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1.
Anticancer Res ; 39(9): 4865-4876, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519589

RESUMO

BACKGROUND/AIM: Hypoxia promotes tumor proliferation and metastasis in colorectal cancer (CRC). Since the tumor microenvironment is generally characterized by hypoxia, its understanding is important for cancer therapy. We hypothesized that hypoxia promotes the mitochondrial function, mobility, and proliferation of CRC by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). MATERIALS AND METHODS: To assess the effects of PGC-1α under hypoxia, we investigated the mitochondrial function, cell motility, and sphere formation as well as proliferation and apoptosis of CRC. RESULTS: Under hypoxia, we confirmed the increased expression of PGC-1α and reduced production of reactive oxygen species (ROS) by activating anti-oxidant enzymes. Also, up-regulation of PGC-1α enhanced the motility, sphere formation, and proliferation of CRC. Under the presence of the anti-cancer drug 5-fluorouracil (5FU), up-regulation of PGC-1α under hypoxia promoted resistance of CRC against 5FU-induced apoptosis. CONCLUSION: Targeting PGC-1α could to be a powerful strategy for CRC therapy.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Hipóxia/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Apoptose , Catalase/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 606-612, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537245

RESUMO

Objective To investigate the effect of fibroblast growth factor 21 (FGF21) on the lipid accumulation and inflammation induced by palmitate treatment in L02 hepatocytes and the underlying mechanism. Methods L02 cells were infected with lentivirus expressing SIRT1 shRNA to knockdown SIRT1 expression. Wild-type and SIRT1-knockdown L02 cells were treated with 250 mol/L palmitate for 5 days, and then administrated with 1 g/ml FGF21 for 72 hours. Triglycerides in the cells were detected with the infinity triglycerides reagent. Malondialdehyde (MDA) in the cells was assessed by MDA detection assay. Tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) levels in supernatant were measured by ELISA. Reactive oxygen species (ROS) levels were tested by the specific Amplex red ROS detection assay kit from Thermo Fisher Company. The gene expression of SIRT1, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), superoxide dismutase 2 (SOD2) and catalase (CAT) were measured by real-time quantitative PCR. The protein levels of SIRT1, PGC1α, SOD2 and CAT were detected by Western blot analysis. Mitochondrial membrane potentials were detected by the JC-1staining kit. Mitochondrial oxygen consumption rate (OCR) was detected with the Seahorse XF Mito stress test kit. Results Palmitate increased the triglycerides level, induced the oxidative stress in both the cells and the mitochondria, decreased the gene expression and protein levels of SIRT1, PGC1α, SOD2 and CAT, increased the levels of TNF-α and IL-6, decreased the mitochondrial membrane potential, and impaired the mitochondrial function. FGF21 treatment could attenuate all of these effects caused by palmitate, while SIRT1 knockdown blocked most of the FGF21 effects on the L02 hepatocytes. Conclusion FGF21 activates SIRT1 pathway and inhibites the lipid accumulation, improves the mitochondrial function, and decreases the oxidative stress as well as inflammation in palmitate-treated L02 cells.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Sirtuína 1/metabolismo , Catalase/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Estresse Oxidativo , Palmitatos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Superóxido Dismutase-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
J Food Sci ; 84(8): 2101-2111, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31369153

