RESUMEN
The heat shock response (HSR) is an ancient and evolutionarily conserved mechanism designed to restore cellular homeostasis following proteotoxic challenges. However, it has become increasingly evident that disruptions in energy metabolism also trigger the HSR. This interplay between proteostasis and energy regulation is rooted in the fundamental need for ATP to fuel protein synthesis and repair, making the HSR an essential component of cellular energy management. Recent findings suggest that the origins of proteostasis-defending systems can be traced back over 3.6 billion years, aligning with the emergence of sugar kinases that optimized glycolysis around 3.594 billion years ago. This evolutionary connection is underscored by the spatial similarities between the nucleotide-binding domain of HSP70, the key player in protein chaperone machinery, and hexokinases. The HSR serves as a hub that integrates energy metabolism and resolution of inflammation, further highlighting its role in maintaining cellular homeostasis. Notably, 5'-adenosine monophosphate-activated protein kinase emerges as a central regulator, promoting the HSR during predominantly proteotoxic stress while suppressing it in response to predominantly metabolic stress. The complex relationship between 5'-adenosine monophosphate-activated protein kinase and the HSR is finely tuned, with paradoxical effects observed under different stress conditions. This delicate equilibrium, known as caloristasis, ensures that cellular homeostasis is maintained despite shifting environmental and intracellular conditions. Understanding the caloristatic controlling switch at the heart of this interplay is crucial. It offers insights into a wide range of conditions, including glycemic control, obesity, type 2 diabetes, cardiovascular and neurodegenerative diseases, reproductive abnormalities, and the optimization of exercise routines. These findings highlight the profound interconnectedness of proteostasis and energy metabolism in cellular function and adaptation.
Asunto(s)
Diabetes Mellitus Tipo 2 , Proteostasis , Humanos , Proteínas HSP70 de Choque Térmico/metabolismo , Respuesta al Choque Térmico , Adenosina Monofosfato/metabolismo , Proteínas Quinasas/metabolismoRESUMEN
La isoforma AMPKß2 (proteína quinasa activada por AMP) favorece la homeostasis glucémica a través de un mecanismo independiente de insulina. Muchos "importagogos" de glucosa como SC4 actúan como activadores de AMPK, pero su consumo prolongado se asocia a efectos indeseables. Objetivo: en este trabajo se utilizó el acoplamiento molecular para analizar la posible interacción entre sapogeninas y AMPK. Métodos: se ha procedido a la preparación de los blancos proteicos, preparación de los ligandos y el acoplamiento molecular. Resultados: los resultados mostraron que ocho sapogeninas presentes en Chenopodium quinoa interactúan en el mismo sitio de unión que SC4 correspondiente al sitio ADaM de AMPK. Estas interacciones puntuaron valores de ΔG que oscilan entre -6,2 y -7,7 kcal/mol, siendo el ácido serjánico la sapogenina con el ΔG más bajo. La adición de grupos hidrofílicos como -OH y -COOH en la estructura química del ácido serjánico mejoró su afinidad de unión a la isoforma AMPKß2 abriendo la posibilidad de generar fármacos semi-sintéticos a partir de compuestos naturales con mayor actividad biológica y mejor especificidad.
The AMPKP2 (AMP-activated protein kinase) isoform promotes glycemic homeostasis through an insulin-independent mechanism. Many glucose "importers" such as SC4 act as AMPK activators, but their prolonged consumption is associated with undesirable effects. Objetive: in this work, molecular docking was used to analyze the possible interaction between sapogenins and AMPK. Methods: the preparation of the protein blanks, preparation of the ligands and molecular coupling have been carried out. Results: the results showed that eight sapogenins present in Chenopodium quinoa interact at the same binding site as SC4 corresponding to the ADaM site of AMPK. These interactions scored ΔG values ranging from -6.2 to -7.7 kcal/mol, with Serjanic acid being the sapogenin with the lowest ΔG. The addition of hydrophilic groups such as -OH and -COOH in the chemical structure of Serjanic acid improved its binding affinity to the AMPKß2 isoform opening the possibility of generating semi-synthetic drugs from natural compounds with higher biological activity and better specificity.
