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1.
Anticancer Res ; 40(2): 653-664, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014906

RESUMO

BACKGROUND/AIM: Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of mitochondrial biogenesis and metabolism. We investigated the effect of PGC-1α knockdown in the human colorectal cancer cell line SW620, which highly expresses PGC-1α. MATERIALS AND METHODS: We established the PGC-1α shRNA-silenced SW620 stable cell line (PGC-1α shRNA-SW620 cells) and examined cell proliferation by cell counts and carboxyfluorescein succinimidyl ester (CFSE) staining, migration by wound-healing and transwell migration assay, and invasion by transwell assays. RESULTS: PGC-1α knockdown inhibited cell proliferation, migration, and invasion in SW620 cells. Western blot analysis showed that p-AKT, p-GSK-3ß, ß-catenin, N-cadherin and vimentin expression were all reduced, but E-cadherin had increased expression in PGC-1α shRNA-SW620 cells. We also examined cell proliferation, migration, invasion and the expression of p-AKT, p-GSK-3ß, ß-catenin, N-cadherin, vimentin, and E-cadherin in PGC-1α overexpressing SW480 cells (a low PGC-1α expressing line). We observed a complete reversal of the results seen in the knockdown. CONCLUSION: PGC-1α might regulate cell proliferation and invasion via AKT/GSK-3ß/ß-catenin pathway in SW620 and SW480 cells.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Técnicas de Silenciamento de Genes , Humanos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais , Transfecção
2.
Gene ; 735: 144394, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31987906

RESUMO

The aim of the current study was to evaluate the effects of conjugated linoleic acid (CLA) on the expression of the genes involved in the reduction of inflammatory conditions induced by tumor necrosis factor alpha (TNF-α). To fulfill this, the C2C12 murine myoblast cell line was used. The experimental treatments consisted of 50 and 100 µM of CLA with 10, 15 and 20 ng/mL of TNF-α. Our results indicated that the concentrations of 50, 100 and 150 µM of CLA at 24 and 48 h increased the cell survival rate (p < 0.05), as compared with the control group. The effect of pre-treating CLA before the inflammation induced by TNF-α showed that the amount of cell death caused by TNF-α was inhibited in both 50 and 100 µM concentrations of CLA (p < 0.05). Modulatory effects of CLA on PGC1-α and Fndc5 transcript levels showed that the PGC1-α and Fndc5 expression levels were significantly increased 48 h after treating with 50 and 100 µM of CLA (p < 0.05). Overall, these findings indicate that using CLA could considerably improve the inflammatory condition induced by TNF-α.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Linoleicos Conjugados/farmacologia , Mioblastos/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Animais , Linhagem Celular , Camundongos , Mioblastos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
3.
J Agric Food Chem ; 67(49): 13605-13616, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31735033

RESUMO

Obesity is a global public health issue. Thermogenesis is a novel way to promote anti-obesity by consuming energy as heat rather than storing it as triacylglycerols. The browning program allows mitochondrial biosynthesis and thermogenesis-related gene expression to occur in subcutaneous white adipose tissue, which results in the formation of beige adipose tissue. Some phytochemicals have exerted the capability to activate the fat browning process. Resveratrol and oxyresveratrol are both natural stilbenoids that have been reported for their anti-obesity efficacy. However, the comparison between the two as they relate to thermogenesis as well as the differences in their underlying mechanisms are still not widely discussed. Our result reveals that both resveratrol and oxyresveratrol could elevate the expression of thermogenesis-related protein expression including UCP1 (uncoupling protein-1) and PRDM (PR domain containing 16) via Sirt1/PGC-1α (sirtuin 1/peroxisome proliferation gamma coactivator-1 α) activation. However, it is suggested that the transcriptional factor PPARα (peroxisome proliferator-activator receptor α) was activated by resveratrol (1.38 ± 0.07 fold) but not oxyresveratrol. Conversely, C/EBPß (CCAAT/enhancer-binding protein ß) was upregulated by oxyresveratrol (1.58 ± 0.05 fold) but not by resveratrol. On the other hand, CPT1 (carnitine palmitoyltransferase) was found to be significantly activated at lower concentrations of oxyresveratrol up to 1.89 ± 0.04 fold as compared to high-fat diet, and it could be a leading reason for UCP1 activation. Lastly, adiponectin expression was promoted in all experimental groups (1.53 ± 0.08 and 1.49 ± 0.11-fold in resveratrol (RES) and high oxyresveratrol (HOXY), respectively), which could be an activator for mitochondrial biosynthesis and UCP1 expression.


