RESUMEN
AIM: Gliomas are primary brain tumours. Gamma-linolenic acid (GLA) exerts anti-proliferative effects. Several ruthenium-containing complexes have antiproliferative effects and can be used as adjuvant therapies in cisplatin-resistant cancer. The present study reports on the anti-proliferative properties and effects on tumour morphology of a novel diruthenium-GLA complex (Ru2GLA) and its comparison with GLA in the C6 rat glioma model both in vitro and in vivo. MATERIALS AND METHODS: In vitro and in vivo experiments were performed on C6 glioma rat cells, and in an orthotopic model. RESULTS: Ru2GLA (100 µM) appears to be an inhibitor of C6 rat glioma cell proliferation. The nuclear area of Ru2GLA-treated cells was 2.18-times larger than that of control cells, suggesting DNA replication occurred but mitosis was blocked in the G2-M phase. Ru2GLA (2 mM) inhibited C6 cell proliferation in vivo and the changes in tumor morphology confirm both cellular uptake and collagen fibre-binding in the extracellular matrix. CONCLUSION: Ru2GLA appears to be a low-toxicity drug and a potential candidate for anti-proliferative therapy of glioma.
Asunto(s)
Glioma/patología , Rutenio/farmacología , Ácido gammalinolénico/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Femenino , Glioma/tratamiento farmacológico , Glioma/ultraestructura , Ratas , Rutenio/administración & dosificación , Carga Tumoral/efectos de los fármacos , Ácido gammalinolénico/administración & dosificaciónRESUMEN
INTRODUCTION: Enteral nutrition (EN) with eicosapentaenoic acid (EPA)/γ-linolenic acid (GLA) is recommended for mechanically ventilated patients with severe lung injury. EPA/GLA has anti-inflammatory benefits, as evidenced by its association with reduction in pulmonary inflammation, improvement in oxygenation and improved clinical outcomes in patients with severe forms of acute lung injury. This study was a prospective, multicenter, randomized, double-blinded, controlled trial designed to investigate whether EPA/GLA could have an effective role in the treatment of patients with early sepsis (systemic inflammatory response syndrome with confirmed or presumed infection and without any organ dysfunction) by reducing the progression of the disease to severe sepsis (sepsis associated with at least one organ failure) or septic shock (sepsis associated with hypotension despite adequate fluid resuscitation). Secondary outcomes included the development of individual organ failure, increased ICU and hospital length of stay, need for mechanical ventilation and 28-day all-cause mortality. METHODS: Randomization was concealed, and patients were allocated to receive, for seven days, either an EPA/GLA diet or an isocaloric, isonitrogenous control diet not enhanced with lipids. Patients were continuously tube-fed at a minimum of 75% of basal energy expenditure × 1.3. To evaluate the progression to severe sepsis and/or septic shock, daily screening for individual organ failure was performed. All clinical outcomes were recorded during a 28-day follow-up period. RESULTS: A total of 115 patients in the early stages of sepsis requiring EN were included, among whom 106 were considered evaluable. Intention-to-treat (ITT) analysis demonstrated that patients fed the EPA/GLA diet developed less severe sepsis and/or septic shock than patients fed the control diet (26.3% versus 50%, respectively; P = 0.0259), with similar results observed for the evaluable patients (26.4% versus 50.9% respectively; P = 0.0217). The ITT analysis demonstrated that patients in the study group developed cardiovascular failure (36.2% versus 21%, respectively; P = 0.0381) and respiratory failure (39.6% versus 24.6%, respectively; P = 0.0362) less often than the control group. Similarly, when considering only the evaluable patients, fewer patients developed cardiovascular failure (20.7% versus 37.7%, respectively; P = 0.03) and respiratory failure (26.4% versus 39.6%, respectively; P = 0.04). The percentage of patients fed the EPA/GLA diet requiring invasive mechanical ventilation was reduced compared with controls (ITT patients: 18.9% versus 33.9%, respectively; P = 0.394; evaluable patients: 17.5% versus 34.5%, respectively; P = 0.295). Patients nourished with the EPA/GLA diet remained in the ICU fewer days than the control population (ITT patients: 21.1 ICU-free days versus 14.7 ICU-free days, respectively; P < 0.0001; evaluable patients: 20.8 ICU-free days versus 14.3 ICU-free days, respectively; P < 0.0001) and fewer days at the hospital (ITT patients: 19.5 hospital-free days versus 10.3 hospital-free days, respectively; P < 0.0001; evaluable patients: 19.1 hospital-free days versus 10.2 hospital-free days, respectively; P < 0.001) (all numbers expressed as means). No significant differences in 28-day all-cause mortality were observed (ITT patients: 26.2% EPA/GLA diet versus 27.6% control diet, respectively; P = 0.72; evaluable: 26.4 EPA/GLA diet versus 30.18 control diet, respectively; P = 0.79). CONCLUSIONS: These data suggest that EPA/GLA may play a beneficial role in the treatment of enterally fed patients in the early stages of sepsis without associated organ dysfunction by contributing to slowing the progression of sepsis-related organ dysfunction, especially with regard to cardiovascular and respiratory dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00981877.
