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1.
Biochimie ; 159: 55-58, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30179647

RESUMEN

The double lipoxygenation of polyunsaturated fatty acids (PUFA) is possible with PUFA having at least three methylene-interrupted double bonds. Several PUFA of the omega-3/n-3 and -6 families may be converted through this route, and the products show interesting inhibitory effects on blood platelet function and cyclooxygenase activities. This review focuses on two main omega-3 PUFA of nutritional interest, namely docosahexaenoic acid (DHA/22:6n-3) and alpha linolenic acid (ALA/18:3n-3). The chemical configuration of the double lipoxygenase end-product from DHA (protectin DX) is compared with that of protectin D1 which is produced through a mono-lipoxygenation step followed by an epoxidation and epoxide hydrolysis process. The different metabolic pathways are discussed as well as the different biological activities of both protectins.


Asunto(s)
Vasos Sanguíneos/metabolismo , Encéfalo/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Lipooxigenasas/metabolismo , Ácido alfa-Linolénico/metabolismo , Humanos
2.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(6): 651-656, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29555597

RESUMEN

The oxygenation metabolism of arachidonic acid (ArA) has been early described in blood platelets, in particular with its conversion into the potent labile thromboxane A2 that induces platelet aggregation and vascular smooth muscle cells contraction. In addition, the primary prostaglandins D2 and E2 have been mainly reported as inhibitors of platelet function. The platelet 12-lipoxygenase (12-LOX) product, i.e. the hydroperoxide 12-HpETE, appears to stimulate platelet ArA metabolism at the level of its release from membrane phospholipids through phospholipase A2 (cPLA2) and cyclooxygenase (COX-1) activities, the first enzymes in prostanoid production cascade. Also, 12-HpETE may regulate the oxygenation of other polyunsaturated fatty acids (PUFA) by platelets, especially that of eicosapentaenoic acid (EPA). On the other hand, the reduced product of 12-HpETE, 12-HETE, is able to antagonize TxA2 action. This is even more obvious for the 12-LOX end-products from docosahexaenoic acid (DHA), 11- and 14-HDoHE. In addition, 12-HpETE plays a key role in platelet oxidative stress as observed in pathophysiological conditions, but may be regulated by DHA with a bimodal way according to its concentration. Other oxygenated products of PUFA, especially omega-3 PUFA, produced outside platelets may affect platelet functions as well.


Asunto(s)
Plaquetas/metabolismo , Ácidos Grasos Insaturados/metabolismo , Estrés Oxidativo/fisiología , Animales , Araquidonato 12-Lipooxigenasa/genética , Araquidonato 12-Lipooxigenasa/metabolismo , Plaquetas/citología , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Ácidos Grasos Insaturados/genética , Humanos , Oxidación-Reducción
3.
Artículo en Inglés | MEDLINE | ID: mdl-27514724

RESUMEN

Docosahexaenoic acid (DHA) is a prominent nutrient of marine lipids. Together with eicosapentaenoic acid, it is recognized as a protective molecule against atherosclerosis and thrombosis through the regulation of blood cell functions, especially platelets. Its high unsaturation index may however make it prone to peroxidation, which is usually considered as deleterious. This short review takes into consideration this possibility related to DHA concentrations both in vitro and in vivo. It is suggested that protective effects of DHA on platelet activation depend on the reduction of oxidative stress, and appear bimodal with the abolishment of such a protection when DHA is used at relatively high concentrations.

4.
Artículo en Inglés | MEDLINE | ID: mdl-27914512

RESUMEN

Patients with cystic fibrosis have increased oxidative stress and impaired antioxidant systems. Moderate intake of docosahexaenoic acid (DHA) may favor the lowering of oxidative stress. In this randomized, double-blind, cross-over study, DHA or placebo capsules, were given daily to 10 patients, 5mg/kg for 2 weeks then 10mg/kg DHA for the next 2 weeks (or placebo). After 9 weeks of wash-out, patients took placebo or DHA capsules. Biomarkers of lipid peroxidation and vitamin E were measured at baseline, and after 2 and 4 weeks of treatment in each phase. The proportions of DHA increased both in plasma and platelet lipids after DHA supplementations. The lipid peroxidation markers did not significantly decrease, in spite of a trend, after the first and/or the second dose of DHA but plasma and platelet vitamin E amounts increased significantly after DHA supplementation. Our findings reinforce the antioxidant potential of moderate DHA intake in subjects displaying increased oxidative stress.