RESUMEN
Recent studies have provided evidence that triiodothyronine (T3) might play an effective role in the recovery of ischemic myocardium, through the preservation of mitochondrial function and the improvement of energy substrate metabolism. To this respect, it has been suggested that T3 could activate AMP-activated protein kinase (AMPK), the cellular 'fuel-gauge' enzyme, although its role has yet to be elucidated. The aim of the present study was to investigate the effects produced by acute treatment with T3 (60 nM) and the pharmacological inhibition of AMPK by compound C on isolated rat left atria subjected to 75 min simulated ischemia-75 min reperfusion. Results showed that T3 increased AMPK activation during simulated ischemia-reperfusion, while compound C prevented it. At the end of simulated reperfusion, acute T3 treatment increased contractile function recovery and cellular viability conservation. Mitochondrial ultrastructure was better preserved in the presence of T3 as well as mitochondrial ATP production rate and tissue ATP content. Calcium retention capacity, a parameter widely used as an indicator of the resistance of mitochondrial permeability transition pore (MPTP) to opening, and GSK-3ß phosphorylation, a master switch enzyme that limits MPTP opening, were increased by T3 administration. All these beneficial effects exerted by T3 acute treatment were prevented when compound C was co-administrated. The present study provided original evidence that T3 enhances intrinsic activation of AMPK during myocardial ischemia-reperfusion, being this enzyme involved, at least in part, in the protective effects exerted by T3, contributing to mitochondrial structure and function preservation, post-ischemic contractile recovery and conservation of cellular viability.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Cardiotónicos/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/enzimología , Miocardio/enzimología , Miocardio/patología , Triyodotironina/uso terapéutico , Adenosina Trifosfato/metabolismo , Animales , Calcio/metabolismo , Cardiotónicos/farmacología , Supervivencia Celular/efectos de los fármacos , Diástole/efectos de los fármacos , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Atrios Cardíacos/ultraestructura , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Contracción Miocárdica/efectos de los fármacos , Daño por Reperfusión Miocárdica/fisiopatología , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Sístole/efectos de los fármacos , Triyodotironina/farmacologíaRESUMEN
BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake-via AMP-activated protein kinase (AMPK)-after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Glucosa/metabolismo , Miocitos Cardíacos , Receptores Androgénicos/metabolismo , Testosterona/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Células Cultivadas , Hipertrofia , Masculino , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Transducción de SeñalRESUMEN
BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptakevia AMP-activated protein kinase (AMPK)after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.
Asunto(s)
Animales , Masculino , Ratas , Testosterona/farmacología , Receptores Androgénicos/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Glucosa/metabolismo , Transducción de Señal , Células Cultivadas , Hipertrofia , Miocardio/patologíaRESUMEN
Metformin, an AMP-activated protein kinase (AMPK) activator, has been shown in previous studies to reduce kidney fibrosis in different models of experimental chronic kidney disease (CKD). However, in all of these studies, the administration of metformin was initiated before the establishment of renal disease, which is a condition that does not typically occur in clinical settings. The aim of the present study was to investigate whether the administration of metformin could arrest the progression of established renal disease in a well-recognized model of CKD, the subtotal kidney nephrectomy (Nx) model. Adult male Munich-Wistar rats underwent either Nx or sham operations. After the surgery (30 days), Nx rats that had systolic blood pressures of >170 mmHg and albuminuria levels of >40 mg/24 h were randomized to a no-treatment condition or to a treatment condition with metformin (300 mg·kg-1·day-1) for a period of either 60 or 120 days. After 60 days of treatment, we did not observe any differences in kidney disease parameters between Nx metformin-treated and untreated rats. However, after 120 days, Nx rats that had been treated with metformin displayed significant reductions in albuminuria levels and in markers of renal fibrosis. These effects were independent of any other effects on blood pressure or glycemia. In addition, treatment with metformin was also able to activate kidney AMPK and therefore improve mitochondrial biogenesis. It was concluded that metformin can arrest the progression of established kidney disease in the Nx model, likely via the activation of AMPK.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Activadores de Enzimas/farmacología , Riñón/efectos de los fármacos , Metformina/farmacología , Nefrectomía , Insuficiencia Renal Crónica/prevención & control , Albuminuria/etiología , Albuminuria/metabolismo , Albuminuria/prevención & control , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Activación Enzimática , Fibrosis , Hipertensión/etiología , Hipertensión/metabolismo , Hipertensión/prevención & control , Riñón/enzimología , Riñón/patología , Riñón/cirugía , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Biogénesis de Organelos , Ratas Wistar , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Factores de TiempoRESUMEN
