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1.
Cell Physiol Biochem ; 52(6): 1398-1411, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075190

RESUMO

BACKGROUND/AIMS: Visfatin is known to act as a mediator in several metabolic disorders, such as obesity, diabetes, and cardiovascular diseases. This study aimed to investigate the effect of visfatin on the adhesion of THP-1 monocytes to human vascular endothelial cells and the underlying mechanism. METHODS: Monocytes adhesion to endothelial cells was determined by using fluorescence-labeled monocytes. ICAM-1 and VCAM-1 expression in endothelial cells were measured by western blotting. Production of reactive oxygen species (ROS) was measured by using a fluorescent dye. The amounts of nuclear factor-kappa B (NF-κB) and phosphorylation of inhibitory factor of NF-κB (IκB) were determined by using western blot analysis. The translocation of NF-κB from the cytoplasm to the nucleus was determined by using immunofluorescence. RESULTS: Here we showed that visfatin significantly caused the upregulation of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells, as well as enhanced monocyte adhesion to endothelial cells. Moreover, we found that inhibition of PI3K, Akt, and p38 MAPK activation significantly prevented visfatin-enhanced expression of ICAM-1 and VCAM-1 and monocyte adhesion to endothelial cells. Visfatin enhanced ROS production and IKK/NF-кB activation and then led to upregulation of ICAM-1 and VCAM-1 and enhanced monocyte adhesion to endothelial cells. These effects were also p38/PI3K/Akt-dependent. CONCLUSION: These results demonstrated that visfatin promoted monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression via the activation of p38/PI3K/Akt signaling and downstream ROS production and IKK/NF-кB activation.


Assuntos
Adesão Celular/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Monócitos/citologia , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Taiwan J Obstet Gynecol ; 57(5): 696-704, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30342654

RESUMO

OBJECTIVE: Hyperandrogenism is the hallmark of polycystic ovary syndrome (PCOS). The use of dehydroepiandrosterone (DHEA)-treated rats is thought to be a suitable animal model to study PCOS. In the present study, we assessed the severity of reproductive and metabolic abnormalities in DHEA-treated rats. MATERIAL AND METHODS: Immature female Sprague-Dawley rats were divided into control and DHEA-treated groups. Reproductive parameters including estrus cycle and sex hormones were measured after sexual maturity. Adiposity, insulin sensitivity, and plasma lipid profiles were analyzed to assess metabolic profiles. After sacrifice, the insulin signaling pathway and lipogenic genes were analyzed by immunoblotting and polymerase chain reaction, respectively. RESULTS: An abnormal estrus cycle was observed in the DHEA-treated rats. DHEA treatment also increased plasma testosterone levels and caused multiple cystic follicle formation, which is compatible with the definition of PCOS. There were no significant changes in fasting glucose, fasting insulin, plasma lipid profiles, and blood pressure levels. The adiposity of the DHEA-treated rats was also lower than in the control rats. Moreover, glucose tolerance and insulin sensitivity were only mildly impaired in the DHEA-treated rats after oral glucose tolerance and insulin tolerance tests, even though insulin signaling in skeletal muscles was decreased in the DHEA-treated group. CONCLUSION: DHEA-treated rats had reproductive abnormalities which mimicked symptoms of human PCOS. In metabolic parameters, DHEA treatment did not show insulin resistance in the female rats, suggesting that the use of DHEA-treated rats is not a good animal model for the study of metabolic abnormalities in PCOS.