Asunto(s)
Plaquetas/metabolismo , Fibrosis Quística/sangre , Ácidos Docosahexaenoicos/administración & dosificación , Vitamina E/sangre , Adolescente , Adulto , Niño , Estudios Cruzados , Ácidos Docosahexaenoicos/farmacología , Método Doble Ciego , Esquema de Medicación , Humanos , Peroxidación de Lípido , Masculino , Estrés Oxidativo/genética , Adulto Joven
5.
Artículo en Inglés | MEDLINE | ID: mdl-27154358

RESUMEN

Docosahexaenoic acid (DHA) is a prominent nutrient of marine lipids. Together with eicosapentaenoic acid, it is recognized as a protective molecule against atherosclerosis and thrombosis through the regulation of blood cell functions, especially platelets. Its high unsaturation index may however make it prone to peroxidation, which is usually considered as deleterious. This short review takes into consideration this possibility related to DHA concentrations both in vitro and in vivo. It is suggested that protective effects of DHA on platelet activation depend on the reduction of oxidative stress, and appear bimodal with the abolishment of such a protection when DHA is used at relatively high concentrations.

6.
Gut ; 65(1): 144-54, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25516417

RESUMEN

OBJECTIVE: Inflammation and oxidative stress drive disease progression in chronic hepatitis C (CHC) towards hepatocellular carcinoma. HCV is known to increase intracellular levels of reactive oxygen species (ROS), but how it eliminates ROS is less well known. The role of the ROS scavenger glutathione peroxidase 4 (GPx4), induced by HCV, in the viral life cycle was analysed. DESIGN: The study was performed using a replicative in vitro HCV infection model and liver biopsies derived from two different CHC patient cohorts. RESULTS: A screen for HCV-induced peroxide scavengers identified GPx4 as a host factor required for HCV infection. The physiological role of GPx4 is the elimination of lipid peroxides from membranes or lipoproteins. GPx4-silencing reduced the specific infectivity of HCV by up to 10-fold. Loss of infectivity correlated with 70% reduced fusogenic activity of virions in liposome fusion assays. NS5A was identified as the protein that mediates GPx4 induction in a phosphatidylinositol-3-kinase-dependent manner. Levels of GPx4 mRNA were found increased in vitro and in CHC compared with control liver biopsies. Upon successful viral eradication, GPx4 transcript levels returned to baseline in vitro and also in the liver of patients. CONCLUSIONS: HCV induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. Modulating oxidative stress in CHC by specifically targeting GPx4 may lower specific infectivity of virions and prevent hepatocarcinogenesis, especially in patients who remain difficult to be treated in the new era of interferon-free regimens.


Asunto(s)
Glutatión Peroxidasa/metabolismo , Hepacivirus/patogenicidad , Hepatitis C Crónica/virología , Peroxidación de Lípido , Hígado/virología , Virión/patogenicidad , Adulto , Biomarcadores , Biopsia , Estudios de Casos y Controles , Línea Celular , Femenino , Cromatografía de Gases y Espectrometría de Masas , Hepacivirus/metabolismo , Hepatitis C Crónica/enzimología , Hepatitis C Crónica/patología , Humanos , Hígado/enzimología , Hígado/patología , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Especies Reactivas de Oxígeno/metabolismo , Virión/metabolismo
7.
J Clin Endocrinol Metab ; 100(5): 2006-14, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25794249

