RESUMEN
PURPOSE: High and low levels of selenium (Se) have been related to metabolic disorders in dams and in their offspring. Their relationship to oxidative balance and to AMP-activated protein kinase (AMPK) is some of the mechanisms proposed. The aim of this study is to acquire information about how Se is involved in metabolic programming. METHODS: Three experimental groups of dam rats were used: control (Se: 0.1 ppm), Se supplemented (Se: 0.5 ppm) and Se deficient (Se: 0.01 ppm). At the end of lactation, the pups' metabolic profile, oxidative balance, Se levels, selenoproteins and IRS-1 hepatic expression, as well as hepatic AMPK activation were measured. RESULTS: The experimental groups present deep changes in Se homeostasis, selenoproteins and IRS-1 hepatic expression, oxidative balance, AMPK activation ratio and insulin levels. They do, however, have different metabolic profiles. CONCLUSIONS: High- and low-Se diets are linked to insulin resistance, yet the mechanisms involved are completely opposite.
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Desarrollo Fetal/fisiología , Homeostasis/fisiología , Resistencia a la Insulina/fisiología , Oxidación-Reducción , Selenio/sangre , Selenio/deficiencia , Proteínas Quinasas Activadas por AMP/sangre , Alimentación Animal , Animales , Suplementos Dietéticos , Modelos Animales de Enfermedad , Femenino , Masculino , Madres , Embarazo , Ratas , Ratas Wistar , Selenio/administración & dosificación , Selenoproteínas/sangreRESUMEN
BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. RESULTS: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. CONCLUSIONS: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.
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Proteínas Quinasas Activadas por AMP/sangre , Adaptación Fisiológica/fisiología , Mal de Altura/sangre , Eritrocitos/metabolismo , Receptor de Adenosina A2B/sangre , 2,3-Difosfoglicerato/sangre , 5'-Nucleotidasa/sangre , 5'-Nucleotidasa/deficiencia , Lesión Pulmonar Aguda/fisiopatología , Adenosina/sangre , Adulto , Mal de Altura/enzimología , Mal de Altura/fisiopatología , Animales , Bisfosfoglicerato Mutasa/sangre , Activación Enzimática , Proteínas Ligadas a GPI/sangre , Humanos , Metaboloma , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxígeno/sangre , Fosforilación , Procesamiento Proteico-PostraduccionalRESUMEN
Alterations in gene expression as a consequence of physical exercise are frequently described. The mechanism of these regulations might depend on epigenetic changes in global or gene-specific DNA methylation levels. The AMP-activated protein kinase (AMPK) plays a key role in maintenance of energy homeostasis and is activated by increases in the AMP/ATP ratio as occurring in skeletal muscles after sporting activity. To analyze whether exercise has an impact on the methylation status of the AMPK promoter, we determined the AMPK methylation status in human blood samples from patients before and after sporting activity in the context of rehabilitation as well as in skeletal muscles of trained and untrained mice. Further, we examined long interspersed nuclear element 1 (LINE-1) as indicator of global DNA methylation changes. Our results revealed that light sporting activity in mice and humans does not alter global DNA methylation but has an effect on methylation of specific CpG sites in the AMPKα2 gene. These regulations were associated with a reduced AMPKα2 mRNA and protein expression in muscle tissue, pointing at a contribution of the methylation status to AMPK expression. Taken together, these results suggest that exercise influences AMPKα2 gene methylation in human blood and eminently in the skeletal muscle of mice and therefore might repress AMPKα2 gene expression.
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Proteínas Quinasas Activadas por AMP/sangre , Traumatismos en Atletas/fisiopatología , Terapia por Ejercicio/métodos , Condicionamiento Físico Animal/métodos , Acondicionamiento Físico Humano/métodos , Resistencia Física , Adolescente , Adulto , Anciano , Animales , Traumatismos en Atletas/rehabilitación , Metilación de ADN , Femenino , Entrenamiento de Intervalos de Alta Intensidad/métodos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Based on their characteristics, we hypothesized that the following parameters, namely collagen IV, glutathione S-transferase, secretory component (SC), and AMP-activated protein kinase α1α2 may be useful serum markers in the detection of comorbidities in treated HIV-infected patients. These parameters were determined in 204 HIV-infected patients and 35 controls by using IEF and densitometry. Collagen IV was undetectable in controls and the majority of HIV-infected patients. Twenty-two HIV-infected patients presented significantly elevated levels of collagen IV, most of them were coinfected with hepatitis C virus and/or hepatitis B virus. SC was undetectable in controls. SC was significantly increased in 81 HIV-infected patients and significantly correlated with aspartate aminotransferase (r = 0.267, p = 0.0049), alkaline phosphatase (r = 0.309, p = 0.0011), and γ-glutamyl-transferase (r = 0.264, p = 0.0054). Glutathione S-transferase levels of HIV-infected patients were significantly higher than the controls (3779 ± 5860 vs. 785 ± 71 DU, p = 0.0007) and significantly correlated with serum urea (r = 0.204, p = 0.0038), triglycerides (r = 0.209, p = 0.0033), and lipase (r = 0.219, p = 0.0025). AMP-activated protein kinase α1α2 levels of HIV-infected patients were significantly higher than the controls (5676 ± 6248 vs. 1189 ± 6248 DU, p = 0.0009). Further studies are needed to demonstrate the relevance of these results to diagnose non-AIDS-related illnesses in HIV-infected patients.
