 2 aerodigestive preneoplastic cell lines. In addition, the p21 gene may be a potential hypothesis-driven biomarker in translational studies of pioglitazone as a chemoprevention agent for aerodigestive cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Leucoplasia Oral/genética , Proteína Oncogênica p21(ras)/genética , PPAR gama/fisiologia , Lesões Pré-Cancerosas/genética , Apoptose/efeitos dos fármacos , Western Blotting , Divisão Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Hipoglicemiantes/farmacologia , Leucoplasia Oral/metabolismo , Leucoplasia Oral/patologia , Proteína Oncogênica p21(ras)/biossíntese , Pioglitazona , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Tiazolidinedionas/farmacologia
16.
Genes Dev ; 32(15-16): 1035-1044, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30006480

RESUMO

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.


Assuntos
Glutamina/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , PPAR gama/fisiologia , Animais , Respiração Celular , Células Cultivadas , Ácidos Graxos/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Interleucina-4/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/genética , Rosiglitazona , Tiazolidinedionas/farmacologia
17.
Biomed Pharmacother ; 105: 1091-1097, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30021345

RESUMO

There are many indications that confirm the vital role of adipocytokines and PPARγ in diabetics. Hence, the current investigation aimed to study the modulatory effects of gallic acid and p-coumaric acid on adipocytokines secretion and PPARγ mRNA expression in type 2 diabetic rats. After induction of type 2 diabetes, diabetic rats were orally treated with 20 mg/kg body mass gallic acid and 40 mg/kg body mass p-coumaric acid for six weeks. Among treatment diabetic rats, glucose and glycosylated hemoglobin levels significantly declined in diabetic rats, while insulin level and body weight significantly increased as compared to control group. Gallic acid and p-coumaric acid markedly decreased the level of TNF-α and increased the levels of PPARγ mRNA and adiponectin. In addition, the tested agents improved markedly lipid profile parameters, cardiovascular indices 1 and 2 and anti-atherogenic index. In conclusion, gallic acid and p-coumaric acid exhibited marked antidiabetic action that could be mediated via modulation of TNF-α and adipocytokines secretions as well as upregulation of PPARγ mRNA expression.


Assuntos
Adipocinas/fisiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Ácido Gálico/administração & dosagem , Hiperglicemia/tratamento farmacológico , PPAR gama/fisiologia , Propionatos/administração & dosagem , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada , Dislipidemias/metabolismo , Hiperglicemia/metabolismo , Masculino , Ratos
18.
BMC Musculoskelet Disord ; 19(1): 129, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703208

RESUMO

BACKGROUND: It was indicated that inhibition of PPARγ probably represents a novel therapy for steroid-related osteonecrosis. In this study, we investigated the preventive effects of PPARγ inhibition on steroid-related osteonecrosis in a rabbit model. METHODS: Rabbits were randomly divided into three groups (normal group, model group and BADGE group). Osteonecrosis was induced in rabbits in the model group and the BADGE group. The BADGE group also received bisphenol a diglycidyl ether(BADGE), a PPARγ antagonist, for 6 weeks. RESULTS: Histopathological results indicated that rabbits treated with BADGE exhibited significantly reduced osteonecrotic changes, incidence of osteonecrosis and bone marrow adiposity. Furthermore, BADGE-treated rabbits exhibited reduced intraosseous pressure and increased femoral blood perfusion. Micro-computed tomography and bone histomorphometry indicated that the BADGE group exhibited significantly improved bone quality and mineral appositional rate compared with the model group. Furthermore, the BADGE group showed a significant increase in circulating levels of the bone formation marker osteocalcin and reduced levels of the bone resorption marker TRACP. Overall, BADGE-treated rabbits exhibited reduced marrow adiposity concomitant with improved bone formation. CONCLUSIONS: In conclusion, these observations demonstrated that pharmacological inhibition of PPARγ might represent an effective therapy for steroid-related osteonecrosis in the near future.


Assuntos
Compostos Benzidrílicos/farmacologia , Modelos Animais de Doenças , Compostos de Epóxi/farmacologia , Osteonecrose/induzido quimicamente , Osteonecrose/prevenção & controle , PPAR gama/antagonistas & inibidores , Esteroides/efeitos adversos , Animais , Compostos Benzidrílicos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Masculino , Metilprednisolona/efeitos adversos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Osteonecrose/diagnóstico por imagem , PPAR gama/fisiologia , Coelhos , Distribuição Aleatória
19.
Mol Hum Reprod ; 24(6): 327-340, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29538677

