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INTRODUCTION: Dengue shock syndrome (DSS) fluid resuscitation by following the World Health Organization (WHO) guideline usually required large volumes of Ringer lactate (RL) that might induce secondary fluid overload. Our objective was to compare the effectiveness of the recommended volume of RL versus a smaller volume of a hypertonic sodium lactate solution (HSL) in children with DSS. The primary end point was to evaluate the effect of HSL on endothelial cell inflammation, assessed by soluble vascular cell adhesion molecule-1 (sVCAM-1) measurements. Secondarily, we considered the effectiveness of HSL in restoring hemodynamic fluid balance, acid-base status, and sodium and chloride balances, as well as in-hospital survival. METHODS: A prospective randomized single-blind clinical trial including 50 DSS children was conducted in the Pediatrics Department of Hasan Sadikin Hospital, Bandung, Indonesia. Only pediatric patients (2 to 14 years old) fulfilling the WHO criteria for DSS and new to resuscitation treatments were eligible. Patients were resuscitated with either HSL (5 ml/kg/BW in 15 minutes followed by 1 ml/kg/BW/h for 12 hours), or RL (20 ml/kg/BW in 15 minutes followed by decreasing doses of 10, 7, 5, and 3 ml/kg BW/h for 12 hours). RESULTS: In total, 50 patients were randomized and included in outcome and adverse-event analysis; 46 patients (8.2 ± 0.5 years; 24.9 ± 1.9 kg; mean ± SEM) completed the protocol and were fully analyzed (24 and 22 subjects in the HSL and RL groups, respectively). Baseline (prebolus) data were similar in both groups. Hemodynamic recovery, plasma expansion, clinical outcome, and survival rate were not significantly different in the two groups, whereas fluid accumulation was one third lower in the HSL than in the RL group. Moreover, HSL was responsible for a partial recovery from endothelial dysfunction, as indicated by the significant decrease in sVCAM-1. CONCLUSION: Similar hemodynamic shock recovery and plasma expansion were achieved in both groups despite much lower fluid intake and fluid accumulation in the HSL group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00966628. Registered 26 August 2009.
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Fluidoterapia , Resucitación , Dengue Grave/terapia , Lactato de Sodio/uso terapéutico , Adolescente , Niño , Preescolar , Femenino , Fluidoterapia/métodos , Humanos , Indonesia , Soluciones Isotónicas/uso terapéutico , Masculino , Estudios Prospectivos , Lactato de Ringer , Método Simple Ciego , Resultado del Tratamiento , Molécula 1 de Adhesión Celular Vascular/sangreRESUMEN
BACKGROUND & AIMS: A high-fat diet affects liver metabolism, leading to steatosis, a complex disorder related to insulin resistance and mitochondrial alterations. Steatosis is still poorly understood since diverse effects have been reported, depending on the different experimental models used. METHODS: We hereby report the effects of an 8 week high-fat diet on liver energy metabolism in a rat model, investigated in both isolated mitochondria and hepatocytes. RESULTS: Liver mass was unchanged but lipid content and composition were markedly affected. State-3 mitochondrial oxidative phosphorylation was inhibited, contrasting with unaffected cytochrome content. Oxidative phosphorylation stoichiometry was unaffected, as were ATPase and adenine nucleotide translocator proteins and mRNAs. Mitochondrial acylcarnitine-related H(2)O(2) production was substantially higher and the mitochondrial quinone pool was smaller and more reduced. Cellular consequences of these mitochondrial alterations were investigated in perifused, freshly isolated hepatocytes. Ketogenesis and fatty acid-dependent respiration were lower, indicating a lower ß-oxidation rate contrasting with higher RNA contents of CD36, FABP, CPT-1, and AcylCoA dehydrogenases. Concomitantly, the cellular redox state was more reduced in the mitochondrial matrix but more oxidized in the cytosol: these opposing changes are in agreement with a significantly higher in situ mitochondrial proton motive force. CONCLUSIONS: A high-fat diet results in both a decrease in mitochondrial quinone pool and a profound modification in mitochondrial lipid composition. These changes appear to play a key role in the resulting inhibition of fatty acid oxidation and of mitochondrial oxidative-phosphorylation associated with an increased mitochondrial ROS production. Mitochondrial quinone pool could have prospects as a crucial event, potentially leading to interesting therapeutic perspectives.