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Biomarcadores/sangre , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Focalización Isoeléctrica/métodos , Proteínas Quinasas Activadas por AMP/sangre , Estudios de Casos y Controles , Colágeno Tipo IV/sangre , Glutatión Transferasa/sangre , Hepatitis B/sangre , Hepatitis C/sangre , HumanosRESUMEN
OBJECTIVE: We investigated whether AMP-activated protein kinase (AMPK) may be involved in the signaling processes leading to exercise-mediated vascular protection. METHODS AND RESULTS: The effects of voluntary exercise on AMPK activity, endothelial NO synthase expression and phosphorylation, vascular reactive oxygen species formation, and cell senescence were tested in α1AMPK knockout and corresponding wild-type mice. Exercise significantly improved endothelial function, and increased plasma nitrite production in wild-type mice, associated with an activation of aortic AMPK assessed by its phosphorylation at threonine 172. In addition, regular physical activity resulted in an upregulation of endothelial NO synthase protein, serine 1177 endothelial NO synthase phosphorylation, and an increase of circulating Tie-2(+)Sca-1(+)Flk-1(+) myeloid progenitor cells. All these changes were absent after α1AMPK deletion. In addition, exercise increased the expression of important regulators of the antioxidative defense including heme oxygenase-1 and peroxisome proliferator-activated receptor γ coactivator 1α, decreased aortic reactive oxygen species levels, and prevented endothelial cell senescence in an α1AMPK-dependent manner. CONCLUSIONS: Intact α1AMPK signaling is required for the signaling events leading to the manifestation of vascular protective effects during exercise. Pharmacological AMPK activation might be a novel approach in the near future to simulate the beneficial vascular effects of physical activity.
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Proteínas Quinasas Activadas por AMP/fisiología , Endotelio Vascular/fisiología , Condicionamiento Físico Animal , Proteínas Quinasas Activadas por AMP/sangre , Adenosina Trifosfato/metabolismo , Animales , Senescencia Celular , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Nitritos/sangre , Estrés Oxidativo , Regeneración , Transducción de SeñalRESUMEN
Insight of how growth and metabolism in skeletal muscle are related is still lacking in early vertebrates. In this context, molecules involved in these processes, such as leptin, AMP-activated protein kinase (AMPK), target of rapamicyn (TOR), peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α, and oxidative phosphorylation complexes (OXPHOS), were assessed in the skeletal muscle of a fish species. Periods of fasting followed by a period of refeeding were implemented, using the fine flounder as a model (Paralichthys adspersus). This species exhibits remarkably slow growth and food intake, which is linked to an inherent growth hormone (GH) resistance and high circulating levels of leptin. Leptin increased during fasting concomitantly with AMPK activation, which was inversely correlated with TOR activation. On the other hand, AMPK was directly correlated with an increase in PGC-1α and OXPHOS complexes contents. Dramatic changes in the activation and content of these molecules were observed during short-term refeeding. Leptin, AMPK activation, and PGC-1α/OXPHOS complexes contents decreased radically; whereas, TOR activation increased significantly. During long-term refeeding these molecules returned to basal levels. These results suggest that there is a relation among these components; thus, during fasting periods ATP-consuming biosynthetic pathways are repressed and alternative sources of ATP/energy are promoted, a phenomenon that is reversed during anabolic periods. These results provide novel insight on the control of metabolism and growth in the skeletal muscle of a non-mammalian species, suggesting that both processes in fish muscle are closely related and coordinated by a subset of common molecules.