RESUMEN

CONTEXT: High-density lipoproteins (HDL) possess atheroprotective properties including anti-thrombotic and antioxidant effects. Very few studies relate to the functional effects of oxidized HDL on platelets in type 2 diabetes (T2D). OBJECTIVE: The objective of our study was to investigate the effects of in vitro glycoxidized HDL and HDL from patients with T2D on platelet aggregation and arachidonic acid signaling cascade. At the same time, the contents of hydroxylated fatty acids were assessed in HDL. RESULTS: Compared with control HDL, in vitro glycoxidized HDL had decreased proportions of linoleic (LA) and arachidonic (AA) acids in phospholipids and cholesteryl esters, and increased concentrations of hydroxy-octadecadienoic acids (9-HODE and 13-HODE) and 15-hydroxy-eicosatetraenoic acid (15-HETE), derived from LA and AA respectively, especially hydroxy derivatives esterified in phospholipids. Glycoxidized HDL dose-dependently decreased collagen-induced platelet aggregation by binding to scavenger receptor BI (SR-BI). Glycoxidized HDL prevented collagen-induced increased phosphorylation of platelet p38 MAPK and cytosolic phospholipase A2, as well as intracellular calcium mobilization. HDL enriched with oxidized phosphatidylcholine (PC), namely PC(16:0/13-HODE) dose-dependently inhibited platelet aggregation. Increased concentrations of 9-HODE, 13-HODE, and 15-HETE in phospholipids (2.1-, 2.1-, and 2.4-fold increase, respectively) were found in HDL from patients with T2D, and these HDL also inhibited platelet aggregation via SR-BI. CONCLUSIONS: Our results suggest that in vitro glycoxidized HDL as well as HDL from patients with T2D inhibit platelet aggregation, and suggest that oxidized LA-containing phospholipids may contribute to the anti-aggregatory effects of glycoxidized HDL and HDL from patients with T2D.


Asunto(s)
Plaquetas/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Lipoproteínas HDL/farmacología , Fosfolípidos/farmacología , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Adulto , Anciano , Plaquetas/metabolismo , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal/efectos de los fármacos , Adulto Joven , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
8.
Biochim Biophys Acta ; 1851(4): 485-95, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25263947

RESUMEN

Numerous epidemiological studies and clinical trials have reported the health benefits of omega-3 polyunsaturated fatty acids (PUFA), including a lower risk of coronary heart diseases. This review mainly focuses on the effects of alpha-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on some risk factors associated with atherothrombosis, including platelet activation, plasma lipid concentrations and oxidative modification of low-density lipoproteins (LDL). Special focus is given to the effects of marine PUFA on the formation of eicosanoids and docosanoids, and to the bioactive properties of some oxygenated metabolites of omega-3 PUFA produced by cyclooxygenases and lipoxygenases. The antioxidant effects of marine omega-3 PUFA at low concentrations and the pro-oxidant effects of DHA at high concentrations on the redox status of platelets and LDL are highlighted. Non enzymatic peroxidation end-products deriving from omega-3 PUFA such as hydroxy-hexenals, neuroketals and EPA-derived isoprostanes are also considered in relation to atherosclerosis. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Fármacos Cardiovasculares/uso terapéutico , Ácidos Grasos Omega-3/uso terapéutico , Trombosis/tratamiento farmacológico , Animales , Aterosclerosis/epidemiología , Aterosclerosis/metabolismo , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/metabolismo , Ácidos Docosahexaenoicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Ácido Eicosapentaenoico/uso terapéutico , Ácidos Grasos Omega-3/efectos adversos , Ácidos Grasos Omega-3/metabolismo , Humanos , Oxidación-Reducción , Medición de Riesgo , Factores de Riesgo , Trombosis/epidemiología , Trombosis/metabolismo , Resultado del Tratamiento , Ácido alfa-Linolénico/uso terapéutico
9.
Biochimie ; 107 Pt A: 91-4, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25223888

RESUMEN

More and more attention is paid to omega-3 fatty acids because of their potential activities in preventing cardiovascular events. In this brief review, we focus on the lipoxygenase end-metabolites of two relevant nutrients belonging to the omega-3 family fatty acids: alpha-linolenic and docosahexaenoic acids, the latter being a prominent component of brain lipids. Dihydroxylated derivatives are described as well as their inhibitory effects on platelet aggregation and cyclooxygenase activities. We point out that only the dihydroxylated products with the trans,cis,trans/E,Z,E conjugated triene geometry exhibit those inhibitory activities. These properties being found with other polyunsaturated fatty acid oxygenated products sharing the same E,Z,E molecular motif, they have been collectively named poxytrins. From alpha-linolenic and docosahexaenoic acids, poxytrins are linotrins and protectin DX, respectively.