RESUMO

Several studies indicated that ginger (Zingiber officinale Roscoe) enhances thermogenesis and/or energy expenditure with which to interpret the beneficial effects of ginger on metabolic disorders. It is well known that mitochondrial activity plays an essential role in these processes. Thus, this study aimed to investigate the effect of ginger extract (GE) and its major components, 6-gingerol and 6-shogaol, on mitochondrial biogenesis and the underlying molecular mechanisms. Our results showed that GE at dose of 2 g/kg promoted oxygen consumption and intrascapular temperature in mice. The mitochondrial DNA (mtDNA) copy number in muscle and liver increased. Expression levels of oxidative phosphorylation (OXPHOS) related proteins and AMP-activated protein kinase ɑ/proliferator-activated receptor gamma coactivator 1 ɑ (AMPK/PGC1ɑ) signaling related proteins in the muscle, liver, and brown adipose tissue (BAT) increased as well. In HepG2 cells, GE at concentration of 2.5 and 5 mg/mL increased mitochondrial mass and mtDNA copy number. GE promoted ATP production, the activities of mitochondrial respiratory chain complex I and IV, and expression levels of OXPHOS complex related proteins and AMPK/PGC1ɑ signaling related proteins. The antagonist of AMPK eliminated partly the effect of GE on mitochondrial biogenesis. 6-Gingerol increased mitochondrial mass, mtDNA copy number and ATP production, and the activities of mitochondrial respiratory chain complexes in HepG2 cells as well. However, both 6-gingerol at high concentration of 200 µM and 6-shogaol at 10 to 200 µM inhibited cell viability. In conclusion, GE promoted mitochondrial biogenesis and improved mitochondrial functions via activation of AMPK-PGC1ɑ signaling pathway, and 6-gingerol other than 6-shogaol, may be the main active component. PRACTICAL APPLICATION: Ginger (Zingiber officinale Roscoe) is a food seasoning and also used as a medical plant in alternative medicine throughout the world. Here, we demonstrated that ginger extract (GE) promoted mitochondrial biogenesis and mitochondrial function via activation of AMPK-PGC1ɑ signaling pathway both in mice and in HepG2 cells, and 6-gingerol may be its main active component. Ginger, with anticipated safety, is expected to be a long-term used dietary supplement and be developed into a new remedy for mitochondrial dysfunctional disorders.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Gengibre/química , Mitocôndrias/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Catecóis/análise , Sobrevivência Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Álcoois Graxos/análise , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ratos , Transdução de Sinais/efeitos dos fármacos
4.
Nat Commun ; 10(1): 2767, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235694

RESUMO

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.


Assuntos
Metabolismo Energético/fisiologia , Fadiga/fisiopatologia , Cinurenina/metabolismo , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Adaptação Fisiológica , Animais , Aspartato Aminotransferases/metabolismo , Ácido Aspártico/metabolismo , Carbidopa/farmacologia , Respiração Celular/efeitos dos fármacos , Respiração Celular/fisiologia , Metabolismo Energético/efeitos dos fármacos , Glicólise/fisiologia , Malatos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Animais , Músculo Esquelético/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Condicionamento Físico Animal/fisiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transaminases/antagonistas & inibidores , Transaminases/metabolismo
5.
Chemosphere ; 234: 822-829, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31247492

RESUMO

Mercury is one of the 10 toxic chemicals with major public health concerns. Continuous exposure to low levels of heavy metals including mercury is related to renal injury, especially in children. This study investigated the possible molecular mechanism of inorganic mercury-induced kidney injury. Twenty eight Kunming mice were divided into four groups (n = 7), and treated with 0, 20, 40, 80 mg/L mercuric chloride (HgCl2) in drinking water for 16 weeks respectively. All the HgCl2 exposure mice displayed different degrees of renal injury, which was diagnosed by hematoxylin and eosin stain, biochemical analysis, and ultrastructure examination. The treatment of HgCl2 inhibited the silent information regulator two ortholog 1 (Sirt1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) signaling pathway and resulted the disorder of mitochondrial dynamics, as evidenced by the increasing expression of dynamin-related protein 1 and decreasing expression of mitofusin 2. Meanwhile, HgCl2 inhibited the nuclear factor erythroid 2-related factor 2 (Nrf2) axis. The abnormality of mitochondrial dynamics and the suppression of Nrf2 axis exacerbated oxidative stress, and then induced cell apoptosis. These findings demonstrated that the disorder of mitochondrial dynamics induced by HgCl2 activated oxidative stress, and further resulted in renal apoptosis through inhibiting the Sirt1/PGC-1α signaling pathway and the Nrf2 axis.