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Proteínas Quinasas Activadas por AMP/sangre , Leptina/sangre , Recambio Mitocondrial/fisiología , Músculo Esquelético/metabolismo , Estado Nutricional/fisiología , Animales , Lenguado/sangre , Lenguado/metabolismo , PPAR gamma , Transducción de SeñalRESUMEN
The influence of adenosine mono phosphate (AMP)-activated protein kinase (AMPK) vs Akt-mammalian target of rapamycin C1 (mTORC1) protein signaling mechanisms on converting differentiated exercise into training specific adaptations is not well-established. To investigate this, human subjects were divided into endurance, strength, and non-exercise control groups. Data were obtained before and during post-exercise recovery from single-bout exercise, conducted with an exercise mode to which the exercise subjects were accustomed through 10 weeks of prior training. Blood and muscle samples were analyzed for plasma substrates and hormones and for muscle markers of AMPK and Akt-mTORC1 protein signaling. Increases in plasma glucose, insulin, growth hormone (GH), and insulin-like growth factor (IGF)-1, and in phosphorylated muscle phospho-Akt substrate (PAS) of 160 kDa, mTOR, 70 kDa ribosomal protein S6 kinase, eukaryotic initiation factor 4E, and glycogen synthase kinase 3a were observed after strength exercise. Increased phosphorylation of AMPK, histone deacetylase5 (HDAC5), cAMP response element-binding protein, and acetyl-CoA carboxylase (ACC) was observed after endurance exercise, but not differently from after strength exercise. No changes in protein phosphorylation were observed in non-exercise controls. Endurance training produced an increase in maximal oxygen uptake and a decrease in submaximal exercise heart rate, while strength training produced increases in muscle cross-sectional area and strength. No changes in basal levels of signaling proteins were observed in response to training. The results support that in training-accustomed individuals, mTORC1 signaling is preferentially activated after hypertrophy-inducing exercise, while AMPK signaling is less specific for differentiated exercise.
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Proteínas Quinasas Activadas por AMP/metabolismo , Ejercicio Físico/fisiología , Complejos Multiproteicos/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/sangre , Acetil-CoA Carboxilasa/metabolismo , Adulto , Glucemia/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Factor 4E Eucariótico de Iniciación/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Hormona del Crecimiento/sangre , Frecuencia Cardíaca , Histona Desacetilasas/metabolismo , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Imagen por Resonancia Magnética , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos/sangre , Fuerza Muscular/fisiología , Músculo Esquelético/anatomía & histología , Consumo de Oxígeno , Fosforilación , Entrenamiento de Fuerza , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Serina-Treonina Quinasas TOR/sangre , Adulto JovenRESUMEN
The aim of this study is to determine by isoelectric focusing the level of AMPKα1, an energy sensor, in sera of patients who are in energy-demanding situation. After Western blotting, detection was performed with specific antibodies against AMPKα and its phosphorylated form. To evaluate the effect of weight loss on AMPK, sera from 24 patients were collected before and after intragastric balloon insertion over a 16-week follow-up period. Compared to baseline, all patients showed postoperatively an increase of AMPK. Patients with ischemic heart, with inflammatory bowel disease, with chronic undernutrition or with hepatic diseases were examined. Compared to control subjects, the majority of them showed a significant increase of AMPK. These results suggest that serum AMPK may have a potential for diagnosis of several metabolic diseases. However, this has to be confirmed by further studies with additional biomarkers and with more specific techniques.
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Proteínas Quinasas Activadas por AMP/sangre , Focalización Isoeléctrica/métodos , Enfermedades Metabólicas/sangre , Proteínas Quinasas Activadas por AMP/química , Adulto , Estudios de Casos y Controles , Femenino , Balón Gástrico , Humanos , Masculino , Persona de Mediana Edad , Obesidad/enzimología , Obesidad/terapiaRESUMEN
Maslinic acid (MA), a pentacyclic triterpenoid, has been reported to exert broad pharmacological properties. However, it is still unclear whether MA exhibits protective effects against ischemia/reperfusion (I/R) injury. Herein, we aimed to investigate the effects of MA on I/R injury and its underlying mechanisms. A rat model of I/R injury was established and administrated with MA by intraperitoneal injection. Cardiac function was assessed with a color ultrasound diagnosis system and PowerLab system. The levels of oxidative stress-related and I/R-related biomarkers were evaluated by using commercial kits. Apoptosis-related biomarkers and sirtuin (SIRT)1/AMP-activated protein kinase (AMPK) signaling proteins were determined by using quantitative reverse transcription PCR and western blotting, respectively. Treatment with MA improved cardiac performance and cardiac hemodynamic parameters in the I/R injury rat model. Besides, treatment with MA (20 mg/kg) ameliorated I/R injury-related biomarkers in serum. Interestingly, treatment with MA (20 mg/kg) also regulated myocardial apoptosis and inhibited oxidative-stress in left ventricular tissue. Mechanistic studies demonstrated that MA upregulated SIRT1 and AMPK phosphorylation in the left ventricular tissue. In summary, MA exerted protective effects against the impairments of cardiac function in I/R injury rats by the regulation of SIRT1/AMPK signaling pathways.
