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Eicosapentaenoic acid (EPA)
(222 References)
Sayanova, O. V. and J. A. Napier (2004). "Eicosapentaenoic acid: biosynthetic routes and the potential for synthesis in transgenic plants." Phytochemistry 65(2): 147-58.
Long chain polyunsaturated fatty acids are now known to play important roles in human health. In particular, eicosapentaenoic acid (20:5Delta(5,8,11,14,17); n-3: EPA) is implicated as a protective agent in a range of pathologies such as cardiovascular disease and Metabolic Syndrome (Syndrome X). Eicosapentaenoic acid is currently sourced from fish oils, the presence of this fatty acid being due to the dietary piscine consumption of EPA-synthesising micro-algae. The biosynthetic pathway of EPA has been elucidated, and contains several alternative metabolic routes. Progress in using "reverse engineering" to transgenically mobilize the trait(s) for EPA are considered. In particular, the prospect of producing this important polyunsaturated fatty acid in transgenic oilseeds is highlighted, as is the urgent need for a sustainable replacement for diminishing fish stocks.
Salvati, S., F. Natali, et al. (2004). "Stimulation of myelin proteolipid protein gene expression by eicosapentaenoic acid in C6 glioma cells." Neurochem Int 44(5): 331-8.
In this study, the role of exogenous fatty acids in the regulation of proteolipid protein (PLP) gene expression was investigated using the following model culture system: C6 glioma cells expressing the green-fluorescent protein (eGFP) driven by different segments of PLP promoter. Eicosapentanoic acid (EPA; 20:5 n-3), but not arachidonic acid (AA; 20:4 n-6), induced a significant increase in medium fluorescence intensity (MFI) determined by fluorescence-activated cell sorting (FACS). The induction of PLP promoter was time-dependent showing maximal activity between 24 and 48 h after EPA exposure. PLP promoter activation was dependent on fatty acid concentration, with maximum activation at 200 microM. Northern blot analysis confirmed the fluorescence data in C6 cells incubated with EPA. Furthermore, this treatment increased the adenylyl cyclase-cyclic AMP (cAMP) levels and the mitogen-activated protein kinase (MAPK) activation in C6 cells. PLP promoter activity was inhibited by pre-treatment with H89 (protein kinase A (PKA) inhibitor), but not with PD98059 (MAPK inhibitor), suggesting that EPA stimulates the expression of PLP via cAMP-mediated pathways.
Muller-Navarra, D. C., M. T. Brett, et al. (2004). "Unsaturated fatty acid content in seston and tropho-dynamic coupling in lakes." Nature 427(6969): 69-72.
Determining the factors that control food web interactions is a key issue in ecology. The empirical relationship between nutrient loading (total phosphorus) and phytoplankton standing stock (chlorophyll a) in lakes was described about 30 years ago and is central for managing surface water quality. The efficiency with which biomass and energy are transferred through the food web and sustain the production of higher trophic levels (such as fish) declines with nutrient loading and system productivity, but the underlying mechanisms are poorly understood. Here we show that in seston (fine particles in water) during summer, specific omega3-polyunsaturated fatty acids (omega3-PUFAs), which are important for zooplankton, are significantly correlated to the trophic status of the lake. The omega3-PUFAs octadecatetraenoic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid, but not alpha-linolenic acid, decrease on a double-logarithmic scale with increasing total phosphorus. By combining the empirical relationship between EPA-to-carbon content and total phosphorus with functional models relating EPA-to-carbon content to the growth and egg production of daphnids, we predict secondary production for this key consumer. Thus, the decreasing efficiency in energy transfer with increasing lake productivity can be explained by differences in omega3-PUFA-associated food quality at the plant-animal interface.
Madani, S., A. Hichami, et al. (2004). "Diacylglycerols containing Omega 3 and Omega 6 fatty acids bind to RasGRP and modulate MAP kinase activation." J Biol Chem 279(2): 1176-83.