Assuntos
Apoptose , Rim/lesões , Cloreto de Mercúrio/toxicidade , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo
6.
Gene ; 710: 131-139, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158446

RESUMO

As a fundamental regulator of mitochondrial function, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) acts as a powerful coactivator of many transcriptional factors that relate to steroidogenesis, while the regulatory mechanism remains unclear. In the present study, testosterone secretion of goat Leydig cells (LCs) mediated by miR-1197-3p via PPARGC1A was investigated. We found PPARGC1A protein was diversely localized in testis, and the expression of PPARGC1A in testis of 9-month-old goat was significantly higher than that in 3-month-old goat. In addition, suppression of PPARGC1A significantly decreased the testosterone secretion in goat LCs, as well as reduced the expressions of key steroidogenesis related genes [steroidogenic acute regulatory protein (StAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and 3 beta-hydroxysteroid dehydrogenase (3BHSD)], and overexpression of PPARGC1A showed the opposite effects. Moreover, we observed suppression of miR-1197-3p increased the synthesis of testosterone and promoted the expressions of PPARGC1A, StAR, CYP11A1, and 3BHSD by directly targeting PPARGC1A in the LCs. Furthermore, overexpression of PPARGC1A could alleviate miR-1197-3p induced aberrant steroidogenesis related gene expressions and testosterone synthesis. Taken together, miR-1197-3p could act as an essential regulator of LC testosterone secretion in goat testis by targeting PPARGC1A. These results provide a novel view of the regulatory mechanisms involved in male sexual maturation and help us to understand the molecular role of PPARGC1A in testosterone synthesis.


Assuntos
Células Intersticiais do Testículo/metabolismo , MicroRNAs/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Testosterona/metabolismo , Animais , Células Cultivadas , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Cabras , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
7.
Life Sci ; 229: 277-287, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150687

RESUMO

AIMS: Secreted protein acidic and rich in cysteine, (SPARC), is a matricellular protein implicated in the modulation of the extracellular matrix (ECM) and mitochondrial proteins expression. MAIN METHODS: To study the mechanism through which SPARC is involved in the possible link between ECM and mitochondria, C2C12 myoblasts were cultured with/without the exogenous addition/inhibition of SPARC as well as activation/inhibition of adenosine monophosphate-activated protein kinase (AMPK). Electrical pulse stimulation (EPS), was applied for 2 days in myotubes. KEY FINDINGS: The expressions of ECM-related (integrin-linked kinase (ILK), glycogen synthase kinase-3 beta (GSK-3ß), phosphorylated-GSK-3ß (p-GSK-3ß) and collagen 1a1), mitochondrial-related (AMPK, phosphorylated-AMPK (p-AMPK), succinate dehydrogenase (SDHB) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)) and SPARC proteins and/or genes were measured after modulation of SPARC and/or AMPK as well as with or without EPS. The addition of SPARC in C2C12 myoblast increased the expression of ILK, p-GSK-3ß and p-AMPK whereas anti-SPARC antibody decreased them at different incubation times (0, 10, and 30 min, and 6 h). The AMPK activation increased SPARC, collagen 1a1, p-AMPK and SDHB proteins level, however, AMPK inhibition blunted the effects. EPS induced Sparc and Pgc1a genes expression. SIGNIFICANCE: Sparc, an EPS-induced gene, may be involved in the link between ECM remodeling and mitochondrial function in muscle via its interaction with ILK/AMPK.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Matriz Extracelular/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mioblastos/metabolismo , Osteonectina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Células Cultivadas , Estimulação Elétrica , Regulação da Expressão Gênica , Camundongos , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Mioblastos/citologia , Osteonectina/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética
8.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083336

RESUMO

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


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Pioglitazona/farmacologia , Insuficiência Renal Crônica/terapia , Adulto , Antioxidantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Biogênese de Organelas , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Priônicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/patologia , Regulação para Cima/efeitos dos fármacos
9.
Methods Mol Biol ; 1966: 7-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041735