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Proteínas Quinasas Activadas por AMP/metabolismo , Miocitos Cardíacos/metabolismo , Daño por Reperfusión , Sirtuina 1/metabolismo , Triterpenos/farmacología , Proteínas Quinasas Activadas por AMP/sangre , Animales , Apoptosis , Biomarcadores/sangre , Estrés Oxidativo , Ratas , Sirtuina 1/sangre , Triterpenos/uso terapéuticoRESUMEN
AMP-activated protein kinase (AMPK) is an energy sensor essential for maintaining cellular energy homeostasis. Here, we report that AMPKalpha1 is the predominant isoform of AMPK in murine erythrocytes and mice globally deficient in AMPKalpha1 (AMPKalpha1(-/-)), but not in those lacking AMPKalpha2, and the mice had markedly enlarged spleens with dramatically increased proportions of Ter119-positive erythroid cells. Blood tests revealed significantly decreased erythrocyte and hemoglobin levels with increased reticulocyte counts and elevated plasma erythropoietin concentrations in AMPKalpha1(-/-) mice. The life span of erythrocytes from AMPKalpha1(-/-) mice was less than that in wild-type littermates, and the levels of reactive oxygen species and oxidized proteins were significantly increased in AMPKalpha1(-/-) erythrocytes. In keeping with the elevated oxidative stress, treatment of AMPKalpha1(-/-) mice with the antioxidant, tempol, resulted in decreased reticulocyte counts and improved erythrocyte survival. Furthermore, the expression of Foxo3 and reactive oxygen species scavenging enzymes was significantly decreased in erythroblasts from AMPKalpha1(-/-) mice. Collectively, these results establish an essential role for AMPKalpha1 in regulating oxidative stress and life span in erythrocytes.
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Proteínas Quinasas Activadas por AMP/metabolismo , Eritrocitos/metabolismo , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas Activadas por AMP/sangre , Proteínas Quinasas Activadas por AMP/genética , Animales , Western Blotting , Supervivencia Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Recuento de Eritrocitos , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Eritropoyetina/sangre , Eritropoyetina/metabolismo , Citometría de Flujo , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Eliminación de Gen , Expresión Génica , Ratones , Ratones Noqueados , Oxidantes/toxicidad , Estrés Oxidativo/efectos de los fármacos , Fenilhidrazinas/toxicidad , Especies Reactivas de Oxígeno/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esplenomegalia/enzimología , Esplenomegalia/genética , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Análisis de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: The present study was conducted to investigate the therapeutic effects of a potent polyphenol, fisetin, on the letrozole-induced rat model of polycystic ovary syndrome (PCOS). METHODOLOGY: Twenty-four female Wistar rats (42 days old) were divided into four groups: control group (received carboxy methylcellulose (CMC 0.5 %)), PCOS group treated with letrozole (1 mg/kg), fisetin group received same dose of letrozole + fisetin (10 mg/kg), and metformin group received same dose of letrozole + metformin (300 mg/kg). At the end of the experiment, biochemical (glucose, lipid profile) and hormonal (insulin, testosterone, estradiol, and progesterone) parameters were analyzed. Histological examinations of ovaries were also conducted by hematoxylin and eosin (H&E) staining. Real-time polymerase chain reaction (PCR) and western blotting were carried out for cytochrome P450 17A1 (CYP17A1), sirtuin-1 (SIRT1), and 5' AMP-activated protein kinase (AMPK) gene expression in the ovaries. Furthermore, enzymatic activities of antioxidants including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the ovaries were analyzed by colorimetric method. RESULTS: Letrozole administration resulted in a remarkable abnormality in biochemical and hormonal parameters. Fisetin normalized levels of glucose, lipid profile, homeostatic model assessment for insulin resistance (HOMA-IR), testosterone, estradiol, and progesterone. Moreover, fisetin increased expression levels of SIRT1 and AMPK, and decreased expression level of CYP17A1 in the ovaries. Additionally, fisetin showed protective effect by enhancing antioxidant activities of CAT, SOD, and GPx depleted secondary to induction of PCOS. Fisetin effects were comparable to metformin, as the standard drug used for treatment of PCOS. CONCLUSION: Our results showed that, fisetin treatment caused significant alleviating effects by restoring PCOS-induced alterations in the key genes involved in energy homeostasis and antioxidant enzymes, suggesting that it may have a key role in combating with PCOS.