OBJECTIVE: Obesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity. RESEARCH DESIGN AND METHODS: 45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation. RESULTS: In the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5'-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of ß-oxidation and ω-oxidation, acyl-carnitines and ketone bodies. CONCLUSIONS: Change in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Fármacos Antiobesidad/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Genisteína/administración & dosificación , Resistencia a la Insulina , Músculo Esquelético/efectos de los fármacos , Obesidad/metabolismo , Obesidad/microbiología , Método Doble Ciego , Ácidos Grasos/metabolismo , Humanos , Músculo Esquelético/metabolismoRESUMEN
The AMP-activated kinase (AMPK) is an important enzyme involved in the regulation of cell metabolism, whose activity is regulated by several mechanisms, mainly the increased concentration of AMP. This enzyme catalyze the phosphorylation of several regulatory proteins implicated in the metabolism of lipids and carbohydrates, upregulating their catabolism. Thus, the AMPK plays an important role in the pathophysiology of some diseases, such as metabolic syndrome and type 2 diabetes mellitus, which have a high prevalence among Mexican population. Because of this, the AMPK has become a relevant target for several drugs used in the management of these pathologies, e.g. metformin and pioglitazone.
La cinasa activada por AMP (AMPK) es una enzima crucial en la regulación del metabolismo energético celular, cuya actividad se encuentra regulada por diversos mecanismos, entre los cuales el principal es el aumento en la concentración intracelular de AMP. Esta enzima cataliza la fosforilación de múltiples proteínas reguladoras de las vías metabólicas de lípidos y de hidratos de carbono, con lo que favorecen su catabolismo. Debido a esto, ejerce un papel importante en la fisiopatología de enfermedades como el síndrome metabólico y la diabetes mellitus tipo 2, las cuales tienen una alta prevalencia en la población mexicana. En vista de lo anterior, la AMPK se ha convertido en diana terapéutica relevante en el que actúan diversos fármacos utilizados en el manejo de estas patologías, como es el caso de la metformina y la pioglitazona.
RESUMEN
Liver preconditioning (PC) refers to the development of an enhanced tolerance to injuring stimuli. For example, the protection from ischemia-reperfusion (IR) in the liver that is obtained by previous maneuvers triggering beneficial molecular and functional changes. Recently, we have assessed the PC effects of thyroid hormone (T3; single dose of 0.1 mg/kg) and n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs; daily doses of 450 mg/kg for 7 days) that abrogate IR injury to the liver. This feature is also achieved by a combined T3 and the n-3 LCPUFA docosahexaenoic acid (DHA) using a reduced period of supplementation of the FA (daily doses of 300 mg/kg for 3 days) and half of the T3 dosage (0.05 mg/kg). T3 -dependent protective mechanisms include (i) the reactive oxygen species (ROS)-dependent activation of transcription factors nuclear factor-κB (NF-κB), AP-1, signal transducer and activator of transcription 3, and nuclear factor erythroid-2-related factor 2 (Nrf2) upregulating the expression of protective proteins. (ii) ROS-induced endoplasmic reticulum stress affording proper protein folding. (iii) The autophagy response to produce FAs for oxidation and ATP supply and amino acids for protein synthesis. (iv) Downregulation of inflammasome nucleotide-bonding oligomerization domain leucine-rich repeat containing family pyrin containing 3 and interleukin-1ß expression to prevent inflammation. N-3 LCPUFAs induce antioxidant responses due to Nrf2 upregulation, with inflammation resolution being related to production of oxidation products and NF-κB downregulation. Energy supply to achieve liver PC is met by the combined DHA plus T3 protocol through upregulation of AMPK coupled to peroxisome proliferator-activated receptor-γ coactivator 1α signaling. In conclusion, DHA plus T3 coadministration favors hepatic bioenergetics and lipid homeostasis that is of crucial importance in acute and clinical conditions such as IR, which may be extended to long-term or chronic situations including steatosis in obesity and diabetes. © 2019 IUBMB Life, 71(9):1211-1220, 2019.
Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Daño por Reperfusión/dietoterapia , Estrés Fisiológico/efectos de los fármacos , Hormonas Tiroideas/uso terapéutico , Suplementos Dietéticos , Metabolismo Energético/efectos de los fármacos , Hígado Graso/dietoterapia , Hígado Graso/patología , Hígado Graso/prevención & control , Humanos , Inflamasomas/efectos de los fármacos , Inflamasomas/genética , Precondicionamiento Isquémico , Hígado/efectos de los fármacos , Hígado/patología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & controlRESUMEN
The sulfur-containing amino acid, taurine (Tau), regulates glucose and lipid homeostasis under normal, pre- and diabetic conditions. Here, we aimed to verify whether Tau supplementation exerts its beneficial effects against obesity, hyperglycemia and alterations in islet functions, in leptin-deficient obese (ob/ob), over a long period of treatment. From weaning until 12 months of age, female ob/ob mice received, or not, 5% Tau in drinking water (obTau group). After this period, a reduction in hypertriglyceridemia and an improvement in glucose tolerance and insulin sensitivity were observed in obTau mice. In addition, the daily metabolic flexibility was restored in obTau mice. In the gastrocnemius muscle of obTau mice, the activation of AMP-activated protein kinase (AMPK) was increased, while total AMPK protein content was reduced. Finally, isolated islets from obTau mice expressed high amounts of pyruvate carboxylase (PC) protein and lower glucose-induced insulin secretion. Taking these evidences together Tau supplementation had long-term positive actions on glucose tolerance and insulin sensitivity, associated with a reduction in glucose-stimulated insulin secretion, in ob/ob mice. The improvement in insulin actions in obTau mice was due, at least in part, to increased activation of AMPK in skeletal muscle, while the increased content of the PC enzyme in pancreatic islets may help to preserve glucose responsiveness in obTau islets, possibly contributing to islet cell survive.
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Glucemia/metabolismo , Homeostasis/efectos de los fármacos , Hipertrigliceridemia , Taurina/farmacología , Animales , Prueba de Tolerancia a la Glucosa , Hipertrigliceridemia/sangre , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/patología , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Ratones , Ratones Obesos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologíaRESUMEN
The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. New members of this system have been characterized and shown to have biologically relevant actions. Alamandine and its receptor MrgD are recently identified components of RAS. In the cardiovascular system, alamandine actions included vasodilation, antihypertensive, and antifibrosis effects. Currently, the actions of alamandine on cardiomyocytes are unknown. Here our goal was twofold: 1) to unravel the signaling molecules activated by the alamandine/MrgD axis in cardiomyocytes; and 2) to evaluate the ability of this axis to prevent angiotensin II (ANG II)-induced hypertrophy. In cardiomyocytes from C57BL/6 mice, alamandine treatment induced an increase in nitric oxide (NO) production, which was blocked by d-Pro7-ANG-(1-7), a MrgD antagonist. This NO rise correlated with increased phosphorylation of AMPK. Alamandine-induced NO production was preserved in Mas-/- myocytes and lost in MrgD-/- cells. Binding of fluorescent-labeled alamandine was observed in wild-type cells, but it was dramatically reduced in MrgD-/- myocytes. We also assessed the consequences of prolonged alamandine exposure to cultured neonatal rat cardiomyocytes (NRCMs) treated with ANG II. Treatment of NRCMs with alamandine prevented ANG II-induced hypertrophy. Moreover, the antihypertrophic actions of alamandine were mediated via MrgD and NO, since they could be prevented by d-Pro7-ANG-(1-7) or inhibitors of NO synthase or AMPK. ß-Alanine, a MrgD agonist, recapitulated alamandine's cardioprotective effects in cardiomyocytes. Our data show that alamandine via MrgD induces AMPK/NO signaling to counterregulate ANG II-induced hypertrophy. These findings highlight the therapeutic potential of the alamandine/MrgD axis in the heart.