Assuntos
Obesidade/tratamento farmacológico , Obesidade/genética , Resveratrol/administração & dosagem , Termogênese/efeitos dos fármacos , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Obesidade/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
4.
PLoS Biol ; 17(10): e3000467, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589602

RESUMO

Skeletal muscles consist of fibers of differing metabolic activities and contractility, which become remodeled in response to chronic exercise, but the epigenomic basis for muscle identity and adaptation remains poorly understood. Here, we used chromatin immunoprecipitation sequencing of dimethylated histone 3 lysine 4 and acetylated histone 3 lysine 27 as well as transposase-accessible chromatin profiling to dissect cis-regulatory networks across muscle groups. We demonstrate that in vivo enhancers specify muscles in accordance with myofiber composition, show little resemblance to cultured myotube enhancers, and identify glycolytic and oxidative muscle-specific regulators. Moreover, we find that voluntary wheel running and muscle-specific peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc1a) transgenic (mTg) overexpression, which stimulate endurance performance in mice, result in markedly different changes to the epigenome. Exercise predominantly leads to enhancer hypoacetylation, whereas mTg causes hyperacetylation at different sites. Integrative analysis of regulatory regions and gene expression revealed that exercise and mTg are each associated with myocyte enhancer factor (MEF) 2 and estrogen-related receptor (ERR) signaling and transcription of genes promoting oxidative metabolism. However, exercise was additionally associated with regulation by retinoid X receptor (RXR), jun proto-oncogene (JUN), sine oculis homeobox factor (SIX), and other factors. Overall, our work defines the unique enhancer repertoires of skeletal muscles in vivo and reveals that divergent exercise-induced or PGC1α-driven epigenomic programs direct partially convergent transcriptional networks.


Assuntos
Epigênese Genética , Histonas/genética , Células Musculares/metabolismo , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Condicionamento Físico Animal , Acetilação , Animais , Reprogramação Celular , Cromatina/química , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Glicólise/genética , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Musculares/citologia , Músculo Esquelético/citologia , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Transdução de Sinais
5.
Mol Cell ; 76(6): 885-895.e7, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31629659

RESUMO

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high KM of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.


Assuntos
Neoplasias Encefálicas/enzimologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Mitocôndrias/enzimologia , Biogênese de Organelas , Oxigênio/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Apoptose , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Metilação , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Carga Tumoral , Hipóxia Tumoral , Microambiente Tumoral
6.
Int J Mol Sci ; 20(20)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31614978

RESUMO

TGF-ß/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-ß/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-ß/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-ß-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFßRI, but not TGFßRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFßRI by PGC-1α was associated with the upregulation of let-7b/c, miRNA for which the 3' untranslated region (UTR) of TGFßRI contains a binding site. In conclusion, PGC-1α suppresses TGF-ß/Smad signaling activation via targeting TGFßRI downregulation by let-7b/c upregulation.


Assuntos
MicroRNAs/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Insuficiência Renal Crônica/genética , Sítios de Ligação/genética , Linhagem Celular , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica/genética , Humanos , Peroxissomos/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteínas Smad/genética , Fatores de Transcrição da Família Snail/genética , Fator de Crescimento Transformador beta/genética
7.
Food Funct ; 10(9): 6157-6169, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501849

RESUMO

Chicoric acid (CA), a major nutraceutical component of a typical Mediterranean vegetable, chicory, possesses excellent antioxidant and anti-inflammatory bioactivities. This work aimed to elucidate the effects of CA on neuron survival against inflammation and the underlying molecular mechanisms. Results demonstrated that CA promoted SH-SY5Y cells' autophagic vesicle formation, up-regulated autophagic elongation phase related gene expressions, and inhibited apoptosis stimulated by microglial conditioned culture medium (MCM). In addition, CA significantly improved mitochondrial function and regulated redox homeostasis related signaling pathways such as MAPKs and PI3K/AKT. MCM with CA notably increased the expressions of PGC-1α, SIRT1 and enhanced the phosphorylation of AMPK, promoting energy metabolism. On the other hand, the underlying mechanisms of the intervention of CA in MCM-induced cell apoptosis were partly due to its direct protective effect on SH-SY5Y cells and inhibition of microglial inflammatory factor release. This establishes a theoretical foundation for neuro-nutrition intervention studies of natural functional food components, and provides new clues for developing health foods containing CA.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Succinatos/farmacologia , Ácidos Cafeicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Succinatos/química
8.
Redox Biol ; 26: 101307, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31473487

