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1.
Crit Care ; 18(5): 466, 2014 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-25189175

RESUMO

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.


Assuntos
Hidratação , Ressuscitação , Dengue Grave/terapia , Lactato de Sódio/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Hidratação/métodos , Humanos , Indonésia , Soluções Isotônicas/uso terapêutico , Masculino , Estudos Prospectivos , Lactato de Ringer , Método Simples-Cego , Resultado do Tratamento , Molécula 1 de Adesão de Célula Vascular/sangue
2.
Intensive Care Med Exp ; 2(1): 19, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26266919

RESUMO

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.

3.
Intensive Care Med ; 39(8): 1413-22, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23749153

RESUMO

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.


Assuntos
Lesões Encefálicas/complicações , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/prevenção & controle , Lactato de Sódio/administração & dosagem , Adolescente , Adulto , Idoso , Líquidos Corporais , Lesões Encefálicas/metabolismo , Cloretos/metabolismo , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Escala de Gravidade do Ferimento , Hipertensão Intracraniana/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sódio/metabolismo , Adulto Jovem
4.
Free Radic Biol Med ; 52(1): 142-50, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22064362

RESUMO

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.


Assuntos
Glucose/efeitos adversos , Células Secretoras de Insulina/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxidos/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Aconitato Hidratase/metabolismo , Monofosfato de Adenosina/metabolismo , Linhagem Celular , Dicarbetoxi-Di-Hidrocolidina/análogos & derivados , Dicarbetoxi-Di-Hidrocolidina/análise , Relação Dose-Resposta a Droga , Complexo I de Transporte de Elétrons/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/enzimologia , Metaloporfirinas/farmacologia , Metacrilatos/farmacologia , Mitocôndrias/enzimologia , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Rotenona/análogos & derivados , Rotenona/farmacologia , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/metabolismo , Superóxidos/análise , Superóxidos/antagonistas & inibidores , Tiazóis/farmacologia
5.
J Hepatol ; 54(2): 348-56, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21109325

RESUMO

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.


Assuntos
Gorduras na Dieta/administração & dosagem , Metabolismo Energético , Fígado/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Composição Corporal , Transporte de Elétrons , Hepatócitos/metabolismo , Lipídeos/análise , Fígado/química , Masculino , Potencial da Membrana Mitocondrial , Mitocôndrias Hepáticas/química , Fosforilação Oxidativa , Ratos , Ratos Wistar , Transcrição Gênica
6.
Acta Biochim Pol ; 57(4): 389-92, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21079817

RESUMO

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.


Assuntos
Resistência à Insulina , Mitocôndrias Hepáticas/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Modelos Biológicos
7.
J Biol Chem ; 284(7): 4308-16, 2009 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-19049970

RESUMO

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.


Assuntos
Ácidos Graxos/metabolismo , Glicerolfosfato Desidrogenase/metabolismo , Hepatócitos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Obesidade , Receptores dos Hormônios Tireóideos/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Gluconeogênese/fisiologia , Glicerol/metabolismo , Glicerofosfatos/metabolismo , Masculino , Transportadores de Ácidos Monocarboxílicos , NAD/metabolismo , Oxirredução , Ratos , Ratos Wistar , Especificidade da Espécie
8.
Intensive Care Med ; 34(10): 1796-803, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18563389

RESUMO

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.


Assuntos
Ponte de Artéria Coronária , Hidratação/métodos , Soluções Hipertônicas/uso terapêutico , Soluções Isotônicas/uso terapêutico , Cuidados Pós-Operatórios/métodos , Lactato de Sódio/uso terapêutico , Débito Cardíaco , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Lactato de Ringer , Lactato de Sódio/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia
9.
Curr Opin Clin Nutr Metab Care ; 11(2): 147-51, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18301090

RESUMO

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.


Assuntos
Necessidades Nutricionais , Apoio Nutricional/métodos , Insuficiência Renal/terapia , Terapia de Substituição Renal/métodos , Cuidados Críticos , Estado Terminal , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/metabolismo , Humanos , Estado Nutricional , Resultado do Tratamento
11.
Cell Physiol Biochem ; 20(6): 925-34, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17982275

RESUMO

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.


Assuntos
Flavonoides/farmacologia , Glucose-6-Fosfatase/antagonistas & inibidores , Glucose-6-Fosfato/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Perfusão , Animais , Di-Hidroxiacetona/farmacologia , Relação Dose-Resposta a Droga , Glucagon/farmacologia , Gluconeogênese/efeitos dos fármacos , Glucose-6-Fosfatase/metabolismo , Glicólise/efeitos dos fármacos , Hidrólise/efeitos dos fármacos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , Silibina , Silimarina/farmacologia
12.
Crit Care Med ; 35(9 Suppl): S454-60, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17713393

RESUMO

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.