We elucidated the effects of different diacylglycerols (DAGs), i.e. 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG), 1-stearoyl-2-docosahexaenoyl-sn-glycerol (SDG), and 1-stearoyl-2-eicosapentaenoyl-sn-glycerol (SEG), on [3H]PDBu binding to RasGRP. The competition studies with these DAGs on [3H]PDBu binding to RasGRP revealed different Ki values for these DAG molecular species. Furthermore, we transfected human Jurkat T cells by a plasmid containing RasGRP and assessed the implication of endogenous DAGs on activation of MAP kinases ERK1/ERK2, induced by phorbol-12-myristate-13-acetate (PMA). In control cells, GF109203X, a protein kinase C inhibitor, inhibited ERK1/ERK2 activation. However, this agent curtailed but failed to completely diminish ERK1/ERK2 phosphorylation in RasGRP-overexpressing cells, though calphostin C, a DAG binding inhibitor, suppressed the phosphorylation of MAP kinases in these cells. In cells incubated with arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), PMA induced the production of endogenous DAGs containing these fatty acids, respectively: DAG-AA, DAG-DHA, and DAG-EPA. The inhibition of production of DAG-AA and DAG-DHA significantly inhibited MAP kinase activation in RasGRP overexpressing, but not in control, cells. Our study demonstrates that three DAG molecular species bind to RasGRP, but only DAG-AA and DAG-DHA participate in the modulation of RasGRP-mediated activation of MAP kinases in Jurkat T cells.
Kankaanpaa, P., B. Yang, et al. (2004). "Effects of polyunsaturated fatty acids in growth medium on lipid composition and on physicochemical surface properties of lactobacilli." Appl Environ Microbiol 70(1): 129-36.
Most probiotic lactobacilli adhere to intestinal surfaces, a phenomenon influenced by free polyunsaturated fatty acids (PUFA). The present study investigated whether free linoleic acid, gamma-linolenic acid, arachidonic acid, alpha-linolenic acid, or docosahexaenoic acid in the growth medium alters the fatty acid composition of lactobacilli and their physical characteristics. The most abundant bacterial fatty acids identified were oleic, vaccenic, and dihydrosterculic acids. PUFA, especially conjugated linoleic acid (CLA) isomers and gamma-linolenic, eicosapentaenoic, docosahexaenoic, and alpha-linolenic acids, also were identified in lactobacilli. When lactobacilli were cultured in MRS broth supplemented with various free PUFA, the incorporation of a given PUFA into bacterial fatty acids was clearly observed. Moreover, PUFA supplementation also resulted in PUFA-dependent changes in the proportions of other fatty acids; major interconversions were seen in octadecanoic acids (18:1), their methylenated derivatives (19:cyc), and CLA. Intermittent changes in eicosapentaenoic acid proportions also were noted. These results were paralleled by minor changes in the hydrophilic or hydrophobic characteristics of lactobacilli, suggesting that PUFA interfere with microbial adhesion to intestinal surfaces through other mechanisms. In conclusion, we have demonstrated that free PUFA in the growth medium induce changes in bacterial fatty acids in relation to the regulation of the degree of fatty acid unsaturation, cyclization, and proportions of CLA and PUFA containing 20 to 22 carbons. The potential role of lactobacilli as regulators of PUFA absorption may represent another means by which probiotics could redirect the delicate balance of inflammatory mediators derived from PUFA within the inflamed intestine.
Kalmijn, S., M. P. van Boxtel, et al. (2004). "Dietary intake of fatty acids and fish in relation to cognitive performance at middle age." Neurology 62(2): 275-80.
OBJECTIVE: To examine the associations of fatty acid and fish intake with cognitive function. METHODS: Data are from a cross-sectional population-based study among 1,613 subjects ranging from 45 to 70 years old. From 1995 until 2000, an extensive cognitive battery was administered and compound scores were constructed for memory, psychomotor speed, cognitive flexibility (i.e., higher order information processing), and overall cognition. A self-administered food-frequency questionnaire was used to assess habitual food consumption. The risk of impaired cognitive function (lowest 10% of the compound score) according to the energy adjusted intake of fatty acids was assessed with logistic regression, adjusting for age, sex, education, smoking, alcohol consumption, and energy intake. RESULTS: Marine omega-3 polyunsaturated fatty acids (PUFA) (eicosapentaenoic acid and docosahexaenoic acid) were inversely related to the risk of impaired overall cognitive function and speed (per SD increase: OR = 0.81, 95% CI 0.66 to 1.00 and OR = 0.72, 95% CI 0.57 to 0.90). Results for fatty fish consumption were similarly inverse. Higher dietary cholesterol intake was significantly associated with an increased risk of impaired memory and flexibility (per SD increase: OR = 1.27, 95% CI 1.02 to 1.57 and OR = 1.26, 95% CI 1.01 to 1.57). Per SD increase in saturated fat intake, the risk of impaired memory, speed, and flexibility was also increased, although not significantly. CONCLUSIONS: Fatty fish and marine omega-3 PUFA consumption was associated with a reduced risk and intake of cholesterol and saturated fat with an increased risk of impaired cognitive function in this middle-aged population.