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Angiotensina II/toxicidad , Cardiomegalia/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Proteínas del Tejido Nervioso/agonistas , Óxido Nítrico/metabolismo , Oligopéptidos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/enzimología , Cardiomegalia/patología , Células Cultivadas , Activación Enzimática , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Proteínas del Tejido Nervioso/metabolismo , Oligopéptidos/metabolismo , Fosforilación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/agonistas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Ratas Wistar , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
AMP-activated protein kinase (AMPK) is a serine-threonine kinase that functions primarily as a metabolic sensor to coordinate anabolic and catabolic processes in the cell, via phosphorylation of multiple proteins involved in metabolic pathways, aimed to re-establish energy homeostasis at a cell-autonomous level. Myocardial ischemia and reperfusion represents a metabolic stress situation for myocytes. Whether AMPK plays a critical role in the metabolic and functional responses involved in these conditions remains uncertain. In this study, in order to gain a deeper insight into the role of endogenous AMPK activation during myocardial ischemia and reperfusion, we explored the effects of the pharmacological inhibition of AMPK on contractile function rat, contractile reserve, tissue lactate production, tissue ATP content, and cellular viability. For this aim, isolated atria subjected to simulated 75 min ischemia-75 min reperfusion (Is-Rs) in the presence or absence of the pharmacological inhibitor of AMPK (compound C) were used. Since in most clinical situations of ischemia-reperfusion the heart is exposed to high levels of fatty acids, the influence of palmitate present in the incubation medium was also investigated. The present results suggest that AMPK activity significantly increases during Is, remaining activated during Rs. The results support that intrinsic activation of AMPK has functional protective effects in the reperfused atria when glucose is the only available energetic substrate whereas it is deleterious when palmitate is also available. Cellular viability was not affected by either of these conditions.
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Metabolismo Energético , Atrios Cardíacos/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Proteínas Quinasas/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Adenosina Trifosfato/metabolismo , Animales , Función Atrial , Ácidos Grasos/metabolismo , Femenino , Glucosa/metabolismo , Ácido Láctico/metabolismo , Contracción Miocárdica , Ratas , Ratas Sprague-DawleyRESUMEN
Normal liver function includes a number of metabolic processes, secretion of cellular mediators and its role in immunobiology; these require a high energy supply, which is further enhanced under adverse conditions triggering hepatic disorders or injury due to the operation of counteracting mechanisms. Alterations in oxygen availability, such as ischemia-reperfusion (IR) leading to liver inflammation and high-fat diet (HFD)-induced hepatic steatosis, are noxious responses encountered in hepatic surgery and obesity, respectively. Several strategies have been developed to attenuate or prevent these disorders, including thyroid hormone (T3), docosahexaenoic acid (DHA) and extra virgin olive oil (EVOO). These hormetic agents that exert beneficial effects in the low dose range were shown to abrogate IR-induced liver injury effectively in the case of T3, DHA, or their combined administration, whereas DHA plus EVOO attenuate HFD-induced hepatic steatosis, although they can induce adverse effects in other experimental settings. The use of combined hepatoprotective protocols (DHAâ¯+â¯T3 or DHAâ¯+â¯EVOO) using low doses or reduced supplementation periods is characterized by the stimulation of different types of molecular defensive mechanisms and similar signaling processes that exhibit synergism, thus constituting suitable experimental liver pharmacological preconditioning strategies with possible future clinical applications.