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Grasas de la Dieta/administración & dosificación , Metabolismo Energético , Hígado/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Composición Corporal , Transporte de Electrón , Hepatocitos/metabolismo , Lípidos/análisis , Hígado/química , Masculino , Potencial de la Membrana Mitocondrial , Mitocondrias Hepáticas/química , Fosforilación Oxidativa , Ratas , Ratas Wistar , Transcripción GenéticaRESUMEN
OBJECTIVE: To compare two solutions for fluid resuscitation in post-coronary artery bypass grafting (CABG) surgery patients: Ringer's lactate (RL) versus a new solution containing half-molar sodium-lactate (HL). DESIGN: Prospective randomized open label study. SETTING: The first 12 h post-CABG surgery in an intensive care unit (ICU). PATIENTS: There were 230 patients enrolled in the study: 208 were analyzed, with 109 from the HL group and 99 from the RL group. INTERVENTIONS: Patients received over the first 12 h post-CABG 10 ml kg BW(-1) HL solution in the HL group versus 30 ml kg BW(-1) of RL solution in the RL group. MEASUREMENTS AND RESULTS: Hemodynamic status, body fluid balance and inotrope utilization were compared in the two groups. Post-operative cardiac index increase was significantly higher in HL than in RL (P = 0.02), while mean arterial pressure and other hemodynamic parameters were comparable together with urinary output, indicating similar tissue perfusion in both the groups despite a much lower fluid infusion in the HL group. Therefore, a significant negative fluid balance was achieved in the HL but not in the RL group (-790 +/- 71 vs. +43 +/- 115 mL 12 h(-1), P < 0.0001 for HL and RL, respectively). None of the enrolled patients exhibited side effects related to the treatment. CONCLUSION: Half-molar lactate solution is effective for fluid resuscitation in post-CABG patients. Compared to Ringer's Lactate, its use results in a significantly higher cardiac index with less volume being infused, resulting in a very negative post-operative body fluid balance.
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Puente de Arteria Coronaria , Fluidoterapia/métodos , Soluciones Hipertónicas/uso terapéutico , Soluciones Isotónicas/uso terapéutico , Cuidados Posoperatorios/métodos , Lactato de Sodio/uso terapéutico , Gasto Cardíaco , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Lactato de Ringer , Lactato de Sodio/metabolismo , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
OBJECTIVE: To investigate the role of the inducible nitric oxide synthase activation-induced excess nitric oxide formation on the rate of hepatic glucose production during fully resuscitated murine septic shock. DESIGN: Prospective, controlled, randomized animal study. SETTING: University animal research laboratory. SUBJECTS: Male C57Bl/6 and B6.129P2-Nos2(tm1Lau)/J (iNOS-/-) mice. INTERVENTIONS: Fifteen hours after cecal ligation and puncture, anesthetized, mechanically ventilated and instrumented mice (wild-type controls, n = 13; iNOS-/-, n = 12; wild-type mice receiving 5 mg.kg(-1) i.p. of the selective iNOS inhibitor GW274150 immediately after cecal ligation and puncture, n =8) received continuous i.v. hydroxyethylstarch and norepinephrine to achieve normotensive and hyperdynamic hemodynamics. MEASUREMENTS AND RESULTS: Measurements were recorded 18, 21 and 24 h after cecal ligation and puncture. Liver microcirculatory perfusion and capillary hemoglobin O2 saturation (laser Doppler flowmetry and remission spectrophotometry) were well maintained in all groups. Despite significantly lower norepinephrine doses required to achieve the hemodynamic targets, the rate of hepatic glucose production (gas chromatography--mass spectrometry measurements of tissue isotope enrichment during continuous i.v. 1,2,3,4,5,6-13C6-glucose infusion) at 24 h after cecal ligation and puncture was significantly higher in both iNOS-/- and GW274150-treated mice, which was concomitant with a significantly higher hepatic phosphoenolpyruvate carboxykinase activity (spectrophotometry) in these animals. CONCLUSIONS: In normotensive, hyperdynamic septic shock, both pharmacologic and genetic deletion of the inducible nitric oxide synthase allowed maintenance of hepatic glucose production, most likely due to maintained activity of the key regulatory enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase.