Asunto(s)
Ácidos Docosahexaenoicos/química , Ácidos Grasos Omega-3/química , Ácidos Grasos Insaturados/química , Ácido alfa-Linolénico/química , Dioxigenasas/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Insaturados/metabolismo , Humanos , Estructura Molecular , Agregación Plaquetaria/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Ácido alfa-Linolénico/metabolismo , Ácido alfa-Linolénico/farmacología
10.
Proc Nutr Soc ; 73(2): 186-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24172820

RESUMEN

DHA is an abundant nutrient from marine lipids: its specific biological effects have been investigated in human volunteers, taking into consideration the dose effects. We report herein that, at dosages below 1 g/d, DHA proved to be effective in lowering blood platelet function and exhibited an 'antioxidant' effect. However, this was no longer the case following 1.6 g/d, showing then a U-shape response. The antioxidant effect has been observed in platelets as well as LDL, of which the redox status is assumed to be crucial in their relationship with atherosclerosis. Second, the oxygenated products of DHA, especially protectins produced by lipoxygenases, have been considered for their potential to affect blood platelets and leucocytes. It is concluded that DHA is an interesting nutrient to reduce atherothrombogenesis, possibly through complementary mechanisms involving lipoxygenase products of DHA.


Asunto(s)
Antioxidantes/metabolismo , Aterosclerosis/prevención & control , Antígenos CD59/sangre , Grasas de la Dieta/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Lipooxigenasas/sangre , Trombosis/prevención & control , Aterosclerosis/sangre , Aterosclerosis/etiología , Plaquetas/efectos de los fármacos , Antígenos CD59/biosíntesis , LDL-Colesterol/sangre , Dieta , Grasas de la Dieta/sangre , Grasas de la Dieta/farmacología , Ácidos Docosahexaenoicos/sangre , Ácidos Docosahexaenoicos/farmacología , Humanos , Leucocitos , Trombosis/sangre
11.
Mol Nutr Food Res ; 57(8): 1347-58, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23818385

RESUMEN

Polyunsaturated fatty acids in mammals may be oxygenated into a myriad of bioactive products through di- and monooxygenases, products that are rapidly degraded to control their action. To evaluate the phenotypes of biological systems regarding this wide family of compounds, a lipidomics approach in function of time and compartments would be relevant. The current review takes into consideration most of the diverse oxygenated metabolites of essential fatty acids at large and their immediate degradation products. Their biological function and life span are considered. Overall, this is a fluxolipidomics approach that is emerging.


Asunto(s)
Ácidos Grasos Esenciales/metabolismo , Ácidos Grasos Insaturados/metabolismo , Ácido Araquidónico/metabolismo , Disponibilidad Biológica , Endocannabinoides/metabolismo , Ácidos Grasos Insaturados/farmacocinética , Humanos , Ácido Linoleico/metabolismo , Peroxidación de Lípido , Oxígeno/metabolismo , Ácido alfa-Linolénico/metabolismo
12.
J Lipid Res ; 54(8): 2083-2094, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23740966

RESUMEN

We have recently described a di-hydroxylated compound called protectin DX (PDX) which derives from docosahexaenoic acid (DHA) by double lipoxygenation. PDX exhibits anti-aggregatory and anti-inflammatory properties, that are also exhibited by similar molecules, called poxytrins, which possess the same E,Z,E conjugated triene geometry, and are synthesized from other polyunsaturated fatty acids with 22 or 20 carbons. Here we present new biological activities of di-hydroxylated metabolites deriving from α-linolenic acid (18:3n-3) treated by soybean 15-lipoxygenase (sLOX). We show that 18:3n-3 is converted by sLOX into mainly 13(S)-OH-18:3 after reduction of the hydroperoxide product. But surprisingly, and in contrast to DHA which is metabolized into only one di-hydroxylated compound, 18:3n-3 leads to four di-hydroxylated fatty acid isomers. We report here the complete characterization of these compounds using high field NMR and GC-MS techniques, and some of their biological activities. These compounds are: 9(R),16(S)-dihydroxy-10E,12E,14E-octadecatrienoic acid, 9(S),16(S)-dihydroxy-10E,12E,14E-octadecatrienoic acid, 9(S),16(S)-dihydroxy-10E,12Z,14E-octadecatrienoic acid, and 9(R),16(S)-dihydroxy-10E,12Z,14E-octadecatrienoic acid. They can also be synthesized by the human recombinant 15-lipoxygenase (type 2). Their inhibitory effect on blood platelet and anti-inflammatory properties were compared with those already reported for PDX.