Assuntos
Mitocôndrias/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Sepse/metabolismo , Trifosfato de Adenosina/biossíntese , Complexo I de Transporte de Elétrons/metabolismo , Metabolismo Energético , Humanos , Insuficiência de Múltiplos Órgãos/fisiopatologia , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Sepse/fisiopatologia
13.
J Am Soc Nephrol ; 18(9): 2583-91, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17656473

RESUMO

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.


Assuntos
Nutrição Parenteral , Desnutrição Proteico-Calórica/mortalidade , Desnutrição Proteico-Calórica/terapia , Diálise Renal/efeitos adversos , Idoso , Índice de Massa Corporal , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Avaliação de Estado de Karnofsky , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Pré-Albumina/metabolismo , Desnutrição Proteico-Calórica/etiologia , Desnutrição Proteico-Calórica/fisiopatologia , Albumina Sérica/metabolismo , Análise de Sobrevida
14.
Intensive Care Med ; 33(6): 1094-101, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17458540

RESUMO

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.


Assuntos
Gluconeogênese/efeitos dos fármacos , Fígado/metabolismo , Óxido Nítrico Sintase/metabolismo , Choque Séptico/metabolismo , Animais , Modelos Animais de Doenças , Glucose-6-Fosfatase , Fluxometria por Laser-Doppler , Masculino , Camundongos , Estudos Prospectivos , Distribuição Aleatória
15.
Contrib Nephrol ; 156: 112-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17464120

RESUMO

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.


Assuntos
Injúria Renal Aguda/terapia , Estado Terminal/terapia , Terapia Nutricional/métodos , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Metabolismo dos Carboidratos/fisiologia , Humanos , Rim/metabolismo , Rim/fisiopatologia , Prognóstico , Terapia de Substituição Renal , Índice de Gravidade de Doença
16.
Intensive Care Med ; 33(4): 694-702, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17237934

RESUMO

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.


Assuntos
Apoptose , Dano ao DNA , Gliadina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Animais , Ensaio Cometa , Cucumis melo , Feminino , Oxigenoterapia Hiperbárica/efeitos adversos , Marcação In Situ das Extremidades Cortadas , Masculino , Traumatismo por Reperfusão/etiologia , Suínos
17.
J Bioenerg Biomembr ; 38(1): 33-42, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16732470

RESUMO

Mitochondrial reactive oxygen species (ROS) production was investigated in mitochondria extracted from liver of rats treated with or without metformin, a mild inhibitor of respiratory chain complex 1 used in type 2 diabetes. A high rate of ROS production, fully suppressed by rotenone, was evidenced in non-phosphorylating mitochondria in the presence of succinate as a single complex 2 substrate. This ROS production was substantially lowered by metformin pretreatment and by any decrease in membrane potential (Delta Phi(m)), redox potential (NADH/NAD), or phosphate potential, as induced by malonate, 2,4-dinitrophenol, or ATP synthesis, respectively. ROS production in the presence of glutamate-malate plus succinate was lower than in the presence of succinate alone, but higher than in the presence of glutamate-malate. Moreover, while rotenone both increased and decreased ROS production at complex 1 depending on forward (glutamate-malate) or reverse (succinate) electron flux, no ROS overproduction was evidenced in the forward direction with metformin. Therefore, we propose that reverse electron flux through complex 1 is an alternative pathway, which leads to a specific metformin-sensitive ROS production.


Assuntos
Complexo I de Transporte de Elétrons/fisiologia , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Mitocôndrias Hepáticas/fisiologia , Espécies Reativas de Oxigênio/metabolismo , 2,4-Dinitrofenol/farmacologia , Trifosfato de Adenosina/biossíntese , Animais , Transporte de Elétrons , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Ácido Glutâmico/farmacologia , Técnicas In Vitro , Malatos/farmacologia , Malonatos/farmacologia , Potenciais da Membrana , Mitocôndrias Hepáticas/efeitos dos fármacos , Oxirredução , Fosforilação , Ratos , Ratos Wistar , Rotenona/farmacologia , Ácido Succínico/farmacologia
18.
Br J Nutr ; 95(1): 152-9, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16441928