Asunto(s)
Antioxidantes/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Nutrición Enteral/métodos , Sepsis/terapia , Ácido gammalinolénico/administración & dosificación , Anciano , Anciano de 80 o más Años , Antioxidantes/metabolismo , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sepsis/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: This meta-analysis of clinical trials compares an inflammation-modulating diet enriched with eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and elevated antioxidants (EPA + GLA) vs a control diet to determine the effectiveness of this specialized diet on oxygenation and clinical outcomes in mechanically ventilated patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). METHODS: MEDLINE, EMBASE, Cochrane Clinical Trials Register, and the U.S. National Institute of Health Clinical Trials databases were searched. The outcome measures assessed were 28-day in-hospital mortality, 28-day ventilator-free and intensive care unit (ICU)-free days, and the development of new organ failures. An evaluation of oxygenation and ventilatory variables was also performed. Outcomes were analyzed using both fixed-effects and random-effects models. RESULTS: Three randomized controlled studies (n = 411 patients) were included in this meta-analysis. Among the most important findings of this evaluation is a significant reduction in the risk of mortality (odds ratio [OR] = 0.40; 95% confidence interval [CI] = 0.24-0.68; P = .001), with significant reductions in the risk of developing new organ failures (OR = 0.17; 95% CI = 0.08-0.34; P < .0001), time on mechanical ventilation (standardized mean difference [SMD] = 0.56; 95% CI = 0.32-0.79; P < .0001), and ICU stay (SMD = 0.51; 95% CI = 0.27-0.74; P < .0001) in patients who received EPA + GLA. CONCLUSIONS: The meta-analysis showed a significant reduction in the risk of mortality as well as relevant improvements in oxygenation and clinical outcomes of ventilated patients with ALI/ARDS given EPA + GLA.