RESUMO

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays a central role in the response and adaptation to environmental and nutritional stimuli by initiating tissue-specific transcriptional reprogramming. Since its discovery in 1998, the field of PGC-1α biology has grown exponentially and a large body of research has elucidated the diverse roles of PGC-1α in brown adipose tissue thermogenesis, fatty acid oxidation, muscle fiber type switching, hepatic gluconeogenesis, and circadian clock regulation, etc. In addition, recent research has identified a splice variant(s) of PGC-1α in humans and rodents. The common misconception relating to PGC-1α is that it migrates at a predicted molecular weight of ~90 kDa by SDS-PAGE gel electrophoresis. However, several recent studies have provided solid evidence that the biologically relevant molecular weight of PGC-1α is ~110 kDa. In this chapter, we describe an optimized immunoblotting protocol that is developed to detect the low abundance protein PGC-1α and its alternatively spliced isoform named NT-PGC-1α in various rodent tissues. We also describe an optimized immunoprecipitation protocol that can isolate and concentrate endogenous PGC-1α and NT-PGC-1α. The protocols presented here will hopefully allow investigators to report accurate and reliable data regarding PGC-1α isoforms.


Assuntos
Immunoblotting/métodos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/análise , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Processamento Alternativo , Animais , Camundongos , Isoformas de Proteínas/análise , Ratos , Roedores/metabolismo
10.
Anim Sci J ; 90(8): 961-976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132807

RESUMO

This study aimed to investigate the effect of (-)-hydroxycitric acid ((-)-HCA) on lipid and glucose metabolism, and further analyzed these actions whether associated with modulation of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) expression in chicken embryos. Results showed that (-)-HCA decreased triglyceride content and lipid droplet counts, while these effects induced by (-)-HCA were reversed in chicken embryos pre-transfected with sh4-ALDH3A2. (-)-HCA decreased malic enzyme, acetyl-CoA carboxylase, fatty acid synthase, and sterol regulatory element binding protein-1c mRNA level, while increased carnitine palmitoyl transferase 1A (CPT1A) and peroxisome proliferators-activated receptor α (PPARα) mRNA level; and the action of (-)-HCA on lipid metabolism factors had completely eliminated in embryos pre-transfected with sh4-ALDH3A2. Chicken embryos pre-transfected with sh4-ALDH3A2 had eliminated the increasing of serum glucose and hepatic glycogen content induced by (-)-HCA. (-)-HCA decreased phosphofructokinase-1 and increased G6P, fructose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase mRNA level in chicken embryos. Similarly, the effect of (-)-HCA on these key enzyme mRNA level was reversed in embryos pre-transfected with sh4-ALDH3A2. Furthermore, (-)-HCA increased PPAR-γ-coactivator-1α (PGC-1α), PPARα, hepatic nuclear factor-4A, PEPCK, and CPT1A protein level, and these actions of (-)-HCA disappeared in embryos pre-transfected with sh4-ALDH3A2. These results indicated that (-)-HCA reduced fat accumulation and accelerated gluconeogenesis via activation of PGC-1α signaling pathway, and these effects of (-)-HCA might associate with the increasing of ALDH3A2 expression level in chicken embryos.


Assuntos
Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Embrião de Galinha/metabolismo , Citratos/farmacologia , Expressão Gênica , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Células Cultivadas , Gluconeogênese/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Int J Mol Sci ; 20(10)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137663

RESUMO

The aim of the present study was to investigate the time and intensity dependent effects of exercise on the heart components of the lipolytic complex. Wistar rats ran on a treadmill with the speed of 18 m/min for 30 min (M30) or 120 min (M120) or with the speed of 28 m/min for 30 min (F30). The mRNA and protein expressions of the compounds adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), G0/G1 switch gene 2 (G0S2), hormone sensitive lipase (HSL) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were examined by real-time PCR and Western blot, respectively. Lipid content of free fatty acids (FFA), diacylglycerols (DG) and triacylglycerols (TG) were estimated by gas liquid chromatography. We observed virtually no changes in the left ventricle lipid contents and only minor fluctuations in its ATGL mRNA levels. This was in contrast with its right counterpart i.e., the content of TG and DG decreased in response to both increased duration and intensity of a run. This occurred in tandem with increased mRNA expression for ATGL, CGI-58 and decreased expression of G0S2. It is concluded that exercise affects behavior of the components of the lipolytic system and the lipid content in the heart ventricles. However, changes observed in the left ventricle did not mirror those in the right one.