Assuntos
Desidroepiandrosterona/administração & dosagem , Modelos Animais de Doenças , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Adiposidade , Animais , Glicemia/análise , Ciclo Estral/efeitos dos fármacos , Jejum , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperandrogenismo , Insulina/sangue , Resistência à Insulina , Lipídeos/sangue , Músculo Esquelético/metabolismo , Ovário/patologia , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Testosterona/sangue
3.
J Chin Med Assoc ; 81(10): 884-891, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30017812

RESUMO

BACKGROUND: The aim of this study was to identify genotypic and phenotypic cardiovascular metabolic risk factors, and to establish risk models of diseases, including diabetes mellitus, cardiovascular disease, stroke, kidney dysfunction and psychiatric disorders, in Taiwanese adults. METHODS: In 2009, a community-based cohort study was initiated in the Shipai area of the Shilin and Beitou districts in Taipei. Residents were randomly sampled by age (young adults: 35-44 years and middle-aged adults: 45-55 years) and urbanization (rural and urban). Residents who agreed to participate were scheduled to receive examinations (physical and blood) and answer questionnaires. A ten-year follow-up is anticipated. Metabolic syndrome (MetS) was defined based on the Adult Treatment Panel III guidelines, and individuals with only one or two of the five MetS components was identified for prevention target. RESULTS: The response rate of the 9000 invited residents was 10.1%. After screening, 906 participants were enrolled. While 31.0% (281) had no MetS components, 29.1% (264) had only one, and 22.0% (199) had two. MetS with at least three components was diagnosed in 17.9% (162) of the cohort. Concerning gender difference, 25.4% of men and 13.2% of women had MetS (p < 0.001). The percentage of MetS was higher in middle-aged participants than in young adults (20.5% versus 13.4%, p = 0.008). Forty-six percent of participants had central obesity. After adjusting for gender, age, and urbanization, the central obesity odds ratio for MetS was 23.7, with a 95% confidence internal of 13.1-42.7. CONCLUSION: Our preliminary results revealed a high MetS percentage among young and middle-aged adults in Taiwan, with central obesity being a particularly urgent prevention target. The research design and operational protocol of this cohort study may stimulate more research in the future.


Assuntos
Doenças Cardiovasculares/etiologia , Síndrome Metabólica/etiologia , Projetos de Pesquisa , Adulto , Fatores Etários , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Fatores de Risco
4.
Proteomics ; 17(1-2)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27928909

RESUMO

Over activity of cannabinoid receptor type 1 (CB1R) plays a key role in increasing the incidence of obesity-induced non-alcoholic fatty liver disease. Tissue proteome analysis has been applied to investigate the bioinformatics regarding the mode of action and therapeutic mechanism. The aim of this study was to explore the potential pathways altered with CB1R in obesity-induced fatty liver. Male C57BL/6 mice were fed either a standard chow diet (STD) or a high-fat diet (HFD) with or without 1-week treatment of CB1R inverse agonist AM251 at 5 mg/kg. Then, liver tissues were harvested for 2DE analysis and protein profiles were identified by using MALDI-MS. Results showed that eight of significantly altered protein spots at the level of changes > twofold were overlapped among the three groups, naming major urinary protein 1, ATP synthase subunit ß, glucosamine-fructose-6-phosphate aminotransferase 1, zine finger protein 2, s-adenosylmethionine synthase isoform type-1, isocitrate dehydrogenase subunit α, epoxide hydrolase 2 and 60S acidic ribosomal protein P0. These identified proteins were involved in glucose/lipid metabolic process, xenobiotic metabolic system, and ATP synthesized process in mitochondria. Based on the findings, we speculated that CB1R blockade might exert its anti-metabolic disorder effect via improvement of mitochondrial function in hepatic steatosis in HFD condition.


Assuntos
Biomarcadores/sangue , Antagonistas de Receptores de Canabinoides/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/sangue , Piperidinas/uso terapêutico , Proteômica/métodos , Pirazóis/uso terapêutico , Receptores de Canabinoides/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo
5.
Obesity (Silver Spring) ; 24(3): 643-53, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26833777