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Antineoplásicos Fitogénicos/farmacología , Flavonoles/farmacología , Letrozol/antagonistas & inhibidores , Ovario/efectos de los fármacos , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/sangre , Proteínas Quinasas Activadas por AMP/genética , Animales , Glucemia/metabolismo , Carboximetilcelulosa de Sodio/administración & dosificación , Catalasa/sangre , Catalasa/genética , Modelos Animales de Enfermedad , Estradiol/sangre , Femenino , Expresión Génica , Glutatión Peroxidasa/sangre , Glutatión Peroxidasa/genética , Humanos , Insulina/sangre , Letrozol/toxicidad , Metformina/farmacología , Ovario/metabolismo , Ovario/patología , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/patología , Progesterona/sangre , Ratas , Ratas Wistar , Sirtuina 1/sangre , Sirtuina 1/genética , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Esteroide 17-alfa-Hidroxilasa/sangre , Esteroide 17-alfa-Hidroxilasa/genética , Superóxido Dismutasa/sangre , Superóxido Dismutasa/genética , Testosterona/sangreRESUMEN
BACKGROUND: There is an urgent need to develop feasible biomarkers for diagnosis and prognosis of Alzheimer's disease (AD). Mounting evidence implicates that dysregulation of energy metabolism is a key and early event in AD pathogenesis. AMP-activated protein kinase (AMPK) is a central molecular sensor that plays a critical role in maintaining cellular energy homeostasis, and aberrant brain AMPK activities are linked to AD pathophysiology. OBJECTIVE: We aimed to investigated protein levels of AMPKα isoforms, AMPKα1 and AMPKα2, in plasma samples from patients clinically diagnosed with mild cognitive impairment (MCI) or AD, along with age-matched healthy controls. METHODS: 30 participants (10 MCI, 10 AD, and 10 controls) were included in our pilot study. Plasma levels of AMPKα1 and AMPKα2 were determined by ELISA. Receiver operating characteristic (ROC) analysis was used to assess sensitivity and specificity. Linear regression was used to assess the correlation between levels of AMPKα isoforms and other biomarkers. RESULTS: Plasma levels of AMPKα1 were decreased in MCI and AD patients, while levels of AMPKα2 were unaltered as compared to controls. ROC analysis showed relatively high sensitivity and specificity for AMPKα1 to distinguish MCI and AD from controls. Linear regression analysis showed that plasma levels of AMPKα1 were correlated with a brain imaging biomarker (AD signature cortical thicknesses). CONCLUSION: Plasma levels of AMPKα1 were decreased in MCI and AD patients. Future endeavor to explore whether blood AMPKα1 protein expression has the value as a potential biomarker for AD and MCI diagnosis shall be encouraged.
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Proteínas Quinasas Activadas por AMP/sangre , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico por imagen , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico por imagen , Anciano , Enfermedad de Alzheimer/psicología , Biomarcadores/sangre , Disfunción Cognitiva/psicología , Femenino , Humanos , Isoenzimas/sangre , Imagen por Resonancia Magnética/tendencias , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proyectos PilotoRESUMEN
Obesity is a notable risk factor for developing type 2 diabetes, augmenting the concern of obese diabetes (ObD). Anti-obesity and antioxidant effects of red pepper seeds extract (RPSE) have increased our expectations that RPSE would also improve the pathological phenotypes of obese diabetes. Therefore, we hypothesized that RPSE would have an anti-diabetic effect in ObD mice. Animals were assigned either as follows: (1) db/+, (2) db/db control, (3) RPSE (200 mg/kg bw), or (4) a comparative control (metformin 150 mg/kg bw). RPSE was orally administered daily for 8 weeks. As a result, RPSE supplementation improved diabetic phenotypes, including fasting glucose, hemoglobin (HbA1c), and insulin levels. Pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), and triglycerides were reduced in RPSE-treated mice. RPSE supplementation also diminished the rate-limiting enzymes of gluconeogenesis, including glucose 6-phosphatas (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the liver. RPSE supplementation increased the phosphorylation of forkhead box protein O1 (FOXO1) and AMP-activated protein kinase (AMPK), which underlined the mechanism of the anti-diabetic effects of RPSE. Taken together, RPSE has the potential to improve glycemic control by repressing hepatic gluconeogenesis via the phosphorylation of FOXO1 and AMPK in ObD mice.