Asunto(s)
Lesión Pulmonar Aguda/terapia , Ácido Eicosapentaenoico/uso terapéutico , Nutrición Enteral/métodos , Mortalidad Hospitalaria , Insuficiencia Multiorgánica/epidemiología , Síndrome de Dificultad Respiratoria/terapia , Ácido gammalinolénico/uso terapéutico , Lesión Pulmonar Aguda/complicaciones , Lesión Pulmonar Aguda/mortalidad , Intervalos de Confianza , Dieta , Ácido Eicosapentaenoico/administración & dosificación , Humanos , Tiempo de Internación , Insuficiencia Multiorgánica/etiología , Oportunidad Relativa , Intercambio Gaseoso Pulmonar , Ensayos Clínicos Controlados Aleatorios como Asunto , Respiración Artificial , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/mortalidad , Resultado del Tratamiento , Ácido gammalinolénico/administración & dosificaciónAsunto(s)
Ácidos Linoleicos/efectos adversos , Materia Medica/efectos adversos , Parto , Aceites de Plantas/efectos adversos , Plantas Medicinales , Púrpura/inducido químicamente , Ácido gammalinolénico/efectos adversos , Adulto , Bebidas , Femenino , Humanos , Recién Nacido , Ácidos Linoleicos/administración & dosificación , Materia Medica/administración & dosificación , Oenothera biennis , Extractos Vegetales/administración & dosificación , Extractos Vegetales/efectos adversos , Hojas de la Planta , Aceites de Plantas/administración & dosificación , Embarazo , Púrpura/sangre , Ácido gammalinolénico/administración & dosificaciónRESUMEN
OBJECTIVE: To test the efficacy and safety of long-chain polyunsaturated fatty acid (LCPUFA) supplementation with gamma-linolenic acid, a precursor of arachidonic acid, and docosahexaenoic acid in preterm infants. STUDY DESIGN: Preterm (<35 weeks, < or =2000 g birth weight) infants (n=238) randomly assigned to unsupplemented or LCPUFA-supplemented formula to 9 months after term. The main outcome measure was the Bayley Mental and Psychomotor Indexes (MDI, PDI) at 18 months after term. Safety outcome measures were anthropometry (9 and 18 months), feed tolerance, infection, and clinical complications. RESULTS: There were no significant differences in neurodevelopment between groups overall. In preplanned subgroup analyses, LCPUFA-supplemented boys had significantly higher Bayley MDI than did control boys (difference, 5.7 points; 95% CI, 0.3 to 11.1; P=.04). LCPUFA-supplemented infants showed significantly greater weight gain (difference, 310 g; 95% CI, 30 to 590 g; P=.03) and length gain (difference, 1.0 cm; 95% CI, 0.02 to 1.9; P=.05) between birth and 9 months, with greater effect in boys (weight difference at 9 months, 510 g; 95% CI, 80 to 930 g; P=.02; length difference at 18 months, 1.8 cm; 95% CI, 0.1 to 1.8; P=.03). CONCLUSIONS: This trial, using the strategy of providing gamma-linolenic acid as a source of arachidonic acid, showed efficacy for growth and for neurodevelopment in boys, with no adverse effects. These data have important implications for LCPUFA-supplementation strategy in preterm infants.
Asunto(s)
Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Fórmulas Infantiles/química , Recien Nacido Prematuro , Ácido gammalinolénico/administración & dosificación , Estatura/fisiología , Cognición/fisiología , Método Doble Ciego , Femenino , Humanos , Lactante , Fenómenos Fisiológicos Nutricionales del Lactante/fisiología , Recién Nacido , Masculino , Leche Humana , Desempeño Psicomotor/fisiología , Factores Sexuales , Aumento de PesoRESUMEN
Gamma-linolenic acid (GLA) is known to be an inhibitor of Walker 256 tumour growth in vivo and causes changes in both mitochondrial structure and cellular metabolism. The aim of the present study was to investigate in greater detail the changes in energy metabolism and ultrastructure induced by GLA in this tumour model. A diet containing 5.5% GLA, which is sufficient to cause a 45% decrease in tumour growth, was found to almost double the triacylglycerol (TAG) content of the tumour and to increase the quantity of 20:3 n-6, 20:4 n-6, 22:4 n-6 and 22:5 n-6 in the TAG fraction as determined by gas chromatography-mass spectrometry (GCMS) analysis. Morphometric analysis of the tumour by electron microscopy confirmed this increase in TAG content, identifying a doubling of lipid droplet content in the GLA dietary group. The surface density of mitochondrial cristae was reduced, along with a reduction in the number of contact sites (CS) and matrix granules. These three parameters are likely indicators of a reduction in mitochondrial metabolic activity. Measurement of hexokinase activity identified that much of the total hexokinase activity was in the mitochondrially bound form (66.5%) in the control tumour and that GLA caused a decrease in the amount of enzyme in the bound form (39.3%). The fatty acyl chain composition of the tumour mitochondrial subfractions, outer membranes (OM), CSs and inner membranes (IM) was determined by GCMS. All subfractions showed considerable increases in 20:3 n-6 and decreases in 18:1 n-9, 18:2 n-6 and 22:6 n-3, when exposed to GLA diet. These changes were reflected in a large increase in the n-6/n-3 ratio in the GLA OM vs. the control OM, 21.299 vs. 6.747, respectively. The maximal activity of OM carnitine palmitoyltransferase I (CPT I) was found to be decreased by 61.6% in the GLA diet group. This was accompanied by a decrease in malonyl CoA sensitivity and a decrease in affinity for 16:0 CoA substrate. Such changes in CPT I may be the cause of cytoplasmic acyl CoA accumulation seen in this tumour model. These effects, together with previously reported increases in lipid peroxidation, lead to the conclusion that GLA may cause inhibition of tumour cell growth through separate but interlinked pathways, all of which eventually lead to apoptosis and a decrease in tumour development. The influence of mitochondrial OM fatty acyl chain composition upon two important enzymes of energy metabolism, hexokinase and CPT I, both of which have been linked to apoptosis, is of considerable importance for future studies on fatty acid-induced cell death.