RESUMO

OBJECTIVE: The aim of this study was to investigate the regulatory mechanism of endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, on adipogenesis in vitro and in vivo. METHODS: 3T3-L1 preadipocytes were used to explore the mechanisms mediating ET-1 actions on preadipocyte proliferation and adipocyte differentiation. To investigate the in vivo effect of ET-1, male Sprague-Dawley rats were infused with ET-1 or saline for 4 weeks via intraperitoneally implanted osmotic pumps, and the fat pad weight and adipocyte size of adipose tissues were measured. RESULTS: ET-1 stimulated preadipocyte proliferation and increased the cell number at the mitotic clonal expansion stage of adipocyte differentiation via the endothelin A receptor (ETAR) and activation of the protein kinase C (PKC) pathway. ET-1, via ETAR, inhibited adipocyte differentiation partially through an ERK-dependent pathway. Furthermore, no significant difference in the body weight and fat pad weight was observed in either ET-1- or saline-infused rats. Compared with saline-infused rats, the adipocyte cell number was significantly increased but the adipocyte size was significantly decreased in ET-1-infused rats. CONCLUSIONS: Chronic ET-1 infusion increased the number of small adipocytes without the change of white adipose tissue mass in rats, which were associated with ET-1-stimulated preadipocyte proliferation, but not ET-1-suppressed adipocyte differentiation.


Assuntos
Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Endotelina-1/farmacologia , Hiperplasia/etiologia , Receptor de Endotelina A/efeitos dos fármacos , Células 3T3-L1/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotelina-1/metabolismo , Hiperplasia/metabolismo , Masculino , Camundongos , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo
6.
Int J Mol Med ; 37(3): 743-54, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26847930

RESUMO

Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA­IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/metabolismo , Resistência à Insulina/fisiologia , Obesidade/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Citrato (si)-Sintase/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 Relacionado a NF-E2/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia
7.
Shock ; 45(4): 460-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26536203

RESUMO

BACKGROUND: Visfatin is produced in and secreted from adipocytes. Increased circulating visfatin level is observed in obese subjects. Previous studies demonstrated that visfatin was involved in obesity-related cardiovascular diseases. AIMS: This study aims to explore the regulatory effects of adipokine visfatin on foam cell formation, a key step in the development of atherosclerosis. METHODS: Effect of visfatin on protein and mRNA expression of scavenger receptor and ATP binding cassette transporter in RAW264.7 macrophages were measured by western blotting and real-time RT-PCR. To confirm the influence of visfatin-regulated scavenger receptor and ATP binding cassette transporter to foam cell formation, the visfatin-caused changes of ox-LDL uptake, cholesterol efflux, and foam cell formation were determined. RESULTS: Visfatin significantly increased the expression of CD36 and scavenger receptor A (SRA), decreased the expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), and had no effect on the expression of SR-B1. Visfatin increased oxidized-LDL (ox-LDL) uptake and decreased cholesterol efflux, which increased foam cell formation. The PI3K inhibitor LY294002 blocked the effect of visfatin on the protein and mRNA expression levels of CD36, SRA, and ABCG1 and ox-LDL uptake and cholesterol efflux. The ERK inhibitor PD98059 also prevented visfatin-induced ABCA1 instability and subsequently decreased cholesterol efflux. CONCLUSIONS: Visfatin upregulated CD36 and SRA expression and downregulated ABCA1 and ABCG1 expression, subsequently increased ox-LDL uptake and decreased cholesterol efflux, and finally promoted foam cell formation via the PI3K- and ERK-dependent pathways.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/biossíntese , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Antígenos CD36/biossíntese , Citocinas/metabolismo , Células Espumosas/metabolismo , Regulação da Expressão Gênica , Nicotinamida Fosforribosiltransferase/metabolismo , Receptores Depuradores/biossíntese , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Células Espumosas/patologia , Sistema de Sinalização das MAP Quinases , Camundongos
8.
Clin Chim Acta ; 453: 197-202, 2016 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-26552040