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Ácidos Docosahexaenoicos/uso terapéutico , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Aceite de Oliva/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Triyodotironina/uso terapéutico , Animales , Dieta Alta en Grasa , Quimioterapia Combinada , Humanos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
This study investigates the effects of replacing dietary casein by soya protein on the underlying mechanisms involved in the impaired metabolic fate of glucose and lipid metabolisms in the heart of dyslipidaemic rats chronically fed (8 months) a sucrose-rich (62·5 %) diet (SRD). To test this hypothesis, Wistar rats were fed an SRD for 4 months. From months 4 to 8, half the animals continued with the SRD and the other half were fed an SRD in which casein was substituted by soya. The control group received a diet with maize starch as the carbohydrate source. Compared with the SRD-fed group, the following results were obtained. First, soya protein significantly (P<0·001) reduced the plasma NEFA levels and normalised dyslipidaemia and glucose homoeostasis, improving insulin resistance. The protein levels of fatty acid translocase at basal state and under insulin stimulation and the protein levels and activity of muscle-type carnitine palmitoyltransferase 1 were normalised. Second, a significant (P<0·001) reduction of TAG, long-chain acyl CoA and diacylglycerol levels was observed in the heart muscle. Third, soya protein significantly increased (P<0·01) GLUT4 protein level under insulin stimulation and normalised glucose phosphorylation and oxidation. A reduction of phosphorylated AMP protein kinase protein level was recorded without changes in uncoupling protein 2 and PPARα. Fourth, hydroxyproline concentration decreased in the left ventricle and hypertension was normalised. The new information provided shows the beneficial effects of soya protein upon the altered pathways of glucose and lipid metabolism in the heart muscle of this rat model.
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Dislipidemias/metabolismo , Glucosa/metabolismo , Hipertensión/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Miocardio/metabolismo , Proteínas de Soja/administración & dosificación , Animales , Carnitina O-Palmitoiltransferasa/análisis , Proteínas en la Dieta/administración & dosificación , Sacarosa en la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Ácidos Grasos no Esterificados/sangre , Glucosa/administración & dosificación , Hidroxiprolina/análisis , Insulina/sangre , Resistencia a la Insulina/fisiología , Masculino , Miocardio/enzimología , PPAR alfa/análisis , Ratas , Ratas WistarRESUMEN
RESUMEN Introducción: la metformina es una biguanida que disminuye gluconeogénesis e incrementa la recaptación de glucosa en los músculos, sin embargo, más allá del glucémico se han documentado beneficios adicionales como la disminución de complicaciones crónicas derivadas de la hiperglucemia, entre ellas las cardiovasculares y del síndrome metabólico per se. Objetivo: identificar los efectos de la metformina diferentes al control control glucémico en población con diabetes mellitus, con el fin de contribuir a difundir el conocimiento. Materiales y método: tres revisores independientes realizaron la búsqueda en distintas bases de datos entre ellas Pubmed y ScienceDirect, utilizando los términos Metfomin AND Cardiovascular disease AND inflamatory response AND Hyperlipidemia, Biguanides, Diabetes Mellitus, Diabetes complications, Obesity, Vascular diseases AND Cancer; y Metfomina y enfermedad cardiovascular, metformina y cáncer se seleccionaron los artículos desde el año 2010, encontrando 13 828 artículos, de los cuales se incluyeron 144. Conclusión: más allá del control glucémico, la metformina, modifica la "memoria metabólica", reduce mediadores inflamatorios y el grosor de pared arterial, disminuye factores trombóticos y reduce la prevalencia de falla cardiaca logrando impactar la morbimortalidad y mediante cambios moleculares o genéticos, tiene potencial uso como anticancerígeno. El clínico debe conocer estos efectos para favorecer su pronto inicio en los casos indicados. MÉD.UIS. 2017;30(1):57-71.
ABSTRACT Introduction: the metformin is a biguanide which main action is to decrease hepatic glucose output, primarily by decreasing gluconeogenesis, and increase glucose uptake by muscles. However, beyond the glycemic target, additional benefits have been documented like a decrease in chronic complications to hyperglycemia, including cardiovascular comorbility and metabolic syndrome. Objetive: to identify effects of metformin other than glycemic control in patients with diabetes mellitus in order to help disseminate knowledge. Materials and methods: three independent reviewers searched in different databases of PubMed and ScienceDirect using the DeCS and MeSH terms: Metfomin AND Cardiovascular disease AND inflamatory response AND Hyperlipidemia, Biguanides, Diabetes Mellitus, Diabetes complications,Obesity, Vascular diseases AND Cancer, selecting the items since 2010 year and prior to warrant mention. Search based publications that were considered most relevant and, additionally, a manual search of the referenced articles in publications retrieved in the initial search was conducted, 13 828 articles were found but 144 were included finally. Conclusion: beyond glycemic control, Metformin, modifies the "metabolic memory", reduces inflammatory mediators and thickness of arterial wall, decreases thrombotic factors and reduces the prevalence of heart failure making an impact morbidity and mortality and because of molecular or genetic changes, it has potential use as anticarcinogenic. The physicians should know it to facilitate the early administration of this medication when it is indicated. MÉD.UIS. 2017;30(1):57-71.