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Gluconeogénesis/efectos de los fármacos , Hígado/metabolismo , Óxido Nítrico Sintasa/metabolismo , Choque Séptico/metabolismo , Animales , Modelos Animales de Enfermedad , Glucosa-6-Fosfatasa , Flujometría por Láser-Doppler , Masculino , Ratones , Estudios Prospectivos , Distribución AleatoriaRESUMEN
OBJECTIVE: We previously reported in healthy volunteers that a cantaloupe melon extract chemically combined with wheat gliadin (melon extract/gliadin) and containing SOD, catalase and residual glutathione peroxidase (GPx), protected against DNA strand-break damage induced by hyperbaric oxygen (HBO), a well-established model of DNA damage resulting from oxidative stress. Aortic cross-clamping is a typical example of ischemia/reperfusion injury-related oxidative stress, and therefore we investigated whether this melon extract/gliadin would also reduce DNA damage after aortic cross-clamping and reperfusion. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Animal laboratory. PATIENTS AND PARTICIPANTS: 18 anesthetized, mechanically ventilated and instrumented pigs. INTERVENTIONS: After 14 days of oral administration of 1250 mg of the melon extract/gliadin (n=9) or vehicle (n=9), animals underwent 30 min of thoracic aortic cross-clamping and 4 h of reperfusion. MEASUREMENTS AND RESULTS: Before clamping, immediately before declamping, and at 2 and 4 h of reperfusion, we measured blood isoprostane (immunoassay) and malondialdehyde concentrations (fluorimetric thiobarbituric acid test), SOD, catalase and GPx activities (spectrophotometric kits), NO formation (nitrate+nitrite; chemoluminescence), DNA damage in whole blood samples and isolated lymphocytes exposed to hyperbaric oxygen (comet assay). Organ function was also evaluated. Kidney and spinal cord specimen were analysed for apoptosis (TUNEL assay). The melon extract/gliadin blunted the DNA damage, reduced spinal cord apoptosis and attenuated NO release, however, without any effect on lipid peroxidation and organ function. CONCLUSIONS: Pre-treatment with the oral melon extract/gliadin may be a therapeutic option to reduce oxidative cell injury affiliated with aortic cross-clamping.
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Apoptosis , Daño del ADN , Gliadina/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Daño por Reperfusión/prevención & control , Animales , Ensayo Cometa , Cucumis melo , Femenino , Oxigenoterapia Hiperbárica/efectos adversos , Etiquetado Corte-Fin in Situ , Masculino , Daño por Reperfusión/etiología , PorcinosRESUMEN
Lactate, indispensable substrate of mammalian intermediary metabolism, allows shuttling of carbons and reducing power between cells and organs at a high turnover rate. Lactate is, therefore, not deleterious, although an increase in its concentration is often a sensitive sign of alteration in energy homeostasis, a rise in it being frequently related to poor prognosis. Such an increase, however, actually signifies an attempt by the body to cope with a new energy status. Hyperlactatemia, therefore, most often represents an adaptive response to an acute energy disorder. Investigation of lactate metabolism at the bedside is limited to the determination of its concentration. Lactate metabolism and acid-base homeostasis are both closely linked to cellular energy metabolism, acidosis being potentially a cause or a consequence of cellular energy deficit.