RESUMO

BACKGROUND: We determined effects of bariatric weight loss surgery on serum tartrate-resistant acid phosphatase 5a (TRACP 5a), inflammatory cytokines and glucose homeostasis in severely obese Chinese adults. METHODS: Severely obese adults undergoing bariatric surgery were recruited. Anthropometry, insulin resistance (IR), inflammatory markers and serum TRACP 5a were measured at baseline and 3, 6 and 12months postoperatively. RESULTS: Data of 93 patients, including 69 non-diabetic (non-DM group) and 24 diabetic (DM group), were analyzed. Anthropometry decreased significantly at 3months postoperatively in both groups; low-density lipoprotein cholesterol decreased obviously at 3, 6 and 12months in non-DM group, while improving significantly at 6 and 12months in DM group. Homeostasis model assessment for IR (HOMA-IR) improved significantly at 3, 6 and 12months in non-DM group and 12months in DM group. In DM group, C-reactive protein (CRP) decreased significantly at 3months postoperatively and inflammatory markers interleukin-6 (IL-6) and TRACP 5a improved at 6months postoperatively; in non-DM group, serum TRACP 5a decreased obviously at 12months postoperatively without significant changes in CRP and IL-6. CONCLUSION: Weight reduction by bariatric surgery decreases anthropometry, IR, lipids and inflammatory markers in severely obese Chinese adults.


Assuntos
Fosfatase Ácida/sangue , Grupo com Ancestrais do Continente Asiático , Cirurgia Bariátrica , Glicemia/metabolismo , Citocinas/sangue , Isoenzimas/sangue , Obesidade/sangue , Obesidade/cirurgia , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/sangue , Resistência à Insulina , Lipídeos/sangue , Masculino , Fosfatase Ácida Resistente a Tartarato , Perda de Peso
9.
PLoS One ; 10(5): e0125935, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26011530

RESUMO

BACKGROUND: Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children. METHODS: We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits. RESULTS: Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%). CONCLUSIONS: Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.


Assuntos
Hiperlipidemias/sangue , Hiperlipidemias/complicações , Inflamação/sangue , Inflamação/complicações , Insulina/sangue , Obesidade/sangue , Obesidade/complicações , Adolescente , Biomarcadores/sangue , Criança , Humanos , Masculino , Análise de Componente Principal , Taiwan
10.
Biochem Biophys Res Commun ; 460(4): 1063-8, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25843798

RESUMO

Hepatic insulin resistance (HIR) is a metabolic abnormality characterized by increased gluconeogenesis which usually contributes from an elevation of free fatty acids. Cannabinoid receptor type 1 (CB1R) and major urinary protein 1 (MUP1) are thought to play pivotal roles in mitochondrial dysfunction, liver steatosis and insulin resistance. The aim of this study was to explore the role of MUP1 in CB1R-mediated HIR through the dysregulation of mitochondrial function in AML12 mouse hepatocytes challenged with high concentration of free fatty acids (HFFA). Firstly we observed that treatment of AM251, a selective CB1R antagonist, obviously reversed the HFFA-induced reduction of MUP1 protein expression both in vivo and in vitro. Additionally, our results revealed that AM251 also reverted HFFA-mediated decrease of the mRNA level of mitochondrial biogenesis-related factors, mtDNA amount, ATP production, mitochondrial respiratory complexes-I and -III, and mitochondrial membrane potential, thus consequently might correlate with a parallel reduction of ROS production. Meanwhile, AM251 attenuated HFFA-induced impairment of insulin signaling phosphorylation and elevation of phosphoenolpyrvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), two key enzymes of gluconeogenesis. Silence of MUP1 gene abolished the inhibitory effect of AM251 on HFFA-mediated elevation of PEPCK and G6Pase expression, whereas the suppression of insulin signaling and mRNA level of mitochondrial biogenesis-related factors were only partially recovered. Altogether, these findings suggest that the anti-HIR effect of AM251 via improvement of mitochondrial functions might occur in a MUP1-dependent manner.


Assuntos
Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Resistência à Insulina , Fígado/metabolismo , Proteínas/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Western Blotting , Dieta Hiperlipídica , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Piperidinas/farmacologia , Proteínas/genética , Pirazóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor CB1 de Canabinoide/antagonistas & inibidores
11.
Biochem Biophys Res Commun ; 460(3): 497-503, 2015 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-25824048

RESUMO

Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ETAR during insulin resistance, ETAR expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ETAR expression, but not ETBR, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ETAR pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ETAR/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ETAR are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ETAR expression, and ET-1-induced mitogenic actions in aortic VSMCs.