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Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Glucemia/efectos de los fármacos , Capsicum , Diabetes Mellitus Experimental/sangre , Proteína Forkhead Box O1/efectos de los fármacos , Gluconeogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Quinasas Activadas por AMP/sangre , Animales , Diabetes Mellitus Experimental/complicaciones , Modelos Animales de Enfermedad , Proteína Forkhead Box O1/sangre , Control Glucémico , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/sangre , Obesidad/complicaciones , Fosforilación , SemillasRESUMEN
OBJECTIVE: To investigate Phosphorylated adenosine monophosphate activated protein kinase (AMPK) levels in healthy pregnant women and pregnant women with preeclampsia (PE). METHODS: Twenty-eight women with mild-PE, 22 with severe-PE, and 30 normotensive controls were included in this cross-sectional study. The serum AMPK levels of these patients were analyzed. The patients were followed up to delivery. RESULTS: No statistically significant difference was found between the groups for age, gravida, parity, and gestational age at the time the blood samples were obtained (p > .05). No significant difference between the group with mild-PE and the control group was found, while in the severe-PE group, serum AMPK levels were significantly higher relative to both the mild-PE and control groups (p < .001 and p < .001, respectively). No correlation was detected between serum AMPK levels and age, body mass index (BMI), and gestational age at the time the blood samples were collected. A negative correlation was found between AMPK levels and gestational week and birthweight at delivery, while a positive correlation was detected between systolic and diastolic blood pressures and AMPK levels. CONCLUSIONS: Serum AMPK was higher in patients with severe-PE compared with healthy pregnant women and patients with PE without severe features so it might be a new biomarker for the prediction of disease and its severity.
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Proteínas Quinasas Activadas por AMP/sangre , Preeclampsia/sangre , Índice de Severidad de la Enfermedad , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Embarazo , Curva ROCRESUMEN
AIMS: Adiponectin improves insulin sensitivity by decreasing lipid accumulation in insulin-sensitive tissues. The aim of this study was to investigate whether these effects are altered in hypertension. MAIN METHODS: Adiponectin receptors (AdipoR1 and AdipoR2) and adiponectin-related enzymes were measured by real-time PCR and Western-blot in insulin-sensitive tissues of 10-week-old male spontaneously hypertensive rats (SHR). Intrahepatic and intramyocellular triglycerides were determined by enzymatic methods. KEY FINDINGS: SHR showed overweight, dyslipidemia, glucose intolerance and insulin resistance. Circulating concentrations of adiponectin as well as the mRNA and protein expression of adiponectin in epididymal and subcutaneous fat depots were significantly increased in hypertensive rats. Adiponectin mRNA levels were strongly associated with PPARgamma mRNA levels in both epididymal (r=0.54, P<0.05) and subcutaneous (r=0.93, P<0.0001) fat. The expression of AdipoR1 and AdipoR2, acetyl-CoA carboxylase (ACC), as well as carnitine palmitoyl transferase 1 (CPT1), were increased in skeletal muscle of SHR. These changes were not observed in the liver of SHR. In addition, in spite of the hyperadiponectinemia, SHR showed similar activation of AMP-activated protein kinase (AMPK) and a lower phosphorylation degree of its downstream ACC in liver and skeletal muscle. Accordingly, SHR exhibited a significant increase in intrahepatic (approximately 40%) and intramyocellular (approximately 60%) lipid accumulation. SIGNIFICANCE: These findings suggest that dysregulation of the adiponectin downstream effectors contributes to increased intrahepatic and intramyocellular triglycerides in SHR. Hyperadiponectinemia together with overexpression of adiponectin receptors in skeletal muscle may reflect a defective compensatory mechanism to overcome adiponectin resistance in hypertensive rats.