Asunto(s)
Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Ácido alfa-Linolénico/química , Ácido alfa-Linolénico/metabolismo , Antiinflamatorios no Esteroideos/química , Araquidonato 15-Lipooxigenasa/metabolismo , Plaquetas/efectos de los fármacos , Humanos , Hidroxilación , Estructura Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Ácido alfa-Linolénico/farmacología
13.
FASEB J ; 27(7): 2855-61, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23507868

RESUMEN

There is evidence that high-density lipoproteins (HDLs) may regulate platelet function, but disparate results exist regarding the effects of oxidized HDLs on platelets. The objective of our study was to determine the role of in vivo oxidized HDLs on platelet aggregation. Platelet aggregation and redox status were investigated in 5 patients with abetalipoproteinemia (ABLP) or homozygous hypobetalipoproteinemia, two rare metabolic diseases characterized by the absence of apolipoprotein B-containing lipoproteins, compared to 5 control subjects. Platelets isolated from plasma of patients with ABLP aggregated 4 to 10 times more than control platelets, depending on the agonist. By contrast, no differences in the extent of platelet aggregation were observed between ABLP platelet-rich plasma (PRP) and control PRP, suggesting the presence of a protective factor in ABLP plasma. ABLP HDLs inhibited agonist-induced platelet aggregation by binding to SR-BI, while control HDLs had no effect. On the other hand, lipoprotein-deficient plasma from patients with ABLP did not inhibit platelet aggregation. Severe oxidative stress was evidenced in patients with ABLP. Compared to control HDLs, ABLP HDLs showed a 40% decrease of α-tocopherol and an 11-fold increased malondialdehyde concentration. These results demonstrate that in vivo oxidized HDLs do not lose their antiaggregatory properties despite oxidation.


Asunto(s)
Abetalipoproteinemia/metabolismo , Plaquetas/fisiología , Lipoproteínas HDL/metabolismo , Agregación Plaquetaria/fisiología , Abetalipoproteinemia/sangre , Abetalipoproteinemia/genética , Adenosina Difosfato/farmacología , Adulto , Apolipoproteínas B/genética , Ácido Araquidónico/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Colágeno/farmacología , Ácidos Grasos Insaturados/metabolismo , Femenino , Humanos , Lipoproteínas HDL/química , Lipoproteínas HDL/farmacología , Malondialdehído/metabolismo , Mutación , Oxidación-Reducción , Estrés Oxidativo , Agregación Plaquetaria/efectos de los fármacos , Receptores Depuradores de Clase B/metabolismo , Adulto Joven , alfa-Tocoferol/sangre , alfa-Tocoferol/metabolismo
14.
FASEB J ; 25(1): 382-8, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20833872

RESUMEN

Docosahexaenoic acid (DHA), an important component of marine lipids, exhibits anti-inflammatory activity related to some of its oxygenated metabolites, such as neuroprotectin/protectin D1 [NPD1/PD1; 10(R),17(S)-dihydroxy-docosa-4Z,7Z, 11E,13E,15Z,19Z-hexaenoic acid] produced through the 15-lipoxygenase pathway. However, other metabolites from DHA can be produced through this pathway, and other polyunsaturated fatty acids (PUFAs) of nutritional value may be oxygenated as well. Their biological activities remain unknown. Isomers of protectin D1 were synthesized using soybean lipoxygenase and tested for their ability to inhibit human blood platelet aggregation. A geometric isomer called PDX, previously described with the 11E,13Z,15E geometry, instead of 11E,13E,15Z in PD1, inhibited platelet aggregation at submicromolar concentrations when induced by either collagen, arachidonic acid, or thromboxane. The inhibition occurred at the level of both the cyclooxygenase activity and thromboxane receptor site. Interestingly, all the metabolites tested exhibiting the E,Z,E-conjugated triene were active, whereas E,E,Z trienes (as in PD1) or all-trans (E,E,E) trienes were inactive. We conclude that PDX and other oxygenated products from PUFAs of nutritional interest, having the E,Z,E-conjugated triene motif and collectively named poxytrins (PUFA oxygenated trienes), might have antithrombotic potential.