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Cuidados Críticos/métodos , Ácido Láctico/sangre , Desequilibrio Ácido-Base/sangre , Biomarcadores/sangre , Metabolismo Energético , Humanos , Consumo de OxígenoRESUMEN
Although hypertonic saline has been proposed as an intravenous resuscitation fluid, the beneficial effects of the sodium load are associated with potentially deleterious effects of chloride. Since the physiological lactate anion is well metabolized, hypertonic lactate solution could represent an interesting alternative. The aim of this study was to compare metabolic and hemodynamic effects of hypertonic infusion of sodium lactate versus sodium chloride in three groups of surgical patients who underwent elective coronary artery bypass grafting (CABG). Hypertonic lactate solution was infused to patients 14 to 16 h after surgery either involving a cardiopulmonary bypass (CPB-Lac, n = 20) or on-off pump (OPCAB-Lac, n = 20), whereas the third group consisted of patients undergoing cardiopulmonary bypass but receiving hypertonic saline solution (CPB-NaCl, n = 20). An equal fluid and sodium load (2.5 mL/2.5 mmol x kg(-1)) was infused in all patients over 15 min. Plasma glucose and sodium increased after infusion in the three groups, but the changes, although significant, were small. As expected, lactate rose only in CPB-Lac and OPCAB-Lac groups, the changes being more marked in CPB-Lac, indicating a slower lactate metabolism in this group compared with OPCAB-Lac. Although both solutions produced significant increases in cardiac index and oxygen delivery, there was a significant decrease in oxygen extraction only in groups receiving sodium lactate (CPB-Lac and OPCAB-Lac) and not in CPB-NaCl. Finally, hypertonic NaCl infusion induced a modest, although significant, decrease in arterial pH and bicarbonate, whereas hypertonic lactate infusion increased these two parameters in both CPB-Lac and OPCAB-Lac. This study demonstrates that hypertonic lactate infusion is safe and well tolerated in patients undergoing elective cardiac surgery.
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Hemodinámica/efectos de los fármacos , Soluciones Hipertónicas/uso terapéutico , Cloruro de Sodio/uso terapéutico , Equilibrio Ácido-Base/efectos de los fármacos , Bicarbonatos/sangre , Glucemia/análisis , Puente Cardiopulmonar , Enfermedad Coronaria/cirugía , Humanos , Soluciones Hipertónicas/administración & dosificación , Infusiones Intravenosas , Lactatos/sangre , Persona de Mediana Edad , Cuidados Posoperatorios , Periodo Posoperatorio , Sodio/sangre , Cloruro de Sodio/administración & dosificación , Lactato de Sodio/uso terapéuticoRESUMEN
OBJECTIVE: We have investigated the role of cardiopulmonary bypass on lactate metabolism in patients undergoing uncomplicated surgery for elective coronary artery bypass grafting (CABG). DESIGN: Prospective non-randomized observational study. SETTINGS: National Cardiovascular Center. PATIENTS. Three independent groups were studied: preoperative ( n=20), postoperative with bypass (CPB, n=20) and postoperative without bypass (NO-CPB, n=20). INTERVENTIONS: Lactate metabolism was investigated with the use of an exogenous lactate challenge test (2.5 mmol Na-lactate/kg body weight in 15 min). Blood lactate was sequentially determined after the end of infusion. Lactate clearance and endogenous production were estimated from the area under the curve, and a bi-exponential fitting permitted modeling the lactate-decay into two compartments. MEASUREMENTS AND MAIN RESULTS: Lactate metabolism parameters (basal lactate, clearance, endogenous production and half-lives [HL] I and II) were not different between the NO-CPB and preoperative groups. In the CPB group, as compared to the other two groups, basal lactate and endogenous production were not significantly affected while lactate clearance (CPB: 6.02+/-0.97 versus preoperative: 9.41+/-0.93 and NO-CPB: 9.6+/-0.8 ml/kg per min) and HL-I (CPB: 10.6+/-1.4 versus preoperative: 17.2+/-2.3 and NO-CPB: 18.8+/-2.5 min) were decreased ( p<0.001) and HL-II was increased (CPB: 171+/-41 versus preoperative: 73+/-12 and NO-CPB: 48+/-2.9 min, p<0.01). CONCLUSION: While surgery and anesthesia per se do not seem to alter lactate metabolism, CPB significantly decreased lactate clearance, this effect being possibly related to a mild liver dysfunction even in uncomplicated elective surgery.