Assuntos
Ventrículos do Coração/metabolismo , Lipólise , Esforço Físico , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Ácidos Graxos não Esterificados/metabolismo , Lipase/genética , Lipase/metabolismo , Masculino , Especificidade de Órgãos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Wistar , Esterol Esterase/genética , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo
12.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100876

RESUMO

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1-PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. METHODS: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5-33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. RESULTS: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. CONCLUSION: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.


Assuntos
Restrição Calórica/métodos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Angiotensina II/metabolismo , Animais , Glicemia , Carbazóis/farmacologia , Cardiomegalia/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Masculino , Malondialdeído/sangue , Mesoporfirinas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Protoporfirinas/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo
13.
Cancer Sci ; 110(6): 2050-2062, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30945396

RESUMO

The PPAR coactivator-1α (PGC1α) is an important transcriptional co-activator in control of fatty acid metabolism. Mitochondrial fatty acid oxidation (FAO) is the primary pathway for the degradation of fatty acids and promotes NADPH and ATP production. Our previous study demonstrated that upregulation of carnitine palmitoyl transferase 1 A (CPT1A), the key regulator of FAO, promotes radiation resistance of nasopharyngeal carcinoma (NPC). In this study, we found that high expression of PGC1α is associated with poor overall survival in NPC patients after radiation treatment. Targeting PGC1α could sensitize NPC cells to radiotherapy. Mechanically, PGC1α binds to CCAAT/enhancer binding protein ß (CEBPB), a member of the transcription factor family of CEBP, to promote CPT1A transcription, resulting in activation of FAO. Our results revealed that the PGC1α/CEBPB/CPT1A/FAO signaling axis promotes radiation resistance of NPC. These findings indicate that the expression of PGC1α could be a prognostic indicator of NPC, and targeting FAO in NPC with high expression of PGC1α might improve the therapeutic efficacy of radiotherapy.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Oxirredução/efeitos da radiação , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos da radiação , Interferência de RNA
14.
Int J Mol Sci ; 20(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959809

RESUMO

Anti-cancer drug resistance is a serious issue for patients with colorectal cancer (CRC). Although recent studies have shown the mechanism by which CRC cells become drug resistant, novel strategies for overcoming this drug resistance have not yet been developed. To address this problem, we characterized 5-fluorouracil (5FU)-resistant CRC cells after treatment with 5FU, and focused on the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in these cells. In 5FU-resistant CRC cells, the 5FU did not considerably decrease the mitochondrial biogenesis or mitochondrial complex I and IV activities, and only partially decreased the antioxidant enzymatic activity, oxygen consumption ratio, and cell survival. The expression of PGC-1α was remarkably increased in the 5FU-resistant CRC cells compared with the 5FU-sensitive CRC cells. The 5FU-resistant CRC cells displayed enhanced mitochondrial biogenesis, oxidative phosphorylation, and antioxidant enzyme activities against 5FU-induced reactive oxygen species, because of the increased expression of PGC-1α. PGC-1α inhibited 5FU-induced endoplasmic reticulum (ER) stress in the 5FU-resistant CRC cells, resulting in the suppression of apoptosis. These findings reveal that PGC-1α plays an important role in drug resistance in 5FU-resistant CRC cells. Moreover, PGC-1α could serve as a novel target in patients with 5FU-resistant CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fluoruracila/farmacologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo
15.
Scand J Med Sci Sports ; 29(8): 1197-1204, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31025412