Kaduce, T. L., X. Fang, et al. (2004). "20-hydroxyeicosatetraenoic acid (20-HETE) metabolism in coronary endothelial cells." J Biol Chem 279(4): 2648-56.
We have investigated the role of endothelial cells in the metabolism of 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoactive mediator synthesized from arachidonic acid by cytochrome P450 omega-oxidases. Porcine coronary artery endothelial cells (PCEC) incorporated 20-[(3)H]HETE primarily into the sn-2 position of phospholipids through a coenzyme A-dependent process. The incorporation was reduced by equimolar amounts of arachidonic, eicosapentaenoic or 8,9-epoxyeicosatrienoic acids, but some uptake persisted even when a 10-fold excess of arachidonic acid was available. The retention of 20-[(3)H]HETE increased substantially when methyl arachidonoyl fluorophosphonate, but not bromoenol lactone, was added, suggesting that a Ca(2+)-dependent cytosolic phospholipase A(2) released the 20-HETE contained in PCEC phospholipids. Addition of calcium ionophore A23187 produced a rapid release of 20-[(3)H]HETE from the PCEC, a finding that also is consistent with a Ca(2+)-dependent mobilization process. PCEC also converted 20-[(3)H]HETE to 20-carboxy-arachidonic acid (20-COOH-AA) and 18-, 16-, and 14-carbon beta-oxidation products. 20-COOH-AA produced vasodilation in porcine coronary arterioles, but 20-HETE was inactive. These results suggest that the incorporation of 20-HETE and its subsequent conversion to 20-COOH-AA in the endothelium may be important in modulating coronary vascular function.
De Groot, R. H., G. Hornstra, et al. (2004). "Effect of alpha-linolenic acid supplementation during pregnancy on maternal and neonatal polyunsaturated fatty acid status and pregnancy outcome." Am J Clin Nutr 79(2): 251-260.
BACKGROUND: Maternal essential fatty acid status declines during pregnancy, and as a result, neonatal concentrations of docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) may not be optimal. OBJECTIVE: Our objective was to improve maternal and neonatal fatty acid status by supplementing pregnant women with a combination of alpha-linolenic acid (ALA, 18:3n-3) and linoleic acid (LA, 18:2n-6), the ultimate dietary precursors of DHA and AA, respectively. DESIGN: From week 14 of gestation until delivery, pregnant women consumed daily 25 g margarine supplying either 2.8 g ALA + 9.0 g LA (n = 29) or 10.9 g LA (n = 29). Venous blood was collected for plasma phospholipid fatty acid analyses at weeks 14, 26, and 36 of pregnancy, at delivery, and at 32 wk postpartum. Umbilical cord blood and vascular tissue samples were collected to study neonatal fatty acid status also. Pregnancy outcome variables were assessed. RESULTS: ALA+LA supplementation did not prevent decreases in maternal DHA and AA concentrations during pregnancy and, compared with LA supplementation, did not increase maternal and neonatal DHA concentrations but significantly increased eicosapentaenoic acid (20:5n-3) and docosapentaenoic acid (22:5n-3) concentrations. In addition, ALA+LA supplementation lowered neonatal AA status. No significant differences in pregnancy outcome variables were found. CONCLUSIONS: Maternal ALA+LA supplementation did not promote neonatal DHA+AA status. The lower concentrations of Osbond acid (22:5n-6) in maternal plasma phospholipids and umbilical arterial wall phospholipids with ALA+LA supplementation than with LA supplementation suggest only that functional DHA status improves with ALA+LA supplementation.
Chiu, L. C., K. F. Tong, et al. (2004). "Synergistic action of piroxicam on the eicosapentaenoic acid-induced apoptosis is associated with enhanced down-regulation of anti-apoptotic Bcl-2 expression but not promoted activation of pro-apoptotic Bid protein." Oncol Rep 11(1): 225-30.