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Puente Cardiopulmonar , Ácido Láctico/sangre , Adulto , Anciano , Humanos , Persona de Mediana Edad , Cuidados Posoperatorios , Cuidados Preoperatorios , Estudios ProspectivosRESUMEN
BACKGROUND: This study aims to test the hypothesis whether lowering glycemia improves mitochondrial function and thereby attenuates apoptotic cell death during resuscitated murine septic shock. METHODS: Immediately and 6 h after cecal ligation and puncture (CLP), mice randomly received either vehicle or the anti-diabetic drug EMD008 (100 µg · g(-1)). At 15 h post CLP, mice were anesthetized, mechanically ventilated, instrumented and rendered normo- or hyperglycemic (target glycemia 100 ± 20 and 180 ± 50 mg · dL(-1), respectively) by infusing stable, non-radioactive isotope-labeled (13)C6-glucose. Target hemodynamics was achieved by colloid fluid resuscitation and continuous i.v. noradrenaline, and mechanical ventilation was titrated according to blood gases and pulmonary compliance measurements. Gluconeogenesis and glucose oxidation were derived from blood and expiratory glucose and (13)CO2 isotope enrichments, respectively; mathematical modeling allowed analyzing isotope data for glucose uptake as a function of glycemia. Postmortem liver tissue was analyzed for HO-1, AMPK, caspase-3, and Bax (western blotting) expression as well as for mitochondrial respiratory activity (high-resolution respirometry). RESULTS: Hyperglycemia lowered mitochondrial respiratory capacity; EMD008 treatment was associated with increased mitochondrial respiration. Hyperglycemia decreased AMPK phosphorylation, and EMD008 attenuated both this effect as well as the expression of activated caspase-3 and Bax. During hyperglycemia EMD008 increased HO-1 expression. During hyperglycemia, maximal mitochondrial oxidative phosphorylation rate was directly related to HO-1 expression, while it was unrelated to AMPK activation. According to the mathematical modeling, EMD008 increased the slope of glucose uptake plotted as a function of glycemia. CONCLUSIONS: During resuscitated, polymicrobial, murine septic shock, glycemic control either by reducing glucose infusion rates or EMD008 improved glucose uptake and thereby liver tissue mitochondrial respiratory activity. EMD008 effects were more pronounced during hyperglycemia and coincided with attenuated markers of apoptosis. The effects of glucose control were at least in part due to the up-regulation of HO-1 and activation of AMPK.
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PURPOSE: Preventive treatments of traumatic intracranial hypertension are not yet established. We aimed to compare the efficiency of half-molar sodium lactate (SL) versus saline serum solutions in preventing episodes of raised intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI). METHODS: This was a double-blind, randomized controlled trial including 60 patients with severe TBI requiring ICP monitoring. Patients were randomly allocated to receive a 48-h continuous infusion at 0.5 ml/kg/h of either SL (SL group) or isotonic saline solution (control group) within the first 12 h post-trauma. Serial measurements of ICP, as well as fluid, sodium, and chloride balance were performed over the 48-h study period. The primary outcome was the number of raised ICP (≥20 mmHg) requiring a specific treatment. RESULTS: Raised ICP episodes were reduced in the SL group as compared to the control group within the 48-h study period: 23 versus 53 episodes, respectively (p < 0.05). The proportion of patients presenting raised ICP episodes was smaller in the SL group than in the saline group: 11 (36 %) versus 20 patients (66 %) (p < 0.05). Cumulative 48-h fluid and chloride balances were reduced in the SL group compared to the control group (both p < 0.01). CONCLUSION: A 48-h infusion of SL decreased the occurrence of raised ICP episodes in patients with severe TBI, while reducing fluid and chloride balances. These findings suggest that SL solution could be considered as an alternative treatment to prevent raised ICP following severe TBI.