Assuntos
Aterosclerose/etiologia , Endotelina-1/fisiologia , Hipertensão/etiologia , Resistência à Insulina , Animais , Aterosclerose/fisiopatologia , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Endotelina-1/metabolismo , Hipertensão/fisiopatologia , Insulina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley
12.
J Investig Med ; 63(1): 29-34, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25415059

RESUMO

BACKGROUND: Physical activity improves body composition and inflammatory markers in obese individuals, but little is known about the nonobese population. OBJECTIVE: The aim of this study was to investigate associations between exercise and inflammatory cytokines in lean male adolescents in Taiwan. METHODS: This interventional study enrolled a total of 79 normal body weight male adolescents [mean age, 16.8 (1.0) years] from the Army Academy of Taiwan. Body composition and inflammatory markers were measured at baseline and upon completion of a 12-week exercise intervention program. RESULTS: Subjects' postintervention anthropometric measures, including waist circumference [74.6 (5.2)→72.6 (5.2) cm], hip circumference [92.3 (4.1)→89.9 (5.0) cm], body fat mass [10.2 (3.2)→8.2 (3.2) kg], and body fat percentage [15.8% (4.2)→12.6 (4.5)%] declined significantly compared to preintervention (all P<0.001), as did systolic blood pressure (P=0.002) and mean blood pressure (P = 0.020). Postintervention body height and free fat mass increased significantly (both P<0.001). Subjects' postintervention lipids including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides increased significantly (all P<0.001). Inflammatory markers including adiponectin [14.32 (6.68)→31.31 (30.53) µg/mL, P<0.001], interleukin 6 [2.15 (4.81)→2.86 (6.37) pg/mL, P=0.005], and C-reactive protein [1.00 (2.57)→2.30 (4.17) µg/mL, P<0.001] increased significantly postintervention, but not leptin. CONCLUSIONS: Exercise training significantly improves body composition and anti-inflammatory adiponectin levels in lean male adolescents.


Assuntos
Exercício/fisiologia , Mediadores da Inflamação/metabolismo , Lipídeos/sangue , Magreza/sangue , Tecido Adiposo , Adolescente , Biomarcadores/sangue , Glicemia/metabolismo , Composição Corporal , Citocinas/sangue , Humanos , Insulina/sangue , Masculino , Estudos Prospectivos
14.
Biochem Biophys Res Commun ; 451(2): 263-9, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25088996

RESUMO

Endothelin-1 (ET-1) is the most potent vasoconstrictor by binding to endothelin receptors (ETAR) in vascular smooth muscle cells (VSMCs). The complex of angiotensin II (Ang II) and Ang II type one receptor (AT1R) acts as a transient constrictor of VSMCs. The synergistic effect of ET-1 and Ang II on blood pressure has been observed in rats; however, the underlying mechanism remains unclear. We hypothesize that Ang II leads to enhancing ET-1-mediated vasoconstriction through the activation of endothelin receptor in VSMCs. The ET-1-induced vasoconstriction, ET-1 binding, and endothelin receptor expression were explored in the isolated endothelium-denuded aortae and A-10 VSMCs. Ang II pretreatment enhanced ET-1-induced vasoconstriction and ET-1 binding to the aorta. Ang II enhanced ETAR expression, but not ETBR, in aorta and increased ET-1 binding, mainly to ETAR in A-10 VSMCs. Moreover, Ang II-enhanced ETAR expression was blunted and ET-1 binding was reduced by AT1R antagonism or by inhibitors of PKC or ERK individually. In conclusion, Ang II enhances ET-1-induced vasoconstriction by upregulating ETAR expression and ET-1/ETAR binding, which may be because of the AngII/Ang II receptor pathways and the activation of PKC or ERK. These findings suggest the synergistic effect of Ang II and ET-1 on the pathogenic development of hypertension.