RESUMO

INTRODUCTION: High-intensity interval training (HIIT) increases mitochondrial biogenesis and cardiorespiratory fitness in chronic disease populations, however has not been studied in people with chronic kidney disease (CKD). The aim of this study was to compare the feasibility, safety, and efficacy of HIIT with moderate-intensity continuous training (MICT) in people with CKD. METHODS: Fourteen individuals with stage 3-4 CKD were randomized to 3 supervised sessions/wk for 12 weeks, of HIIT (n = 9, 4 × 4 minute intervals, 80%-95% peak heart rate [PHR]) or MICT (n = 5, 40 minutes, 65% PHR). Feasibility was assessed via session attendance and adherence to the exercise intensity. Safety was examined by adverse event reporting. Efficacy was determined from changes in cardiorespiratory fitness (VO2 peak), exercise capacity (METs), and markers of mitochondrial biogenesis (PGC1α protein levels), muscle protein catabolism (MuRF1), and muscle protein synthesis (p-P70S6k Thr389 ). RESULTS: Participants completed a similar number of sessions in each group (HIIT = 33.0[7.0] vs MICT = 33.5[3.3] sessions), and participants adhered to the target heart rates. There were no adverse events attributable to exercise training. There was a significant time effect for exercise capacity (HIIT = +0.8 ± 1.2; MICT = +1.3 ± 1.6 METs; P = 0.01) and muscle protein synthesis (HIIT = +0.6 ± 1.1; MICT = +1.4 ± 1.7 au; P = 0.04). However, there were no significant (P > 0.05) group × time effects for any outcomes. CONCLUSION: This pilot study demonstrated that HIIT is a feasible and safe option for people with CKD, and there were similar benefits of HIIT and MICT on exercise capacity and skeletal muscle protein synthesis. These data support a larger trial to further evaluate the effectiveness of HIIT.


Assuntos
Aptidão Cardiorrespiratória , Terapia por Exercício , Treinamento Intervalado de Alta Intensidade , Insuficiência Renal Crônica/terapia , Idoso , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Biogênese de Organelas , Consumo de Oxigênio , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Projetos Piloto , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
16.
Eur J Pharmacol ; 854: 328-337, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31028741

RESUMO

Cancer metabolism is an attractive target of the therapeutic strategy for cancer. The present study identified bouchardatine (Bou) as a potent suppressor of rectal cancer growth by cycle-arresting independent of apoptosis. In cultured HCT-116 rectal cancer cells, Bou increased glucose uptake/oxidation and capacity of mitochondrial oxidation. These effects were associated with an upregulation of uncoupling protein 2 (UCP2) and the activation of its upstream Sirtuin 1 (SIRT1)/(Liver kinase B1) LKB1- (Adenosine monophosphate-activated protein kinase) AMPK axis. The pivotal role of UCP2 in the cancer-suppressing effect was demonstrated by overexpressing UCP2 in HCT-116 cells with similar metabolic effects to those produced by Bou. Interestingly, Bou activated peroxisome proliferators activated receptor γ coactivator 1α (PGC-1α) and recruited it to the promoter of UCP2 in HCT-116 cells along with deacetylation (thus activation) by SIRT1. The requirement of SIRT1 for the cancer-suppressing effect through the PGC-1α-UCP2 was confirmed by the reciprocal responses to Bou in HCT-116 with defected and overexpressed SIRT1. Whereas knockdown, mutation or pharmacological inhibition of SIRT1 all abolished Bou-induced deacetylation/activation of PGC-1α, the opposing effects were observed after overexpressing SIRT1. In mice, administration of Bou (50 mg/kg) also suppressed the growth of rectal cancer associated with increases the UCP2 expression and mitochondria capacity in the tumor. Collectively, our findings suggest that Bou has a therapeutic potential for the treatment of rectal cancer by disrupting the metabolic path of cancer cells via activating the PGC-1α-UCP2 axis with SIRT1 as its primary target.