Asunto(s)
Carcinoma 256 de Walker/enzimología , Carnitina O-Palmitoiltransferasa/metabolismo , Hexoquinasa/metabolismo , Membranas Intracelulares/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Ácido gammalinolénico/farmacología , Animales , Carcinoma 256 de Walker/ultraestructura , Dieta , Cromatografía de Gases y Espectrometría de Masas , Membranas Intracelulares/enzimología , Masculino , Microscopía Electrónica , Mitocondrias/enzimología , Unión Proteica , Ratas , Ratas Wistar , Ácido gammalinolénico/administración & dosificaciónRESUMEN
The modulating effect of dietary enrichment in mistol seed oil (MO) containing 25% of alpha-linolenic acid (ALA), evening primrose oil (EPO) enriched in gamma-linolenic acid (GLA) and corn oil (CO) as sources of omega-6 and omega-9 fatty acids on the growth parameters of one transplantable mammary tumor were compared. Mice fed on different lipid formulae were inoculated with a mammary gland adenocarcinoma and different growth development tumor parameters were recorded. Results showed that corn oil feeding slowed down most of the tumor growth parameters, as did the EPO diet. MO also showed antitumor activity. Olein feeding, which induces an essential fatty acid deficiency (EFAD), increased the incidence and the multiplicity of metastases when compared with the controls. It may be concluded that a diet enriched in omega-6 fatty acids did not behave as a tumor promoter in this mammary gland tumor model. The antitumor activities of EPO and MO are corroborated in present experiments, suggesting that both oils may be of value in nutritional approaches of mammary gland tumor therapies. In addition, present data add further experimental proof about the proposed protumorigenic proneness induced by the EFAD state.
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Adenocarcinoma/dietoterapia , Adenocarcinoma/metabolismo , Grasas Insaturadas en la Dieta/administración & dosificación , Ácidos Grasos Esenciales/deficiencia , Neoplasias Mamarias Experimentales/dietoterapia , Neoplasias Mamarias Experimentales/metabolismo , Aceites de Plantas/administración & dosificación , Adenocarcinoma/secundario , Animales , Aceite de Maíz/administración & dosificación , Ácidos Grasos Esenciales/administración & dosificación , Femenino , Ácidos Linoleicos , Magnoliopsida , Masculino , Ratones , Ratones Endogámicos BALB C , Oenothera biennis , Rosales , Ácido alfa-Linolénico/administración & dosificación , Ácido gammalinolénico/administración & dosificaciónRESUMEN
We have studied the effect of a gamma-linolenic acid (18:3 n-6, GLA)-supplemented diet on the growth of a human lung mucoepidermoid carcinoma (HLMC) implanted in athymic mice and on its uptake of human low density lipoproteins labeled with 99mTc (99mTc-LDL). Mice bearing the HLMC were divided into two experimental groups. One of them was administered a control diet (C diet) and the other one was given a diet supplemented with 25 mg GLA/g pellet (GLA diet) for three weeks (Table 1). A tumor growth inhibition with the GLA diet was evident at the second week of treatment, and a marked inhibition (56%) was reached at the end of the third week (Fig. 1). The GLA diet produced some changes in the total fatty acid composition of tumor, plasma and liver of host mice: GLA and arachidonic acid (20:4 n-6, AA) induced significant increases, whereas oleic (18:1 n-9, OA) and linoleic acids (18:2 n-6, LA) were decreased (Table 2). Tumors of those animals fed both diets were labeled by 99mTc-LDL, and no difference was observed in the ratio of tumor/liver and tumor/kidney uptake of host animal (Table 3). Results obtained using this experimental model suggest that the inhibitory effect of GLA on tumor growth is not related to the LDL tumor uptake.