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has a critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have a critical role in fibrotic repair, but the contribution of MCU in macrophage metabolism is not known. Here, we show that MCU regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and metabolic reprogramming to fatty acid oxidation (FAO) in macrophages. MCU regulated PGC-1α expression by increasing the phosphorylation of ATF-2 by the p38 MAPK in a redox-dependent manner. The expression and activation of PGC-1α via the p38 MAPK was regulated by MCU-mediated mitochondrial calcium uptake, which is linked to increased mitochondrial ROS (mtROS) production. Mice harboring a conditional expression of dominant-negative MCU in macrophages had a marked reduction in mtROS and FAO and were protected from pulmonary fibrosis. Moreover, IPF lung macrophages had evidence of increased MCU and mitochondrial calcium, increased phosphorylation of ATF2 and p38, as well as increased expression of PGC-1α. These observations suggest that macrophage MCU-mediated metabolic reprogramming contributes to fibrotic repair after lung injury.


Assuntos
Canais de Cálcio/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Adulto , Idoso , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH2/metabolismo , Consumo de Oxigênio , Fenótipo , Fibrose Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
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
10.
Turk J Med Sci ; 49(4): 1089-1094, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31390852

RESUMO

Background/aim: Environmental and genetic factors may play a major role in the development of nonalcoholic fatty liver disease (NAFLD) among people with obesity and type 2 diabetes mellitus. Based on the fact that PGC-1α, as the protein encoded by the PPARGC1A gene, plays a key role in energy metabolism pathways, it has been hypothesized that polymorphisms within the PPARGC1Agene may be associated with increased risks of NAFLD. Thus, this study was designed to evaluate the Gly482Ser polymorphism (rs8192678) within the PPARGC1A gene and its association with the increased risk of NAFLD in Iranian patients with type 2 diabetes. Materials and methods: A total of 145 NAFLD patients with a history of type 2 diabetes and 145 healthy control subjects were included in the study. Gly482Ser polymorphism genotyping was done using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. Results: The results showed a significant difference between the PPARGC1A Gly482Serpolymorphism in NAFLD patients and the healthy controls. Accordingly, the AA genotype and A allele were increased in the NAFLD patients when compared to the healthy controls. However, no significant correlation was observed between the Gly482Ser polymorphism and the physiological and biochemical parameters. Conclusion: Based on the results, the AA genotype, which is associated with the insertion of Ser, can be considered as a risk factor for the development of NAFLD in Iranian patients with diabetes type 2.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Hepatopatia Gordurosa não Alcoólica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único/genética
11.
Nat Commun ; 10(1): 3412, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363081

RESUMO

Skeletal muscle insulin resistance, decreased phosphatidylinositol 3-kinase (PI3K) activation and altered mitochondrial function are hallmarks of type 2 diabetes. To determine the relationship between these abnormalities, we created mice with muscle-specific knockout of the p110α or p110ß catalytic subunits of PI3K. We find that mice with muscle-specific knockout of p110α, but not p110ß, display impaired insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p110αKO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion, and increased PGC1α expression, especially PCG1α2 and PCG1α3. This leads to enhanced mitochondrial oxidative capacity, increased muscle NADH content, and higher muscle free radical release measured in vivo using pMitoTimer reporter. Thus, p110α is the dominant catalytic isoform of PI3K in muscle in control of insulin sensitivity and muscle mass, and has a unique role in mitochondrial homeostasis in skeletal muscle.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Mitocôndrias/enzimologia , Músculo Esquelético/enzimologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Homeostase , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , NAD/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo
12.
Mol Cell ; 76(3): 500-515.e8, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31422874

RESUMO

Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity.