Asunto(s)
Ácidos Dicarboxílicos/farmacología , Ácidos Docosahexaenoicos/farmacología , Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos Insaturados/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Ácido Araquidónico/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Colágeno/farmacología , AMP Cíclico/metabolismo , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/metabolismo , Ácidos Docosahexaenoicos/química , Ácidos Docosahexaenoicos/metabolismo , Ácidos Grasos Insaturados/química , Humanos , Isomerismo , Oxígeno/metabolismo , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Receptores de Tromboxanos/antagonistas & inhibidores , Receptores de Tromboxanos/metabolismo , Tromboxanos/farmacología
15.
Atherosclerosis ; 208(2): 467-72, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19717153

RESUMEN

OBJECTIVE: To determine the effect of supplementation with increasing doses of docosahexaenoic acid (DHA), as the only n-3 polyunsaturated fatty acid (PUFA), on low-density lipoprotein (LDL) redox status and oxidizability. METHODS: Twelve healthy men aged 53-65 years ingested consecutive doses of DHA (200, 400, 800 and 1600 mg/day), each dose for two weeks. RESULTS: The proportions of DHA increased dose-dependently in LDL phospholipids and cholesteryl esters, even after two weeks of supplementation with 200mg/day DHA. The daily intake of 200, 400 and 800 mg DHA resulted in increased alpha-tocopherol concentrations, decreased MDA concentrations, and a longer lag time for copper-induced LDL oxidation. Supplementation with 1600 mg/day DHA had no effect on the above parameters. In plasma, concentrations of 4-hydroxy-hexenal, specifically derived from the peroxidation of n-3 fatty acids, significantly increased after 800 and 1600 mg DHA, representing 0.01% of plasma n-3 PUFAs, while 4-hydroxy-nonenal concentrations, derived from the peroxidation of n-6 fatty acids, did not change. CONCLUSION: Our results clearly show that an intake of 200-800 mg/day DHA may have protective and antioxidant effects on LDL and could represent optimal doses for cardiovascular disease prevention in a healthy population.


Asunto(s)
Suplementos Dietéticos , Ácidos Docosahexaenoicos/uso terapéutico , Ácidos Grasos Insaturados/metabolismo , Lipoproteínas LDL/metabolismo , Anciano , Antioxidantes/metabolismo , Estudios de Cohortes , Cobre/metabolismo , Ácidos Grasos/metabolismo , Humanos , Peroxidación de Lípido , Masculino , Malondialdehído/metabolismo , Persona de Mediana Edad , Oxígeno/química , Vitamina E/metabolismo , alfa-Tocoferol/metabolismo
16.
FASEB J ; 23(9): 2909-16, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19443612

RESUMEN

Docosahexaenoic acid (DHA) can prevent cardiovascular events. However, few studies have addressed the effects of DHA on both platelet reactivity and redox status in healthy subjects, and dose-related studies are scarce. The main objectives of the present study were to determine the effects of increasing doses of DHA on platelets and redox status in humans. Twelve healthy male volunteers (aged 53-65 yr) were assigned to consume an intake of successively 200, 400, 800, and 1600 mg/d DHA, as the only omega-3 fatty acid, for 2 wk each dose. Blood and urine samples were collected before and after each dose of DHA and at 8 wk after arrest of supplementation. DHA was incorporated in a dose-response fashion in platelet phospholipids. After supplementation with 400 and 800 mg/d DHA, platelet reactivity was significantly decreased. Platelet vitamin E concentration increased only after 200 mg/d DHA, while p38 MAP kinase phosphorylation decreased. Urinary isoprostane was also significantly lowered after 200 mg/d DHA but was increased after 1600 mg/d. Therefore, supplementation with only 200 mg/d DHA for 2 wk induced an antioxidant effect. It is concluded that low consumption of DHA could be an effective and nonpharmacological way to protect healthy men from platelet-related cardiovascular events.


Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Activación Plaquetaria/efectos de los fármacos , Anciano , Antioxidantes/farmacología , Plaquetas/química , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Ácidos Grasos Omega-3/farmacología , Humanos , Isoprostanos/orina , Masculino , Persona de Mediana Edad , Oxidación-Reducción/efectos de los fármacos , Fosfolípidos/metabolismo , Vitamina E/análisis , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
17.
Br J Nutr ; 101(6): 852-8, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18710607

RESUMEN

Dietary intake of long-chain n-3 PUFA has been reported to decrease several markers of lymphocyte activation and modulate monocyte susceptibility to apoptosis. However, most human studies examined the combined effect of DHA and EPA using relatively high daily amounts of n-3 PUFA. The present study investigated the effects of increasing doses of DHA added to the regular diet of human healthy volunteers on lymphocyte response to tetradecanoylphorbol acetate plus ionomycin activation, and on monocyte apoptosis induced by oxidized LDL. Eight subjects were supplemented with increasing daily doses of DHA (200, 400, 800, 1600 mg) in a TAG form containing DHA as the only PUFA, for 2 weeks each dose. DHA intake dose-dependently increased the proportion of DHA in mononuclear cell phospholipids, the augmentation being significant after 400 mg DHA/d. The tetradecanoylphorbol acetate plus ionomycin-stimulated IL-2 mRNA level started to increase after ingestion of 400 mg DHA/d, with a maximum after 800 mg intake, and was positively correlated (P < 0.003) with DHA enrichment in cell phospholipids. The treatment of monocytes by oxidized LDL before DHA supplementation drastically reduced mitochondrial membrane potential as compared with native LDL treatment. Oxidized LDL apoptotic effect was significantly attenuated after 400 mg DHA/d and the protective effect was maintained throughout the experiment, although to a lesser extent at higher doses. The present results show that supplementation of the human diet with low DHA dosages improves lymphocyte activability. It also increases monocyte resistance to oxidized LDL-induced apoptosis, which may be beneficial in the prevention of atherosclerosis.


Asunto(s)
Antioxidantes/administración & dosificación , Ácidos Docosahexaenoicos/administración & dosificación , Leucocitos Mononucleares/inmunología , Análisis de Varianza , Apoptosis/efectos de los fármacos , Biomarcadores/análisis , Células Cultivadas , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Ácidos Grasos/análisis , Humanos , Interleucina-2/genética , Activación de Linfocitos/efectos de los fármacos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Persona de Mediana Edad , Fosfolípidos/química , ARN Mensajero/análisis
18.
Biochem Biophys Res Commun ; 372(4): 924-8, 2008 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-18539141

RESUMEN

Beneficial effects of docosahexaenoic acid (DHA) intake in the prevention of cardiovascular diseases are known, and platelets play a crucial role in cardiovascular complications. However, high doses of DHA may increase lipid peroxidation and induce deleterious effects, notably in platelets. This led us to investigate the effect of DHA on gene expression of some enzymes controlling redox status and prostanoid formation in human megakaryoblastic cells (MEG-01 cell line). MEG-01 cells were incubated in presence of DHA (10 and 100 micromol/L) for 6h. DHA enrichment up-regulated glutathione peroxidase-1 and thromboxane synthase mRNA. DHA increased gene catalase expression and up-regulated PPAR beta/delta and PPAR gamma mRNA in presence of high concentration of DHA. In conclusion, our results support an antioxidant mechanism of DHA. The effects of DHA on cellular redox status could, with others, provide an explanation for the beneficial influence of low consumption of DHA on cardiovascular events.


Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Expresión Génica/efectos de los fármacos , Glutatión Peroxidasa/genética , Prostaglandinas/biosíntesis , Ácido Araquidónico/metabolismo , Línea Celular , Ácidos Grasos/análisis , Humanos , Malondialdehído , Megacariocitos/efectos de los fármacos , Megacariocitos/enzimología , Oxidación-Reducción/efectos de los fármacos , PPAR delta/genética , PPAR-beta/genética , Fosfolípidos/química , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandinas/genética , Glutatión Peroxidasa GPX1
19.
Br J Nutr ; 100(4): 829-33, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18304388

RESUMEN

n-3 PUFA supplementation helps in the prevention or treatment of inflammatory diseases and CVD. However, many supplementations reported sofar are either a combination of n-3 PUFA or used large daily amounts of n-3 PUFA dosages. The present study investigated the influence of increasing dose intake of DHA on the fatty acid composition of phospholipids in neutrophils and on their capability to produce leukotrienes(LT) B4 and B5 in vitro. Twelve healthy volunteers were supplemented with increasing daily doses of DHA (200, 400, 800 and 1600 mg, each dose in TAG containing DHA as the only PUFA and for a 2-week period). At the end of each supplementation period, neutrophil fatty acid composition,and LTB4 and LTB5 production were determined by GC and liquid chromatography-tandem MS, respectively. The DHA/arachidonic acid ratio increased in a dose-dependent manner with respect to the increasing doses of DHA supplementation and was significantly different from baseline after supplementation with either 400, 800 or 1600 mg DHA. The LTB5/LTB4 ratio was significantly increased compared to baseline after supplementation with 800 and 1600 mg DHA. LTB5/LTB4 and DHA/arachidonic acid ratios were correlated (r 0.531, P<0.0001). The present data suggest that both changes in neutrophil lipid composition and LT production occurred with daily supplementation with 800 and 1600 mg DHA. The clinical benefits associated with these doses of DHA in inflammatory diseases remain to be investigated.


Asunto(s)
Grasas de la Dieta/administración & dosificación , Ácidos Docosahexaenoicos/administración & dosificación , Leucotrienos/biosíntesis , Lípidos/análisis , Neutrófilos/química , Anciano , Ácido Araquidónico/sangre , Células Cultivadas , Suplementos Dietéticos , Ácidos Docosahexaenoicos/análisis , Relación Dosis-Respuesta a Droga , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/biosíntesis , Ácido Eicosapentaenoico/sangre , Humanos , Leucotrieno B4/análogos & derivados , Leucotrieno B4/biosíntesis , Leucotrieno B4/sangre , Leucotrienos/sangre , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Espectrometría de Masas en Tándem
20.
J Clin Endocrinol Metab ; 92(5): 1961-4, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17341567

RESUMEN

CONTEXT: Platelet hyperactivation contributes to the increased risk for atherothrombosis in type 2 diabetes and is associated with oxidative stress. Plasma low-density lipoproteins (LDLs) are exposed to both hyperglycemia and oxidative stress, and their role in platelet activation remains to be ascertained. OBJECTIVE: The aim of this study was to investigate the effects of LDLs modified by both glycation and oxidation in vitro or in vivo on platelet arachidonic acid signaling cascade. The activation of platelet p38 MAPK, the stress kinase responsible for the activation of cytosolic phospholipase A(2), and the concentration of thromboxane B(2), the stable catabolite of the proaggregatory arachidonic acid metabolite thromboxane A(2), were assessed. RESULTS: First, in vitro-glycoxidized LDLs increased the phosphorylation of platelet p38 MAPK as well as the concentration of thromboxane B(2). Second, LDLs isolated from plasma of poorly controlled type 2 diabetic patients stimulated both platelet p38 MAPK phosphorylation and thromboxane B(2) production and possessed high levels of malondialdehyde but normal alpha-tocopherol concentrations. By contrast, LDLs from sex- and age-matched healthy volunteers had no activating effects on platelets. CONCLUSIONS: Our results indicate that LDLs modified by glycoxidation may play an important contributing role in platelet hyperactivation observed in type 2 diabetes via activation of p38 MAPK.


Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Glicoproteínas/sangre , Lipoproteínas LDL/farmacología , Activación Plaquetaria/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Plaquetas/enzimología , Femenino , Humanos , Técnicas In Vitro , Lipoproteínas LDL/sangre , Lipoproteínas LDL/aislamiento & purificación , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Oxidación-Reducción , Fosforilación , Tromboxano B2/sangre
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