Asunto(s)
Carcinoma Mucoepidermoide/patología , Dieta , Alimentos Fortificados , Lipoproteínas LDL/sangre , Neoplasias Pulmonares/patología , Ácido gammalinolénico/administración & dosificación , Análisis de Varianza , Animales , Ácidos Grasos/química , Femenino , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Compuestos de OrganotecnecioRESUMEN
Se estudió el efecto de una dieta suplementada con ácido gama-linolénico (18:3 n-6, GLA) sobre el crecimiento de un tumor mucoepidermoide de pulmón humano (HLMC) implantado en ratones atímicos y sobre la captación por el mismo de lipoproteínas de baja densidad humana marcadas con 99mTc (99mTc-LDL). Los ratones portadores de HLMC se dividieron en dos grupos experimentales, uno que recibió dieta control (dieta C) y el otro, dieta suplementada con GLA (dieta GLA), durante tres semanas. Se observó una marcada inhibición del crecimiento tumoral al finalizar el tratamiento. La dieta enriquecida en GLA indujo cambios en la composición en ácidos grasos totales del tumor y del plasma e hígado de los ratones huéspedes. Los tumores de los animales alimentados con ambas dietas captaron radiactividad de las 99mTc-LDL y no se observaron diferencias significativas en la relación entre la captación por el tumor y por el hígado y riñón de los animales huéspedes. Los resultados obtenidos utilizando este modelo experimental sugieren que el efecto inhibitorio del GLA sobre el crecimiento tumoral es independiente de la captación de LDL por parte del tumor.(AU)
Asunto(s)
Humanos , Femenino , Ratones , Animales , Neoplasias Pulmonares/patología , Carcinoma Mucoepidermoide/patología , Dieta , Alimentos Fortificados , Ácido gammalinolénico/administración & dosificación , Lipoproteínas LDL/sangre , Trasplante de Neoplasias , Ácidos Grasos/química , Ratones Desnudos , Análisis de Varianza , Lipoproteínas LDL , Compuestos de OrganotecnecioRESUMEN
Se estudió el efecto de una dieta suplementada con ácido gama-linolénico (18:3 n-6, GLA) sobre el crecimiento de un tumor mucoepidermoide de pulmón humano (HLMC) implantado en ratones atímicos y sobre la captación por el mismo de lipoproteínas de baja densidad humana marcadas con 99mTc (99mTc-LDL). Los ratones portadores de HLMC se dividieron en dos grupos experimentales, uno que recibió dieta control (dieta C) y el otro, dieta suplementada con GLA (dieta GLA), durante tres semanas. Se observó una marcada inhibición del crecimiento tumoral al finalizar el tratamiento. La dieta enriquecida en GLA indujo cambios en la composición en ácidos grasos totales del tumor y del plasma e hígado de los ratones huéspedes. Los tumores de los animales alimentados con ambas dietas captaron radiactividad de las 99mTc-LDL y no se observaron diferencias significativas en la relación entre la captación por el tumor y por el hígado y riñón de los animales huéspedes. Los resultados obtenidos utilizando este modelo experimental sugieren que el efecto inhibitorio del GLA sobre el crecimiento tumoral es independiente de la captación de LDL por parte del tumor.