RESUMO

Lipid, oxidative and inflammatory parameters are frequently altered in dialysis patients and may be worsened by intravenous lipid emulsions (ILE). We assessed the efficacy and tolerance of olive as compared with standard soybean oil-based ILE during intradialytic parenteral nutrition (IDPN). IDPN mixtures containing amino acids, glucose, and either olive oil (OO group, n 17) or soybean oil-based ILE (SO group, n 18) were administered in a 5-week randomized, double-blind study. On days 0 and 35, patients' nutritional status was assessed by BMI, normalized protein catabolic rate, predialytic creatinine, serum albumin and transthyretin; lipid metabolism by plasma LDL- and HDL-cholesterol, triacylglycerols, phospholipids, apo A-I, A-II, B, C-II, C-III, E and lipoprotein (a); oxidative status by alpha-tocopherol, retinol, selenium, glutathione peroxidase, malondialdehyde and advanced oxidized protein products; inflammatory status by serum C-reactive protein, orosomucoid, IL-2 and IL-6. No serious adverse event was observed. Significant changes were observed from day 0 to day 35 (P<0.05): nutritional criteria improved (albumin in OO; albumin, transthyretin and creatinine in SO); LDL-cholesterol, apo B, C-II, C-III and apo A-I/A-II ratio increased in both groups. HDL-cholesterol decreased in OO; apo E increased and lipoprotein (a) decreased in SO; alpha-tocopherol/cholesterol ratio increased in OO; malondialdehyde decreased in both groups; IL-2 increased in both groups. The between-group comparison only showed the following differences: alpha-tocopherol/cholesterol increased in OO; lipoprotein (a) decreased in SO. From these data, it was concluded that OO- and SO-based IDPNs similarly improved nutritional status and influenced plasma lipid, oxidative, inflammatory and immune parameters.


Assuntos
Emulsões Gordurosas Intravenosas/administração & dosagem , Nutrição Parenteral/métodos , Óleos de Plantas/administração & dosagem , Óleo de Soja/administração & dosagem , Idoso , Colesterol/sangue , Gorduras Insaturadas na Dieta/administração & dosagem , Método Duplo-Cego , Emulsões Gordurosas Intravenosas/química , Feminino , Humanos , Masculino , Distúrbios Nutricionais/imunologia , Distúrbios Nutricionais/terapia , Azeite de Oliva , Estresse Oxidativo , Nutrição Parenteral/efeitos adversos , Fosfolipídeos/sangue , Estudos Prospectivos , Diálise Renal , Triglicerídeos/sangue
19.
J Nutr ; 136(1 Suppl): 299S-307S, 2006 01.
Artigo em Inglês | MEDLINE | ID: mdl-16365103

RESUMO

During renal failure, abnormalities of BCAA and branched-chain keto acid (BCKA) metabolism are due to both the lack of renal contribution to amino acid metabolism and the impact of renal failure and acidosis on whole-body nitrogen metabolism. Abnormal BCAA and BCKA metabolism result in BCAA depletion as reflected by low plasma BCAAs and cellular valine. BCAA metabolic disturbances can alter tissue activities, particularly brain function, and nutritional status. In dialysis patients, BCAA oral supplementation can induce an improvement of appetite and nutritional status. During chronic renal failure, the aims of nutritional interventions are to minimize uremic toxicity, avoid malnutrition and delay progression of kidney disease. BCAA and BCKA supplements have been proposed to decrease further protein intake while maintaining satisfactory nutritional status. In this setting, BCAAs or BCKAs have not been administrated solely but in association with other essential AA or keto analogs. Therefore, the proper effects of BCAAs and/or BCKAs have not been studied separately. Protein restriction together with keto acids and/or essential AAs has been reported to improve insulin sensitivity and hyperparathyroidism and to be compatible with a preservation of nutritional status. Nonetheless, a careful monitoring of protein-calorie intake and nutritional status is needed. A recent meta-analysis concluded that reducing protein intake in patients with chronic renal failure reduces the occurrence of renal death by approximately 40% as compared with larger or unrestricted protein intake. The additional effect of essential amino acids and keto acids on retardation of progression of renal failure has not been demonstrated.


Assuntos
Aminoácidos de Cadeia Ramificada/administração & dosagem , Insuficiência Renal/terapia , Aminoácidos de Cadeia Ramificada/metabolismo , Proteínas Alimentares/administração & dosagem , Suplementos Nutricionais , Humanos , Cetoácidos/administração & dosagem , Cetoácidos/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Diálise Renal
20.
Crit Care ; 9(6): 622-3, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16356247

RESUMO

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.


Assuntos
Cuidados Críticos/métodos , Ácido Láctico/sangue , Desequilíbrio Ácido-Base/sangue , Biomarcadores/sangue , Metabolismo Energético , Humanos , Consumo de Oxigênio
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