Assuntos
Alcaloides Indólicos/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Neoplasias Retais/tratamento farmacológico , Sirtuína 1/metabolismo , Proteína Desacopladora 2/metabolismo , Acetilação/efeitos dos fármacos , Aerobiose/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Alcaloides Indólicos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução/efeitos dos fármacos , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Neurochem Res ; 44(7): 1678-1689, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982205

RESUMO

Intracerebral hemorrhage (ICH) is a stroke subtype that is associated with high mortality and disability rate. Mitochondria plays a crucial role in neuronal survival after ICH. This study first showed that activation of adiponectin receptor 1 (AdipoR1) by AdipoRon could attenuate mitochondrial dysfunction after ICH. In vivo, experimental ICH model was established by autologous blood injection in mice. AdipoRon was injected intraperitoneally (50 mg/kg). Immunofluorescence staining were performed to explicit the location of AdipoR1, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1a (PGC1α). The PI staining was used to quantify neuronal survival. The expression of AdipoR1 and its downstream signaling molecules were detected by Western blotting. In vitro, 10 µM oxyhemoglobin (OxyHb) was used to induce the neuronal injury in SH-SY5Y cells. Annexin V-FITC/PI staining was used to detect the neuronal apoptosis and necrosis. Mitochondrial membrane potential (Δψm) was measured by a JC-1 kit and mitochondrial mass was quantified by mitochondrial fluorescent probe. In vivo, PI staining showed that the administration of AdipoRon could reduce neuronal death at 72 h after ICH in mice. AdipoRon treatment enhanced ATP levels and reduced ROS levels in perihematoma tissues, and increased the protein expression of AdipoR1, P-AMPK, PGC1α, NRF1 and TFAM. In vitro, the JC-1 staining and Mito-tracker™ Green showed that AdipoRon significantly alleviated OxyHb-induced collapse of Δψm and enhanced mitochondrial mass. Moreover, flow cytometry analysis indicated that the neurons treated with AdipoRon showed low necrotic and apoptotic rate. AdipoRon alleviates mitochondrial dysfunction after intracerebral hemorrhage via the AdipoR1-AMPK-PGC1α pathway.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Piperidinas/uso terapêutico , Receptores de Adiponectina/agonistas , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/prevenção & controle , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Necrose/tratamento farmacológico , Neurônios/patologia , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Adiponectina/metabolismo
18.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987128

RESUMO

Obesity, a major risk factor for chronic diseases such as type 2 diabetes (T2D), represents a serious primary health problem worldwide. Dietary habits are of special interest to prevent and counteract the obesity and its associated metabolic disorders, including lipid steatosis. Capsaicin, a pungent compound of chili peppers, has been found to ameliorate diet-induced obesity in rodents and humans. The purpose of this study was to examine the effect of capsaicin on hepatic lipogenesis and to delineate the underlying signaling pathways involved, using HepG2 cells as an experimental model. Cellular neutral lipids, stained with BODIPY493/503, were quantified by flow cytometry, and the protein expression and activity were determined by immunoblotting. Capsaicin reduced basal neutral lipid content in HepG2 cells, as well that induced by troglitazone or by oleic acid. This effect of capsaicin was prevented by dorsomorphin and GW9662, pharmacological inhibitors of AMPK and PPARγ, respectively. In addition, capsaicin activated AMPK and inhibited the AKT/mTOR pathway, major regulators of hepatic lipogenesis. Furthermore, capsaicin blocked autophagy and increased PGC-1α protein. These results suggest that capsaicin behaves as an anti-lipogenic compound in HepG2 cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Capsaicina/farmacologia , Lipogênese/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Lipídeos/análise , Modelos Biológicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Theriogenology ; 132: 72-82, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31003067