Assuntos
Adipócitos Bege/enzimologia , Tecido Adiposo Bege/enzimologia , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Obesidade/enzimologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Processamento de Proteína Pós-Traducional , Termogênese , Acetilação , Tecido Adiposo Bege/fisiopatologia , Adiposidade , Adolescente , Adulto , Idoso , Animais , Estudos de Casos e Controles , Dieta Hiperlipídica , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Acetiltransferase N-Terminal A/deficiência , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/deficiência , Acetiltransferase N-Terminal E/genética , Células NIH 3T3 , Obesidade/genética , Obesidade/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fenótipo , Transdução de Sinais , Adulto Jovem
13.
Food Funct ; 10(9): 5555-5565, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31429458

RESUMO

Exposure to chromium (Cr) causes a number of respiratory diseases, including lung cancer and pulmonary fibrosis. However, there is currently no safe treatment for Cr-induced lung damage. Here, we used in vivo and in vitro approaches to examine the protective effects of melatonin (MEL) on Cr-induced lung injury and to identify the underlying molecular mechanisms. We found that treatment of rats or a mouse lung epithelial cell MLE-12 with MEL attenuated K2Cr2O7-induced lung injury by reducing the production of oxidative stress and inflammatory mediators and inhibiting cell apoptosis. MEL treatment upregulated the expression of silent information regulator 1 (Sirt1), which deacetylated the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α). In turn, this increased the expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and key anti-oxidant target genes. These results suggest that melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1α/Nrf2 pathway. Dietary MEL supplement may be a potential new strategy for the treatment of Cr poisoning.


Assuntos
Cromo/toxicidade , Lesão Pulmonar/tratamento farmacológico , Melatonina/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Animais , Suplementos Nutricionais/análise , Humanos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/genética
14.
J Therm Biol ; 84: 236-244, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31466759

RESUMO

The present study aimed to analyze the time- and temperature-responses of boar sperm and clarify the mechanism underlying the protective effects of L-arginine on heat-induced low sperm motility. Mature boar sperm was used to evaluate the effects of temperature, exposure time, L-arginine level and their interactions on sperm motility, respectively. Results showed increasing exposure time resulted in the decreased total motility and rate of rapid progressive sperm, and the increased rates of the immotile sperm and the sperm shaking in place at 38 and 39 °C, respectively (P < 0.05). L-arginine supplementation at the dose of 1.0 mM increased total motility and decreased rate of immotile sperm (P < 0.05). Heat at 39 °C decreased total motile and rate of rapid progressive sperm (P < 0.05), increased the level of sperm reactive oxygen species (ROS) (P < 0.05), reduced mitochondrial membrane potential (ΔΨm), ATP content and the activities of mitochondrial respiratory chain complexes (MRCC) ΙΙΙ and V (P < 0.05), which were attenuated by L-arginine supplementation. There were significant increases in the relative mRNA expression of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha in heat-exposed group without L-arginine supplementation. In conclusion, the rising temperatures impacted boar sperm motility in a time-dependent manner. In vitro addition of L-arginine to boar semen had a dose-dependent effect on sperm motility and sperm incubated with 1.0 mM L-arginine showed elevated motility. L-arginine supplementation can ameliorate heat-induced increase in ROS level and decreases in MRCC activities, which further maintain mitochondrial oxidative phosphorylation function, ATP synthesis and boar sperm motility.


Assuntos
Arginina/farmacologia , Temperatura Alta/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Motilidade Espermática/efeitos dos fármacos , Animais , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/fisiologia , Fator 1 Relacionado a NF-E2/genética , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Suínos
15.
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
16.
J Med Food ; 22(8): 833-840, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268397

RESUMO

Piceatannol (PIC) is a natural hydroxylated analog of resveratrol (RSV) and considered as a potential metabolic regulator. The purpose of this study was to compare the effects of PIC and RSV on parameters affecting inflammation, oxidative stress, and sirtuins (Sirt). Male C57BL/6J mice, 20 weeks old, were assigned to the following groups; (1) lean control, (2) high-fat diet control (HF), (3) HF_PIC, and (4) HF_RSV. Oral administration of PIC and RSV (10 mg/kg/day) for 4 weeks improved glucose control as shown by decreasing levels of area under the curve (AUC) during the oral glucose tolerance test compared with HF group. PIC improved glycemic control by increasing hepatic levels of insulin receptor and AMP-activated protein kinase. PIC increased the levels of Sirt1, Sirt3, and Sirt6 and also increased two downstream targets of Sirt, peroxisome proliferator-activated receptor gamma coactivator 1-alpha and forkhead box O1, in the liver. The inflammatory markers, interleukin (IL)-1 and IL-6, in the liver were downregulated by RSV treatment. Exposure to PIC and RSV significantly lowered hepatic levels of tumor necrosis factor-alpha. However, PIC and RSV treatments showed minimal effects on hepatic markers of oxidative stress. The levels of antioxidant enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), were only increased in livers of RSV-treated mice compared with HF control mice. In conclusion, PIC was superior to an equal concentration of RSV in the regulation of Sirt and its downstream targets as well as insulin signaling-related parameters, while RSV potentially suppressed levels of proinflammatory markers and increased NQO1 protein levels.