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Lesiones Encefálicas/complicaciones , Hipertensión Intracraneal/etiología , Hipertensión Intracraneal/prevención & control , Lactato de Sodio/administración & dosificación , Adolescente , Adulto , Anciano , Líquidos Corporales , Lesiones Encefálicas/metabolismo , Cloruros/metabolismo , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Puntaje de Gravedad del Traumatismo , Hipertensión Intracraneal/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sodio/metabolismo , Adulto JovenRESUMEN
Excess reactive oxygen species (ROS) production is thought to play a key role in the loss of pancreatic ß-cell number and/or function, in response to high glucose and/or fatty acids. However, contradictory findings have been reported showing that in pancreatic ß cells or insulin-secreting cell lines, ROS are produced under conditions of either high or low glucose. Superoxide production was measured in attached INS1E cells as a function of glucose concentration, by following in real time the oxidation of dihydroethidine. Minimal values of superoxide production were measured at glucose concentrations of 5-20 mM, whereas superoxide generation was maximal at 0-1 mM glucose. Superoxide generation started rapidly (15-30 min) after exposure to low glucose and was suppressed by its addition within minutes. Superoxide was totally suppressed by rotenone, but not myxothiazol, suggesting a role for complex I in this process. Indirect evidence for mitochondrial ROS generation was also provided by a decrease in aconitase activity. Activation of AMPK, a cellular metabolic sensor, and its downstream target ACC by low glucose concentration was largely inhibited by addition of MnTBAP, a MnSOD and catalase mimetic that also totally suppressed superoxide production. Taken together, the data show that low glucose activates AMPK in a superoxide-dependent, AMP-independent way.
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Glucosa/efectos adversos , Células Secretoras de Insulina/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Superóxidos/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Aconitato Hidratasa/metabolismo , Adenosina Monofosfato/metabolismo , Línea Celular , Dicarbetoxidihidrocolidina/análogos & derivados , Dicarbetoxidihidrocolidina/análisis , Relación Dosis-Respuesta a Droga , Complejo I de Transporte de Electrón/metabolismo , Activación Enzimática/efectos de los fármacos , Humanos , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/enzimología , Metaloporfirinas/farmacología , Metacrilatos/farmacología , Mitocondrias/enzimología , Oxidación-Reducción/efectos de los fármacos , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Rotenona/análogos & derivados , Rotenona/farmacología , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/metabolismo , Superóxidos/análisis , Superóxidos/antagonistas & inhibidores , Tiazoles/farmacologíaRESUMEN
With a steadily increasing prevalence, insulin resistance (IR) is a major public health issue. This syndrome is defined as a set of metabolic dysfunctions associated with, or contributing to, a range of serious health problems. These disorders include type 2 diabetes, metabolic syndrome, obesity, and non-alcoholic steatohepatitis (NASH). According to the literature in the field, several cell types like ß-cell, myocyte, hepatocyte and/or adipocyte, as well as related complex signaling environment involved in peripheral insulin sensitivity are believed to be central in this pathology. Because of the central role of the liver in the whole-body energy homeostasis, liver insulin sensitivity and its potential relationship with mitochondrial oxidative phosphorylation appear to be crucial. The following short review highlights how liver mitochondria could be implicated in IR and should therefore be considered as a specific therapeutic target in the future.
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Resistencia a la Insulina , Mitocondrias Hepáticas/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/fisiopatología , Síndrome Metabólico/complicaciones , Síndrome Metabólico/fisiopatología , Modelos BiológicosRESUMEN
Besides its well recognized role in lipid and carbohydrate metabolisms, glycerol is involved in the regulation of cellular energy homeostasis via glycerol-3-phosphate, a key metabolite in the translocation of reducing power across the mitochondrial inner membrane with mitochondrial glycerol-3-phosphate dehydrogenase. Here, we report a high rate of gluconeogenesis from glycerol and fatty acid oxidation in hepatocytes from Lou/C, a peculiar rat strain derived from Wistar, which is resistant to age- and diet-related obesity. This feature, associated with elevated cellular respiration and cytosolic ATP/ADP and NAD(+)/NADH ratios, was linked to a high expression and activity of mitochondrial glycerol-3-phosphate dehydrogenase. Interestingly, this strain exhibited high expression and protein content of thyroid hormone receptor, whereas circulating thyroid hormone levels were slightly decreased and hepatic thyroid hormone carrier MCT-8 mRNA levels were not modified. We propose that an enhanced liver thyroid hormone receptor in Lou/C may explain its unique resistance to obesity by increasing fatty acid oxidation and lowering liver oxidative phosphorylation stoichiometry at the translocation of reducing power into mitochondria.