RESUMO

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A) acts as a powerful coactivator of many transcriptional factors that relate to granulosa cell (GC) apoptosis. In this study, the miRNAs mediating goat follicular atresia and luteinized granulosa cell (LGC) apoptosis induced by hydrogen peroxide (H2O2) via PPARGC1A were investigated. Our results showed that miR-1197-3p targeted PPARGC1A was predicted by bioinformatics algorithm and verified by luciferase reporter assay. In addition, miR-1197-3p promoted goat LGC apoptosis via PPARGC1A through mitochondrial-dependent apoptosis pathway, and these effects could be restored by PPARGC1A overexpression. Moreover, H2O2-induced LGC apoptosis significantly upregulated miR-1197-3p expression and downregulated PPARGC1A level. Pretreatment of miR-1197-3p inhibitor alleviated LGC apoptosis induced by 400 µM H2O2 for 12 h, and preserved the mitochondrial membrane potential by increasing PPARGC1A expression. In conclusion, miR-1197-3p might act as an essential regulator of goat LGC apoptosis potentially via the mitochondrial-dependent apoptosis pathway by targeting PPARGC1A.


Assuntos
Apoptose/efeitos dos fármacos , Cabras , Células da Granulosa/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , MicroRNAs/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Sobrevivência Celular , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/fisiologia , MicroRNAs/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética
20.
Food Funct ; 10(4): 1903-1914, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30869672

RESUMO

This study explores the roles of l-arginine (Arg) and N-carbamylglutamate (NCG) supplementation in the diet in intestine damage, energy state, as well as the associated protein kinase signaling pathways activated by AMP in intrauterine growth retarded (IUGR) suckling lambs. A total of 48 newborn Hu lambs with a normal birth weight (CON) and those with IUGR were randomly divided into four groups, CON, IUGR, IUGR + 1% Arg, and IUGR + 0.1% NCG, with 12 animals in each group. All animals were fed for 21 days, from day 7-28, following birth. Our results indicated that the IUGR suckling Hu lambs in the Arg or NCG groups were associated with reduced (P < 0.05) plasma diamine oxidase (DAO) and d-lactic acid levels compared with IUGR suckling lambs. In addition, IUGR suckling Hu lambs in the Arg or NCG group were also linked with a higher (P < 0.05) villous height : crypt depth ratio (VCR), as well as villous height in the duodenum relative to those obtained for IUGR suckling Hu lambs. Relative to IUGR suckling Hu lambs, IUGR suckling Hu lambs in the Arg or NCG groups were found to have higher (P < 0.05) ATP, ADP and TAN contents, and AEC levels, and smaller (P < 0.05) AMP : ATP ratios in the duodenum, jejunum and ileum. Moreover, IUGR suckling Hu lambs in the Arg or NCG group were also linked with higher citrate synthase, isocitrate dehydrogenase and alpha-oxoglutarate dehydrogenase complex activities in the duodenum, jejunum and ileum compared with those found for IUGR suckling Hu lambs (P < 0.05), except for the activity of isocitrate dehydrogenase in the ileum. IUGR suckling Hu lambs in the Arg or NCG group were linked with a lower ratio of pAMPKα/tAMPKα and protein expression of Sirt1 and PGC1α in the ileum relative to those of the IUGR suckling Hu lambs (P < 0.05). Taken together, these findings show that supplementation of NCG and Arg in the diet can ameliorate intestinal injury, improve energy status, motivate key enzyme activities in the tricarboxylic acid (TCA) cycle, and also inhibit the AMP-activated protein kinase signaling pathways in IUGR suckling Hu lambs.


Assuntos
Arginina/metabolismo , Suplementos Nutricionais/análise , Retardo do Crescimento Fetal/metabolismo , Glutamatos/metabolismo , Mucosa Intestinal/metabolismo , Ovinos/metabolismo , Ração Animal/análise , Animais , Arginina/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Feminino , Retardo do Crescimento Fetal/tratamento farmacológico , Glutamatos/administração & dosagem , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ovinos/crescimento & desenvolvimento , Sirtuína 1/genética , Sirtuína 1/metabolismo
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