Assuntos
Hepatopatias/tratamento farmacológico , Fígado/imunologia , Resveratrol/administração & dosagem , Sirtuínas/genética , Estilbenos/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Fígado/efeitos dos fármacos , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/imunologia , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/imunologia , Sirtuínas/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
17.
Genes (Basel) ; 10(7)2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261764

RESUMO

Intensive artificial and natural selection have shaped substantial variation among European horse breeds. Whereas most equine selection signature studies employ divergent genetic population structures in order to derive specific inter-breed targets of selection, we screened a total of 1476 horses originating from 12 breeds for the loss of genetic diversity by runs of homozygosity (ROH) utilizing a 670,000 single nucleotide polymorphism (SNP) genotyping array. Overlapping homozygous regions (ROH islands) indicating signatures of selection were identified by breed and similarities/dissimilarities between populations were evaluated. In the entire dataset, 180 ROH islands were identified, whilst 100 islands were breed specific, all other overlapped in 36 genomic regions with at least one ROH island of another breed. Furthermore, two ROH hot spots were determined at horse chromosome 3 (ECA3) and ECA11. Besides the confirmation of previously documented target genes involved in selection for coat color (MC1R, STX17, ASIP), body size (LCORL/NCAPG, ZFAT, LASP1, HMGA2), racing ability (PPARGC1A), behavioral traits (GRIN2B, NTM/OPCML) and gait patterns (DMRT3), several putative target genes related to embryonic morphogenesis (HOXB), energy metabolism (IGFBP-1, IGFBP-3), hair follicle morphogenesis (KRT25, KRT27, INTU) and autophagy (RALB) were highlighted. Furthermore, genes were pinpointed which might be involved in environmental adaptation of specific habitats (UVSSA, STXBP4, COX11, HLF, MMD).


Assuntos
Cruzamento , Homozigoto , Cavalos/genética , Proteína Agouti Sinalizadora/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas de Transporte/genética , Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Ontologia Genética , Genoma , Proteína HMGA2/genética , Proteínas de Homeodomínio/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Queratinas Específicas do Cabelo/genética , Proteínas de Membrana/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Proteínas de Transporte Vesicular/genética , Proteínas ral de Ligação ao GTP/genética
18.
Taiwan J Obstet Gynecol ; 58(4): 526-530, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31307745

RESUMO

OBJECTIVE: The alternations of mtDNA may play an important role in the molecular pathogenesis and process of Pelvic Organ Prolapse (POP) formation in both pre-menopausal and post-menopausal women. The aim of the present study is to analyze the association between the mitochondrial biogenesis gene and development of POP in the uterosacral ligaments (UL) of pre-menopausal women. MATERIALS AND METHODS: Seventy one pre-menopausal women, all below 52 years of age, were enrolled in this study. UL biopsies were obtained from uterine specimens taken from 33 women with POP (n = 33, study group) and 38 myoma patients without POP (n = 38, control group). Quantitative Real-Time PCR was performed to measure mitochondrial DNA (mtDNA) copy number and mtDNA4977. Western blotting and immunohistochemistry were used to assess the protein expression of PGC-1α, TFAM, NRF-1 and NRF-2. Statistical analysis was performed using SPSS statistical software and the Mann-Whitney U test, and the continuous variables were analyzed using the Student's t-test in demographic data. RESULTS: There were no significant differences in the patient demographics between the two groups (p > 0.05). The mtDNA copy number in the UL of pre-menopausal patients with prolapse was significantly higher than that in the no prolapse group (p = 0.008). There were no significant differences between the mtDNA4977 of the POP and non-POP groups, but a significantly higher expression of PGC-1α in the POP group compared to the non-POP group (1.59 ± 1.30 v.s. 0.66 ± 0.53; p = 0.036). The expression of TFAM in the POP group was higher than in the non-POP group). There was no significant difference in the TFAM(p = 0.377), NRF-1 and NRF-2 expression between the POP and non-POP groups (p = 0.647; p = 0.682). CONCLUSIONS: Changes in the PGC-1α and mtDNA copy number may play a role in the development of Pelvic Organ Prolapse in pre-menopausal patients.