Asunto(s)
Proteínas Quinasas Activadas por AMP/fisiología , Adiponectina/fisiología , Hipoglucemiantes/farmacología , Insulina/farmacología , Proteínas Quinasas Activadas por AMP/sangre , Adiponectina/sangre , Tejido Adiposo/enzimología , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Western Blotting , Epidídimo/enzimología , Epidídimo/metabolismo , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Células Musculares/metabolismo , Oxidación-Reducción , ARN/biosíntesis , ARN/aislamiento & purificación , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Receptores de Adiponectina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
An effective treatment for non-alcoholic fatty liver disease (NAFLD) is urgently needed. In the present study, we investigated whether the Chinese medicine Chai Hu Li Zhong Tang (CHLZT) could protect against the development of NAFLD. Rats in an animal model of NAFLD were treated with CHLZT, and their serum levels of cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were detected with an automatic biochemical analyzer. A cellular model of NAFLD was also established by culturing HepG2 cells in a medium that contained a long chain fat emulsion. Those cells were treated with CHLZT that contained serum from rats. After treatment, the levels of adenylate-activated protein kinase (AMPK) α (AMPKα), p-AMPKα, acetyl coenzyme A carboxylase (ACC) α (ACCα), pACCα, PPARγ, and SREBP-2 were detected. The AMPK agonist, acadesine (AICAR), was used as a positive control compound. Our results showed that CHLZT or AICAR significantly decreased the serum levels of TG, TC, LDL-C, AST, ALT, and insulin in NAFLD rats, and significantly increased their serum HDL-C levels. Treatments with CHLZT or AICAR significantly decreased the numbers of lipid droplets in NAFLD liver tissues and HepG2 cells. CHLZT and AICAR increased the levels of p-AMPKα and PPARγ in the NAFLD liver tissues and HepG2 cells, but decreased the levels of ACC-α, p-ACC-α, SREBP-2, and 3-hydroxyl-3-methylglutaryl-coenzyme A reductase (HMGR). CHLZT protects against NAFLD by activating AMPKα, and also by inhibiting ACC activity, down-regulating SREBP2 and HMGR, and up-regulating PPAR-γ. Our results suggest that CHLZT might be useful for treating NAFLD in the clinic.
Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Bupleurum/química , Medicamentos Herbarios Chinos/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteínas Quinasas Activadas por AMP/sangre , Acetil-CoA Carboxilasa/sangre , Alanina Transaminasa/sangre , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Aspartato Aminotransferasas/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Medicamentos Herbarios Chinos/química , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Medicina Tradicional China/métodos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Ratas , Ribonucleósidos/farmacología , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Triglicéridos/sangreRESUMEN
The purpose of this study was to clarify the hepatoprotective mechanisms of fish oil in ethanol-fed rats based on lipid metabolism. Thirty eight-week-old male Wistar rats were divided into six groups: C (control), CF25 (control diet with 25% fish oil substitution), CF57 (control diet with 57% fish oil substitution), E (ethanol-containing diet) group, EF25 (ethanol-containing diet with 25% fish oil substitution), and EF57 (ethanol-containing diet with 57% fish oil substitution) groups. All of the groups were pair-fed an isoenergetic diet based on E group. Rats were sacrificed after eight weeks. When compared with C group, the plasma aspartate transaminase (AST) activity and hepatic steatosis and inflammatory cell infiltration were significantly higher, while plasma adiponectin level and hepatic AMP-activated protein kinase α (AMPKα) protein expression was significantly lower in the E group. However, the hepatic damage, including steatosis and inflammation were ameliorated in the EF25 and EF57 groups. Moreover, mRNA levels of fatty acid-oxidative enzymes, such as medium-chain acyl-coenzyme A dehydrogenase (MCAD) and carnitine palmitoyltransferase I (CPT-1) were significantly elevated in the EF57 group than those in E group. Partial replacement with fish oil might improve the fatty acid oxidation by raising mRNA levels of downstream transcription factors, finally inhibit the ethanol-induced hepatic steatosis in rats.