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Ácidos Grasos/metabolismo , Glicerolfosfato Deshidrogenasa/metabolismo , Hepatocitos/metabolismo , Mitocondrias Hepáticas/metabolismo , Obesidad , Receptores de Hormona Tiroidea/metabolismo , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Gluconeogénesis/fisiología , Glicerol/metabolismo , Glicerofosfatos/metabolismo , Masculino , Transportadores de Ácidos Monocarboxílicos , NAD/metabolismo , Oxidación-Reducción , Ratas , Ratas Wistar , Especificidad de la EspecieRESUMEN
PURPOSE OF REVIEW: Intradialytic nutritional support has been used for more than 30 years both in critically ill patients with acute renal failure and during maintenance hemodialysis. Present knowledge allows better estimation of its metabolic and nutritional efficacy, as well its effect on patient outcome. RECENT FINDINGS: Recent data showed that intradialytic nutritional support is able to counteract these effects of dialysis on protein metabolism and to improve both nitrogen and energy balance. In maintenance hemodialysis patients, the improvement of nutritional status during nutritional support was shown to improve long-term survival. In critically ill patients with acute renal failure, protein sparing is one of the main therapeutic goals. The effect of nutritional support on patient outcome is not demonstrated. Recent data, however, showed that the improvement of nitrogen balance may be associated with a better outcome. SUMMARY: Current information helps to better assess the effects of intradialytic nutritional support, to clarify the nutritional management of renal failure patients and to provide recommendations. Future research should focus on the possible means to improve the efficacy of nutritional support, either by modifying its components of by associating anabolic or anticatabolic agents.
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Necesidades Nutricionales , Apoyo Nutricional/métodos , Insuficiencia Renal/terapia , Terapia de Reemplazo Renal/métodos , Cuidados Críticos , Enfermedad Crítica , Proteínas en la Dieta/administración & dosificación , Proteínas en la Dieta/metabolismo , Humanos , Estado Nutricional , Resultado del TratamientoRESUMEN
Carbohydrates and lipid oxidations support energy metabolism by distinct pathways exhibiting similarities and differences. Alterations of energy metabolism during sepsis are well recognized; however, failure of oxygen or substrate supply is not a prominent cause. The occurrence of a "mitochondrial cytopathy" induced by sepsis explains some of these abnormalities, which may represent a "metabolic hibernation," a potential strategy of defense during the very acute phase of the illness. Our view of the involvement of mitochondrial metabolism in cell signaling has evolved considerably. Because of the structure of the respiratory chain, the way electrons are provided (upstream or downstream of complex 1 [i.e., nicotinamide adenine dinucleotide {reduced form} or flavin adenine dinucleotide {reduced form}]) plays an important role in the regulation of several functions, including the yield of adenosine triphosphate synthesis and the production of reactive oxygen species. Moreover, the modern view of energy channeling and compartmentation in the cell may open attractive hypotheses regarding the changes in cellular energy distribution in pathologic states, such as sepsis.
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Mitocondrias/metabolismo , Insuficiencia Multiorgánica/metabolismo , Sepsis/metabolismo , Adenosina Trifosfato/biosíntesis , Complejo I de Transporte de Electrón/metabolismo , Metabolismo Energético , Humanos , Insuficiencia Multiorgánica/fisiopatología , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismo , Sepsis/fisiopatologíaRESUMEN
There are now powerful compensatory therapies to counteract kidney deficiency and the prognosis of patients with acute renal failure is mainly related to the severity of the initial disease. Renal failure is accompanied by an increase in both severity and duration of the catabolic phase leading to stronger catabolic consequences. The specificity of the metabolic and nutritional disorders in the most severely ill patients is the consequence of three additive phenomena: (1) the metabolic response to stress and to organ dysfunction, (2) the lack of normal kidney function and (3) the interference with the renal treatment (hemodialysis, hemofiltration or both, continuous or intermittent, lactate or bicarbonate buffer, etc.). As in many other diseases of similar severity, adequate nutritional support in acutely ill patients with ARF is of great interest in clinical practice, although the real improvement as a result of this support is still difficult to assess in terms of morbidity or mortality.