Assuntos
Variações do Número de Cópias de DNA , Regulação da Expressão Gênica , Prolapso de Órgão Pélvico/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Pré-Menopausa/genética , Estudos de Coortes , DNA Mitocondrial/análise , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Prolapso de Órgão Pélvico/epidemiologia , Prolapso de Órgão Pélvico/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos Retrospectivos , Papel (figurativo) , Estatísticas não Paramétricas
19.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340436

RESUMO

Status epilepticus may decrease mitochondrial biogenesis, resulting in neuronal cell death occurring in the hippocampus. Sirtuin 1 (SIRT1) functionally interacts with peroxisome proliferator-activated receptors and γ coactivator 1α (PGC-1α), which play a crucial role in the regulation of mitochondrial biogenesis. In Sprague-Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure activity. SIRT1, PGC-1α, and other key proteins involving mitochondrial biogenesis and the amount of mitochondrial DNA were investigated. SIRT1 antisense oligodeoxynucleotide was used to evaluate the relationship between SIRT1 and mitochondrial biogenesis, as well as the mitochondrial function, oxidative stress, and neuronal cell survival. Increased SIRT1, PGC-1α, and mitochondrial biogenesis machinery were found in the hippocampus following experimental status epilepticus. Downregulation of SIRT1 decreased PGC-1α expression and mitochondrial biogenesis machinery, increased Complex I dysfunction, augmented the level of oxidized proteins, raised activated caspase-3 expression, and promoted neuronal cell damage in the hippocampus. The results suggest that the SIRT1 signaling pathway may play a pivotal role in mitochondrial biogenesis, and could be considered an endogenous neuroprotective mechanism counteracting seizure-induced neuronal cell damage following status epilepticus.


Assuntos
Região CA3 Hipocampal/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Sirtuína 1/genética , Estado Epiléptico/genética , Animais , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Caspase 3/genética , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Injeções Intraventriculares , Ácido Caínico/administração & dosagem , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Biogênese de Organelas , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Técnicas Estereotáxicas
20.
Inflamm Res ; 68(10): 867-876, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312857

RESUMO

OBJECTIVES: A drastic reduction in myocardial cell apoptosis plays a crucial role in the treatment/management of myocardial infarction, a major cardiovascular health challenge confronting the world, especially the Western world. Accumulating evidence indicates that the cardiotoxicity caused by the apoptotic machinery is partly regulated by miRNAs. The aim of this research is to investigate the role of miR-138-5p on hypoxia/reperfusion-induced heart injury. METHODS: The expression of miR-138-5p was determined in heart tissue from myocardial infarction patients and rats. Rats were transfection with a miR-138-5p inhibitor to silence miR-138-5p. The cardiac function of rats was detected via echocardiography. SIRT1 and PGC-1α expression in cardiac infarction was detected via quantitative Real-time PCR (qPCR) and Western blot analysis, while the TUNEL assay was used to determine myocardial apoptosis. RESULTS: Our observations showed that miR-138-5p expression was upregulated after the induction of myocardial infarction. The miR-138-5p inhibitor significantly improved cardiac function, increased the expression of SIRT1 and PGC-1α, and decreased the rate of myocardial apoptosis, whereas siRNA-SIRT1 reversed these protective effects. CONCLUSIONS: In conclusion, our study demonstrated that miR-138-5p could promote cardiac ischemia injury via inhibition of the silent information regulator 1 and peroxisome proliferator-initiated receptor gamma and coactivator 1 alpha (SIRT1-PGC-1α) axis.


Assuntos
Hipóxia , MicroRNAs , Traumatismo por Reperfusão Miocárdica , Animais , Células HEK293 , Humanos , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , MicroRNAs/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , 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 Sprague-Dawley , Sirtuína 1/genética , Função Ventricular Esquerda
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