Asunto(s)
Etanol/efectos adversos , Hígado Graso/terapia , Aceites de Pescado/farmacología , Metabolismo de los Lípidos , Proteínas Quinasas Activadas por AMP/sangre , Adiponectina/sangre , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Colesterol/sangre , Etanol/administración & dosificación , Hígado Graso/inducido químicamente , Regulación de la Expresión Génica , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Tamaño de los Órganos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Triglicéridos/sangreRESUMEN
BACKGROUND AND AIMS: Chronic low-grade inflammation is involved in the development of metabolic disorders including atherosclerosis, type 2 diabetes (T2D) and metabolic syndrome. Aerobic exercise has been shown to be anti-inflammatory and attenuate postprandial blood lipids, however, the effect of exercise on postprandial inflammation remains unclear. The aim of this study was to determine the protective effect of a single bout of aerobic exercise against postprandial lipemia and peripheral blood mononuclear cell (PBMC) inflammation and to evaluate associations with changes in the energy-sensing enzyme, AMP-activated protein kinase (AMPK). MATERIALS AND METHODS: Healthy male subjects (n=12, age=23±2, %Fat=19±2) reported to the laboratory following an overnight fast (12-14h) on two separate occasions for consumption of a high-fat meal (HFM). Participants completed an acute bout of aerobic exercise the afternoon prior to one of the HFM visits. RESULTS AND CONCLUSION: Results indicate that the single bout of moderate aerobic exercise increased AMPK signaling in PBMCs, as shown by increased phosphorylated acetyl-CoA carboxylase (p-ACC). This may be due to decreases in the AMPK inhibitory kinases PKD and GSK3ß. Additionally, prior moderate intensity exercise decreased postprandial lipemia (PPL) and some mediators of the inflammatory pathway, such as p-NF-κB. These findings that acute aerobic exercise improves AMPK and NF-κB signaling in human PBMCs contribute support to the anti-inflammatory roles of exercise.
Asunto(s)
Dieta Alta en Grasa , Grasas de la Dieta/efectos adversos , Terapia por Ejercicio/métodos , Ejercicio Físico , Inflamación/inducido químicamente , Inflamación/prevención & control , Proteínas Quinasas Activadas por AMP/sangre , Estudios Cruzados , Humanos , Lípidos/sangre , Masculino , Monocitos/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Adulto JovenRESUMEN
SCOPE: Chronic inflammation plays a major role in the formation and progression of atherosclerotic plaques. To clarify the mode of action of aged garlic extract (AGE) to retard atherosclerosis, we investigated whether AGE suppresses the inflammation in apolipoprotein E-knockout (ApoE-KO) mice. METHODS AND RESULTS: ApoE-KO mice were fed standard diet with or without 3% AGE for 12 wk. AGE feeding inhibited the progression of atherosclerotic lesion by 27% and reduced the level of C-reactive protein (CRP) and thromboxane B2 (TXB2 ), a marker of platelet activation, in serum by 39 and 33%, respectively, compared to ApoE-KO mice without AGE treatment. AGE treatment also decreased the level of tumor necrosis factor alpha (TNF-α), a major stimulus inducing CRP production, in the liver by 35%. AGE decreased the level of interleukin-1 receptor-associated kinase 4 (IRAK4) by 60% and almost doubled the level of phospho-AMP-activated protein kinase (p-AMPK) in the liver. CONCLUSION: The anti-atherosclerotic effect of AGE involves the suppression of inflammation by reducing the serum level of CRP and TXB2 , and the protein level of TNF-α and IRAK4, and increasing AMPK activity in liver.
Asunto(s)
Ajo/química , Inflamación/tratamiento farmacológico , Extractos Vegetales/farmacología , Proteínas Quinasas Activadas por AMP/sangre , Animales , Aterosclerosis/prevención & control , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Dieta , Progresión de la Enfermedad , Inflamación/sangre , Quinasas Asociadas a Receptores de Interleucina-1/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Extractos Vegetales/sangre , Tromboxano B2/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Aim: This study was to investigate the change of high-molecula-weight (HMW) adiponectin (APN) isoform, the association between type 2 diabetes mellitus (T2DM) and HMW APN isoform, the variation of Disulfide-bond A oxidoreductase-like protein (DsbA-L), the effect of HMW APN isoform on AMP-dependent protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) in Chinese T2DM. Method: 169 patients aged at (48.7±9.4) years and 107 healthy control subjects aged at (42.6±7.8) years took part in this study. Anthropometric measures of the characters were assayed and different APN isoforms, DsbA-L, AMPK and eNOS levels were determined. Results: Ln(sRAGE) and Ln(Adiponectin) were significantly lower and significantly higher for the other characteristics in T2DM. Ln(Adiponectin) was negatively and significantly correlated with WHR, Ln(triglycerides), fasting plasma glucose, HbA1c (%) in control subjects and T2DM patients. Plasma and adipose tissue total APN and HMW APN were significantly reduced in newly diagnosed T2DM patients. DsbA-L was markedly down-regulated in diabetic adipose tissue. HMW APN caused significant decreases in AMPK and eNOS phosphorylation levels of human umbilical vein endothelial cells (HUVECs). Conclusions: Our results demonstrated that total APN levels was closely related to the risk of T2DM and HMW APN reduction was involved in the diabetic vascular AMPK/eNOS signal pathway. The findings will provide insight into novel therapeutic approaches for reducing the elevated cardiovascular risk associated with T2DM.