Assuntos
Angiotensina II/metabolismo , Endotelina-1/metabolismo , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Vasoconstrição/fisiologia , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Linhagem Celular , Imidazóis/farmacologia , Losartan/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteína Quinase C/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Vasoconstrição/efeitos dos fármacos
15.
Gen Comp Endocrinol ; 196: 41-51, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24291305

RESUMO

Resistin is known as an adipocyte-specific hormone that can cause insulin resistance and decrease adipocyte differentiation. It can be regulated by transcriptional factors, but the possible role of forkhead transcription factor FOXO1 in regulating resistin gene expression is still unknown. Using 3T3 fibroblast and C3H10T1/2 and 3T3-L1 adipocytes, we found that transient overexpression of a non-phosphorylatable, constitutively active FOXO1, but not the wild type of FOXO1 or a DNA binding-deficient FOXO1, activated resistin promoter-directed luciferase expression. However, transient overexpression of a dominant-negative FOXO1 inactivated resistin promoter activity and reduced resistin mRNA expression. These observations indicate that the action of FOXO1 on resistin gene expression requires the activation of FOXO1 and that the effect of FOXO1 depends on the phosphorylation and dephosphorylation of FOXO1. The FOXO1 protein target sites on the resistin promoter were localized to the proximal -3545 to -787bp of 5'-flanking region of the resistin promoter. A chromatin immunoprecipitation assay also showed that FOXO1 bound the resistin promoter at nucleotide regions of -1539 to -1366bp and -1016 to -835bp, but not at the regions of -795 to -632bp. Results of this study suggest that FOXO1 transcription factor likely activates the expression of adipocyte resistin gene via direct association with the upstream resistin promoter.


Assuntos
Adipócitos/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Regulação da Expressão Gênica/fisiologia , Regiões Promotoras Genéticas/genética , Resistina/genética , Células 3T3-L1 , Animais , Western Blotting , Diferenciação Celular , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Proteína Forkhead Box O1 , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Células NIH 3T3 , Fosforilação , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Resistina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Artigo em Inglês | MEDLINE | ID: mdl-24348460

RESUMO

Co-heritability of hypertension and insulin resistance (IR) within families not only implies genetic susceptibility may be responsible for these complex traits but also suggests a rational that biological candidate genes for hypertension may serve as markers for features of the metabolic syndrome (MetS). Thus we determined whether the T323C polymorphism (rs5333) of endothelin type A (ETA) receptor, a predominant receptor evoking potent vasoconstrictive action of endothelin-1, contributes to susceptibility to IR-associated hypertension in 1694 subjects of Chinese and Japanese origins. Blood pressures (BPs) and biochemistries were measured. Fasting insulin level, insulin-resistance homeostasis model assessment (HOMAIR) score, and area under curve of insulin concentration (AUCINS) were selected for assessing insulin sensitivity. Genotypes were obtained by methods of polymerase chain reaction-restriction fragment length polymorphism. Foremost findings were that minor allele frequency of the T323C polymorphism was noticeable lower in our overall Asian subjects compared to multi-national population reported in gene database; moreover both the genotypic and allelic frequencies of the polymorphism were significantly different between the two ethnic groups we studied. The genotype distributions at TT/TC/CC were 65, 31, 4% in Chinese and 51, 41, 8% in Japanese, respectively (p < 0.0001). Additionally, carriers of the C homozygote revealed characteristics of IR, namely significantly higher levels of fasting insulin, HOMAIR score, and AUCINS at 29.3, 35.3, and 39.3%, respectively, when compared to their counterparts with TT/TC genotypes in Chinese. Meanwhile, the CC genotype was associated with a higher level of high density lipoprotein cholesterol in Japanese. No association of the polymorphism with BP was observed. This study demonstrated for the first time that T323C polymorphism of ETA receptor gene was associated with an adverse insulin response in Chinese and a favorite atherogenic index in Japanese.