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Lesión Renal Aguda/terapia , Enfermedad Crítica/terapia , Terapia Nutricional/métodos , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/fisiopatología , Metabolismo de los Hidratos de Carbono/fisiología , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Pronóstico , Terapia de Reemplazo Renal , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND/AIMS: The flavonoid silibinin has been reported to be beneficial in several hepatic disorders. Recent evidence also suggests that silibinin could be beneficial in the treatment of type 2 diabetes, owing to its anti-hyperglycemic properties. However, the mechanism(s) underlying these metabolic effects remains unknown. METHODS: The effects of silibinin on liver gluconeogenesis were studied by titrating hepatocytes from starved rats with sub-saturating concentrations of various exogenous substrates in a perifusion system. Hepatocytes from fed rats were also used to investigate glycogenolysis from endogenous glycogen. The effect of silibinin on glucose-6-phosphatase kinetics was determined in intact and permeabilized rat liver microsomes. RESULTS: Silibinin induced a dose-dependent inhibition of gluconeogenesis associated with a potent decrease in glucose-6-phosphate hydrolysis. This effect was demonstrated whatever the gluconeogenic substrates used, i.e. dihydroxyacetone, lactate/pyruvate, glycerol and fructose. In addition, silibinin decreased the glucagon-induced stimulation of both gluconeogenesis and glycogenolysis, this being associated with a reduction of glucose-6-phosphate hydrolysis. Silibinin inhibits glucose-6-phosphatase in rat liver microsomes in a concentration-dependent manner that could explain the decrease in glucose-6-phosphate hydrolysis seen in intact cells. CONCLUSION: The inhibitory effect of silibinin on both hepatic glucose-6-phosphatase and gluconeogenesis suggests that its use may be interesting in treatment of type 2 diabetes.
Asunto(s)
Flavonoides/farmacología , Glucosa-6-Fosfatasa/antagonistas & inhibidores , Glucosa-6-Fosfato/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Perfusión , Animales , Dihidroxiacetona/farmacología , Relación Dosis-Respuesta a Droga , Glucagón/farmacología , Gluconeogénesis/efectos de los fármacos , Glucosa-6-Fosfatasa/metabolismo , Glucólisis/efectos de los fármacos , Hidrólisis/efectos de los fármacos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Permeabilidad/efectos de los fármacos , Ratas , Ratas Wistar , Silibina , Silimarina/farmacologíaRESUMEN
Although intradialytic parenteral nutrition (IDPN) is a method used widely to combat protein-calorie malnutrition in hemodialysis patients, its effect on survival has not been thoroughly studied. We conducted a prospective, randomized trial in which 186 malnourished hemodialysis patients received oral nutritional supplements with or without 1 year of IDPN. IDPN did not improve 2-year mortality (primary end point), hospitalization rate, Karnofsky score, body mass index, or laboratory markers of nutritional status. Instead, both groups demonstrated improvement in body mass index and the nutritional parameters serum albumin and prealbumin (P < 0.05). Multivariate analysis showed that an increase in prealbumin of >30 mg/L within 3 months, a marker of nutritional improvement, independently predicted a 54% decrease in 2-year mortality, as well as reduced hospitalizations and improved general well-being as measured by the Karnofsky score. Therefore, although we found no definite advantage of adding IDPN to oral nutritional supplementation, this is the first prospective study demonstrating that an improvement in prealbumin during nutritional therapy is associated with a decrease in morbidity and mortality in malnourished hemodialysis patients.