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Humanos , Diabetes Mellitus , Metformina , Enfermedades Vasculares , Glucemia , Endocrinología , Proteínas Quinasas Activadas por AMP , Neoplasias , ObesidadRESUMEN
Thyroid hormone (T3) induces liver preconditioning (PC) against ischemia-reperfusion (IR), a response energetically supported by AMP-activated protein kinase (AMPK) upregulation. The aim of this work is to evaluate the influence of T3 on IR-induced liver NLRP3 inflammasome activation and the relevance of AMPK activity on liver injury by the use of the AMPK inhibitor compound C (CC). Male Sprague-Dawley rats were given 0.1mgT3/kg (time zero) and 10mg CC/kg (time zero and 24h) or the respective vehicles, and subjected to 1h ischemia-20h reperfusion 48h after hormone treatment. Measurements included parameters of liver injury, hepatic levels of mRNAs (qPCR) and proteins (Western Blot or ELISA). IR induced substantial distortion of liver architecture, hepatocyte necrosis, and neutrophil infiltration with increased serum aspartate aminotransferase (AST) levels. T3 suppressed IR liver injury and AST enhancement, effects that were reverted by CC. Concomitantly, IR-induced liver mRNA and protein expression of NLRP3 and interleukin-1ß (IL-1ß) were restrained by T3, whereas CC eliminated T3-dependent PC. In conclusion, in vivo T3 administration triggers liver PC against IR injury by suppressing the inflammatory response associated with hepatic NLRP3 and IL-1ß upregulation, with AMPK playing a causal role regulating energy dynamics to upkeep PC.
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Inflamasomas/metabolismo , Hepatopatías/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Daño por Reperfusión/metabolismo , Hormonas Tiroideas/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Modelos Animales de Enfermedad , Expresión Génica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Hepatopatías/genética , Hepatopatías/patología , Masculino , Ratas , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Hormonas Tiroideas/farmacología , Triyodotironina/metabolismo , Triyodotironina/farmacologíaRESUMEN
ABSTRACT Various studies have linked metformin, a universally antidiabetic drug, with semen quality; however, such a direct link has not been established. This review systematically addresses and summarizes the effect of metformin on semen quality, particularly sperm function. We searched the MEDLINE electronic database for English articles and abstracts containing the key words 'metformin' and 'sperm', and relevant articles were reviewed. In summary, metformin appears to have improved and provided positive impact on sperm quality. This effect may be due to the ability of metformin to reduce oxidative stress and lipid peroxidation, enhance 5'-AMP activated protein kinase activity, and restore the normal levels of pituitary-gonadal hormones. However, further clinical research is still necessary to confirm such effect.
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Semen/metabolismo , Metformina/análisis , Metformina/efectos adversos , Testosterona/farmacología , Estrés OxidativoRESUMEN
Obesity and insulin resistance have been associated with deterioration in asthma outcomes. High oxidative stress and deficient activation of AMP-activated protein kinase (AMPK) have emerged as important regulators linking insulin resistance and inflammation. This study aimed to evaluate the effects of resveratrol on obesity-associated allergic pulmonary inflammation. Male C57/Bl6 mice fed with high-fat diet to induce obesity (obese group) or standard-chow diet (lean group) were treated or not with resveratrol (100mg/kg/day, two weeks). Mice were sensitized and challenged with ovalbumin (OVA). At 48h thereafter, bronchoalveolar lavage fluid was performed, and lungs collected for morphological studies and Western blot analysis. Treatment of obese mice with resveratrol significantly reduced hyperglycemia and insulin resistance, as well as the body measures (body mass, fat mass, % fat, and body area). OVA-challenge promoted a higher increase in pulmonary eosinophil infiltration in obese compared with lean mice, which was nearly abrogated by resveratrol treatment. Resveratrol markedly increased the phosphorylated AMPK expression in lung tissues of obese compared with lean mice. Resveratrol reduced the p47phox expression and reactive-oxygen species (ROS) production, and elevated the superoxide dismutase (SOD) levels in lung tissues of obese mice. The increased pulmonary levels of TNF-α and inducible nitric oxide synthase (iNOS) in obese mice were also normalized after resveratrol treatment. In lean mice, resveratrol failed to affect the levels of fasting glucose, p47phox, ROS levels, TNF-α, iNOS and phosphorylated AMPK. Resveratrol exhibits protective effects in obesity-associated lung inflammation that is accompanied by local AMPK activation and antioxidant property.