17.
PLoS One ; 8(5): e61127, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23658685

RESUMO

Ganoderma lucidum (G. lucidum) is a medicinal mushroom renowned in East Asia for its potential biological effects. To enable a systematic exploration of the genes associated with the various phenotypes of the fungus, the genome consortium of G. lucidum has carried out an expressed sequence tag (EST) sequencing project. Using a Sanger sequencing based approach, 47,285 ESTs were obtained from in vitro cultures of G. lucidum mycelium of various durations. These ESTs were further clustered and merged into 7,774 non-redundant expressed loci. The features of these expressed contigs were explored in terms of over-representation, alternative splicing, and natural antisense transcripts. Our results provide an invaluable information resource for exploring the G. lucidum transcriptome and its regulation. Many cases of the genes over-represented in fast-growing dikaryotic mycelium are closely related to growth, such as cell wall and bioactive compound synthesis. In addition, the EST-genome alignments containing putative cassette exons and retained introns were manually curated and then used to make inferences about the predominating splice-site recognition mechanism of G. lucidum. Moreover, a number of putative antisense transcripts have been pinpointed, from which we noticed that two cases are likely to reveal hitherto undiscovered biological pathways. To allow users to access the data and the initial analysis of the results of this project, a dedicated web site has been created at http://csb2.ym.edu.tw/est/.


Assuntos
Etiquetas de Sequências Expressas/metabolismo , Micélio/genética , Reishi/genética , Análise de Sequência , Processamento Alternativo/genética , Biblioteca Gênica , Genes Fúngicos/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
PLoS Genet ; 9(3): e1003379, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23555291

RESUMO

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.


Assuntos
Apolipoproteínas A/genética , Estudo de Associação Genômica Ampla , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Afro-Americanos/genética , Apolipoproteína A-V , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/genética , Lipoproteínas LDL/sangue , Lipoproteínas LDL/genética , Pró-Proteína Convertase 9 , Triglicerídeos/sangue , Triglicerídeos/genética
19.
Growth Factors ; 31(2): 66-73, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23452315

RESUMO

We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Cronoterapia Farmacológica , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/farmacologia , Resistência à Insulina , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Técnica Clamp de Glucose , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Masculino , Octreotida/administração & dosagem , Octreotida/sangue , Octreotida/farmacologia
20.
Am J Chin Med ; 41(1): 85-98, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23336509

RESUMO

Endothelin-1 (ET-1) is a powerful vasoconstrictor that contributes to blood pressure elevation. The biological effects of ETs are mediated by two receptors, namely, endothelin type A receptor (ET(A)R) and endothelin type B receptor (ET(B)R). Chinese herbal medicines (CHM) with antagonist activity for these two receptors were screened by establishing stable clones of CHO-K1 cells expressing high levels of human ET(A)R and ET(B)R, namely CHO-ET(A)R and CHO-ET(B)R.The aqueous extract of Prunellae Spica (P1) inhibited the binding of (125)I-ET-1 to ET(A)R and ET(B)R in CHO-ET(A)R and CHO-ET(B)R cells, respectively. P1 suppressed the ET-1-induced mobilization of intracellular Ca(2+) . Through the alcohol fractionation of P1, the antagonists of human ET(A)R and ET(B)R were found to belong to different, separable ingredients and the antagonist of ET(A)R is more soluble in alcohol. The two antagonists were also effective in the test on human primary cells, HASMC and HUVEC. P1 successfully prevented the development of ET-1-associated hypertension in rats without further purification. These results indicate the presence of anti-hypertensive ingredients in P. Spica extract, at least through the inactivation of ET(A)R and/or ET(B)R.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Fitoterapia , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO/metabolismo , Cálcio/metabolismo , Cricetinae , Medicamentos de Ervas Chinesas/uso terapêutico , Endotelina-1/metabolismo , Endotelina-1/fisiologia , Humanos , Hipertensão/prevenção & controle , Ratos , Ratos Wistar , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Solubilidade , Água
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