RESUMO

STUDY QUESTION: What are the consequences of inhibiting mTOR, the mechanistic target of rapamycin (mTOR), and the peroxisome proliferator activated receptor gamma (PPARγ) and PPARδ pathways in the early post-implantation period on decidual function, embryo viability and feto-placental growth in the rat? SUMMARY ANSWER: mTOR inhibition from Days 7 to 9 of pregnancy in rats caused decidual PPARγ and PPARδ upregulation on Day 9 of pregnancy and resulted in embryo resorption by Day 14 of pregnancy. PPARγ and PPARδ inhibition differentially affected decidual mTOR signaling and levels of target proteins relevant to lipid histotrophic nutrition and led to reduced feto-placental weights on Day 14 of pregnancy. WHAT IS KNOWN ALREADY: Although mTOR, PPARγ and PPARδ are nutrient sensors important during implantation, the role of these signaling pathways in decidual function and how they interact in the early post-implantation period are unknown. Perilipin 2 (PLIN2) and fatty acid binding protein 4 (FABP4), two adipogenic proteins involved in lipid histotrophic nutrition, are targets of mTOR and PPAR signaling pathways in a variety of tissues. STUDY DESIGN, SIZE, DURATION: Rapamycin (mTOR inhibitor, 0.75 mg/kg, sc), T0070907 (PPARγ inhibitor, 0.001 mg/kg, sc), GSK0660 (PPARδ inhibitor, 0.1 mg/kg, sc) or vehicle was injected daily to pregnant rats from Days 7 to 9 of pregnancy and the studies were performed on Day 9 of pregnancy (n = 7 per group) or Day 14 of pregnancy (n = 7 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: On Day 9 of pregnancy, rat decidua were collected and prepared for western blot and immunohistochemical studies. On Day 14 of pregnancy, the resorption rate, number of viable fetuses, crown-rump length and placental and decidual weights were determined. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibition of mTOR in the early post-implantation period led to a reduction in FABP4 protein levels, an increase in PLIN2 levels and an upregulation of PPARγ and PPARδ in 9-day-pregnant rat decidua. Most embryos were viable on Day 9 of pregnancy but had resorbed by Day 14 of pregnancy. This denotes a key function of mTOR in the post-implantation period and suggests that activation of PPAR signaling was insufficient to compensate for impaired nutritional/survival signaling induced by mTOR inhibition. Inhibition of PPARγ signaling resulted in decreased decidual PLIN2 and FABP4 protein expression as well as in inhibition of decidual mTOR signaling in Day 9 of pregnancy. This treatment also reduced feto-placental growth on Day 14 of pregnancy, revealing the relevance of PPARγ signaling in sustaining post-implantation growth. Moreover, following inhibition of PPARδ, PLIN2 levels were decreased and mTOR complex 1 and 2 signaling was altered in decidua on Day 9 of pregnancy. On Day 14 of pregnancy, PPARδ inhibition caused reduced feto-placental weight, increased decidual weight and increased resorption rate, suggesting a key role of PPARδ in sustaining post-implantation development. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: This is an in vivo animal study and the relevance of the results for humans remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The early post-implantation period is a critical window of development and changes in the intrauterine environment may cause embryo resorption and lead to placental and fetal growth restriction. mTOR, PPARγ and PPARδ signaling are decidual nutrient sensors with extensive cross-talk that regulates adipogenic proteins involved in histotrophic nutrition and important for embryo viability and early placental and fetal development and growth. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Agencia Nacional de Promoción Científica y Tecnológica de Argentina (PICT 2014-411 and PICT 2015-0130), and by the International Cooperation (Grants CONICET-NIH-2014 and CONICET-NIH-2017) to A.J. and T.J. The authors have no conflicts of interest.


Assuntos
Decídua/fisiologia , PPAR delta/fisiologia , PPAR gama/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Decídua/metabolismo , Desenvolvimento Embrionário , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Desenvolvimento Fetal , Imuno-Histoquímica , PPAR delta/genética , PPAR delta/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Gravidez , Ratos Wistar , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
20.
Biochem Biophys Res Commun ; 498(4): 1037-1044, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29550470

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) participates in the process of insulin resistance (IR), a crucial pathophysiology in non-alcoholic fatty liver disease (NAFLD). Meanwhile, suppressor of cytokine signaling3 (SOCS3) also regulates IR in NAFLD. Both PPARγ and SOCS3 play a role in NAFLD through regulating IR, while it is unclear whether these two proteins interact to regulate hepatic steatosis. PPARγ, SOCS3 and its associated JAK2/STAT3 pathway were analyzed using Kuppfer cells (KCs) treatment with LPS and BRL-3A cells treatment with palmitic acid, KC-conditioned medium (KCCM), PPARγ agonist rosiglitazone (ROZ) or JAK2 inhibitor AG490 to demonstrate the role of PPARγ and SOCS3 in hepatocytes steatosis. As LPS concentration increasing, phagocytosis activity of KCs decreased; but releasing of TNF-α and IL-6 increased. After treatment with KCCM, mRNA level of SOCS3, JAK2 and STAT3 as well as protein expression of SOCS3, p-JAK2 and p-STAT3 in steatosis BRL-3A cells increased significantly, which were inhibited by AG490 or ROZ treatment. Taken together, these results indicated that KCCM attributed to KCs dysfunction facilitated hepatocyte steatosis through promoting expressing SOCS3; but PPARγ agonist ROZ alleviated steatosis through reducing SOCS3 expression by inhibiting JAK2/STAT3 in hepatocytes.


Assuntos
Hepatócitos/patologia , Janus Quinase 2/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , PPAR gama/fisiologia , Fator de Transcrição STAT3/antagonistas & inibidores , Proteína 3 Supressora da Sinalização de Citocinas/efeitos dos fármacos , Animais , Linhagem Celular , Meios de Cultivo Condicionados , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Resistência à Insulina , Janus Quinase 2/metabolismo , Macrófagos do Fígado , PPAR gama/agonistas , Ratos , Rosiglitazona , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Tiazolidinedionas/farmacologia
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