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Antioxidantes/uso terapéutico , Asma/tratamiento farmacológico , Eosinófilos/fisiología , Pulmón/efectos de los fármacos , Obesidad/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Estilbenos/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Progresión de la Enfermedad , Pulmón/patología , Ratones , Ratones Endogámicos , ResveratrolRESUMEN
The aim of this study was to determine the ergogenic effects of metformin in high-intensity exercise, as well as its effects on anaerobic capacity, in healthy and physically active men. Ten subjects (mean (± standard deviation) maximal oxygen uptake (VËO2max ) 38.6 ± 4.5 mL/kg per min) performed the following tests in a cycle ergometer: (i) an incremental test; (ii) six submaximal constant workload tests at 40%-90% (VËO2max ); and (iii) two supramaximal tests (110% (VËO2max ). Metformin (500 mg) or placebo was ingested 60 min before the supramaximal test. There were no significant differences between the placebo and metformin groups in terms of maximum accumulated oxygen deficit (2.8 ± 0.6 vs 3.0 ± 0.8 L, respectively; P = 0.08), lactate concentrations (7.8 ± 2.6 vs 7.5 ± 3.0 mmol/L, respectively; P = 0.75) or O2 consumed in either the last 30 s of exercise (40.4 ± 4.4 vs 39.9 ± 4.0 mL/kg per min, respectively; P = 0.35) or the first 110 s of exercise (29.0 ± 2.5 vs 29.5 ± 3.0 mL/kg per min, respectively; P = 0.42). Time to exhaustion was significantly higher after metformin than placebo ingestion (191 ± 33 vs 167 ± 32 s, respectively; P = 0.001). The fast component of VËO2 recovery was higher in the metformin than placebo group (12.71 vs 12.18 mL/kg per min, respectively; P = 0.025). Metformin improved performance and anaerobic alactic contribution during high-intensity exercise, but had no effect on overall anaerobic capacity in healthy subjects.
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Ejercicio Físico/fisiología , Voluntarios Sanos , Metformina/farmacología , Sustancias para Mejorar el Rendimiento/farmacología , Adenosina Trifosfato/biosíntesis , Anaerobiosis/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Glucólisis/efectos de los fármacos , Humanos , Masculino , Contracción Muscular/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Adulto JovenRESUMEN
INTRODUCTION: adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor, and it has recently been suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating the AMPK system. This study aimed to evaluate the effects of candesartan, an angiotensin II receptor blocker, on cardiac and hepatic AMPK activity basally as well as after surgical stress under general anesthesia. MATERIALS AND METHODS: Male Wistar rats were treated with 5 mg/kg/day candesartan in their drinking water for two weeks. Levels of cardiac and hepatic AMPK activity were determined, using a kinase activity assay, basally and after surgical stress under general anesthesia. RESULTS: Chronic administration of candesartan increased hepatic AMPK activity approximately 4 times (p<0.05) while no significant change was demonstrated in cardiac AMPK. Cardiac and hepatic AMPK activities were not significantly increased by surgical stress alone performed under anesthesia. However, chronic treatment with candesartan decreased AMPK activity in both liver and heart after surgical stress under anesthesia (p<0.01 for both comparisons). CONCLUSIONS: While chronic candesartan treatment may stimulate AMPK activity in certain organs such as the liver, when combined with surgical stress under anesthesia it inhibits pathways regulating AMPK activity.