Asunto(s)
Humanos , Femenino , Ratones , Animales , Ácido gammalinolénico/administración & dosificación , Carcinoma Mucoepidermoide/patología , Dieta , Alimentos Fortificados , Lipoproteínas LDL/sangre , Neoplasias Pulmonares/patología , Ácidos Grasos/química , Análisis de Varianza , Lipoproteínas LDL , Ratones Desnudos , Trasplante de Neoplasias , Compuestos de OrganotecnecioRESUMEN
The effects of an intravenously administered lipid emulsion supplemented with gamma-linolenic acid on the fatty acid profile of premature infants were compared with those of two conventional lipid emulsions. Fifty-nine premature neonates receiving total parenteral nutrition were randomly assigned to receive either fat emulsion containing gamma-linolenic acid and long-chain triglycerides (LCT), an LCT emulsion, or a 50% (wt/wt) mixture of medium-chain triglycerides and LCT emulsion. Forty-nine infants completed the study. During the 6-day study there was a significant tenfold increase in the plasma levels of gamma-linoleic acid in the supplemented group versus the other two groups. A significant threefold to fivefold increase in the omega 6 long-chain polyunsaturated fatty acids was observed in all groups. These changes seemed to be attributable mostly to linoleic acid from the lipid emulsion, despite the 50% lower dose in the medium- and long-chain triglycerides group. The increase in the omega 3 long-chain polyunsaturated fatty acids also was mainly caused by a similar increase in the level of alpha-linolenic acid. No differences were recorded in the linoleic/alpha-linolenic acid ratio among the groups. Plasma levels of some of the semiessential fatty acids were significantly higher in the medium- and long-chain triglycerides group than in the LCT group. This may be related to slower elimination of LCT, to the difference between emulsions, or to less substrate inhibition on delta-6-desaturase, which seems to be less of a rate-limiting enzyme than previously considered. Further intravenous feeding trials are needed to identify the optimal balance of fatty acids for nutrition of these premature infants.
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Emulsiones Grasas Intravenosas/farmacología , Ácidos Grasos Insaturados/sangre , Recien Nacido Prematuro/sangre , Método Doble Ciego , Emulsiones Grasas Intravenosas/administración & dosificación , Emulsiones Grasas Intravenosas/química , Ácidos Grasos Esenciales/administración & dosificación , Ácidos Grasos Esenciales/sangre , Ácidos Grasos Omega-3/sangre , Humanos , Recién Nacido , Nutrición Parenteral Total , Triglicéridos/administración & dosificación , Ácido gammalinolénico/administración & dosificación , Ácido gammalinolénico/sangreRESUMEN
The effects of a dietary alphalinolenic acid (18: 3w3) deficiency on reproduction and post natal growth in rats during 3 successive generations were studied. Female rats received respectively a diet with sunflower oil at 10% (deficient diet) or a diet with soya oil at 10% (control diet). The results showed that in our experimental conditions deficient diet affects: fecundity, fertility, post natal growth and cause a high rates of perinatal mortality from birth to post partum day 3: Perinatal mortality increased with successive gestation from 14.6% to 18.6% compared with the survival of control. The fatty acid composition of placenta phospholipids and milk lipids reflected the nature of the dietary oil. The possibility that 18: 3w3 might function in a way different from the EFA role of 18: 2w6 in reproduction at least in rats has been discussed.
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Dieta , Crecimiento , Reproducción , Ácido alfa-Linolénico/administración & dosificación , Animales , Femenino , Masculino , Leche/química , Placenta/química , Ratas , Ratas Wistar , Ácido alfa-Linolénico/análisis , Ácido gammalinolénico/administración & dosificación , Ácido gammalinolénico/análisisRESUMEN
The effects of a dietary alphalinolenic acid (18: 3w3) deficiency on reproduction and post natal growth in rats during 3 successive generations were studied. Female rats received respectively a diet with sunflower oil at 10 (deficient diet) or a diet with soya oil at 10 (control diet). The results showed that in our experimental conditions deficient diet affects: fecundity, fertility, post natal growth and cause a high rates of perinatal mortality from birth to post partum day 3: Perinatal mortality increased with successive gestation from 14.6 to 18.6 compared with the survival of control. The fatty acid composition of placenta phospholipids and milk lipids reflected the nature of the dietary oil. The possibility that 18: 3w3 might function in a way different from the EFA role of 18: 2w6 in reproduction at least in rats has been discussed.