Eicosapentaenoic acid (EPA) is a dietary polyunsaturated fatty acid (PUFA) that is found abundantly in fish oils and induces apoptosis in human promyelocytic leukemia HL-60 cells. Cyclooxygenase (COX) converts EPA intracellularly into various inflammatory mediators that may affect the bioavailability of this fatty acid for inducing apoptosis in the cancer cells. In this study, effect of piroxicam (PRX), a COX inhibitor, on the EPA-induced apoptosis in HL-60 cells was investigated. EPA arrested cell cycle of the leukemic cells at G0/G1 phase after 8-h incubation and induced apoptosis after 24-h incubation. PRX induced neither cell-cycle arrest nor apoptosis significantly in HL-60 cells even after 48-h incubation. However, 24-h incubation with PRX followed by 24-h incubation with EPA significantly elevated both early-phase and late-phase apoptotic cells by 35% and 166% respectively, when compared to those induced by the fatty acid only. This synergistic action of PRX on the EPA-induced apoptosis was associated with enhanced down-regulation of anti-apoptotic Bcl-2 protein expression, but not promoted activation of pro-apoptotic Bid protein.
Buckley, M. S., A. D. Goff, et al. (2004). "Fish oil interaction with warfarin." Ann Pharmacother 38(1): 50-2.
OBJECTIVE: To report a case of elevated international normalized ratio (INR) in a patient taking fish oil and warfarin. CASE SUMMARY: A 67-year-old white woman had been taking warfarin for 1(1/2) years due to recurrent transient ischemic attacks. Her medical history included hypothyroidism, hyperlipidemia, osteopenia, hypertension, and coronary artery disease. She also experienced an inferior myocardial infarction in 1995 requiring angioplasty, surgical repair of her femoral artery in 1995, and hernia repair in 1996. This patient has her INR checked in the anticoagulation clinic and is followed monthly by the clinical pharmacist. Prior to the interaction, her INR was therapeutic for 5 months while she was taking warfarin 1.5 mg/d. The patient admitted to doubling her fish oil dose from 1000 to 2000 mg/d. Without dietary, lifestyle, or medication changes, the INR increased from 2.8 to 4.3 within 1 month. The INR decreased to 1.6 one week after subsequent fish oil reduction, necessitating a return to the original warfarin dosing regimen. DISCUSSION: Fish oil supplementation could have provided additional anticoagulation with warfarin therapy. Fish oil, an omega-3 polyunsaturated fatty acid, consists of eicosapentaenoic acid and docosahexaenoic acid. This fatty acid may affect platelet aggregation and/or vitamin K-dependent coagulation factors. Omega-3 fatty acids may lower thromboxane A(2) supplies within the platelet as well as decrease factor VII levels. Although controversial, this case report illustrates that fish oil can provide additive anticoagulant effects when given with warfarin. CONCLUSIONS: This case reveals a significant rise in INR after the dose of concomitant fish oil was doubled. Patients undergoing anticoagulation therapy with warfarin should be educated about and monitored for possible drug-herb interactions. Pharmacists can play a crucial role in identifying possible drug interactions by asking patients taking warfarin about herbal and other alternative medicine product use.
Bruder, E. D., P. C. Lee, et al. (2004). "Metabolomic Analysis of Adrenal Lipids During Hypoxia in the Neonatal Rat: Implications In Steroidogenesis." Am J Physiol Endocrinol Metab.
The nursing rat pup exposed to hypoxia from birth exhibits ACTH-independent increases in corticosterone and renin/angiotensin II-independent increases in aldosterone. These increases are accompanied by significant elevation of plasma lipid concentrations in the hypoxic neonates. The purpose of the present study was to compare changes in the concentrations of specific fatty acid metabolites and lipid classes in serum and adrenal tissue from normoxic and hypoxic rat pups. We hypothesize that lipid alterations due to hypoxia may partly explain increases in steroidogenesis. Rats were exposed to normoxia or hypoxia from birth, and pooled serum and adrenal tissue from 7-day-old pups were subjected to metabolomic analyses. Hypoxia resulted in specific and significant changes in a number of fatty acid metabolites in both serum and the adrenal. Hypoxia increased the concentrations of oleic (18:1n9), eicosapentaenoic (EPA; 20:5n3), and arachidonic (20:4n6) acids in the triacylglyceride fraction of serum and decreased oleic and EPA concentrations in the cholesterol ester fraction. In the adrenal, hypoxia caused an increase in several n6 fatty acids in the triacylglyceride fraction, including linoleic (18:2n6) and arachidonic acid. There was also an increase in the concentration of alpha-linolenic acid (18:3n3) in the triacylglyceride fraction of the hypoxic adrenal, along with an increase in linoleic acid concentration in the diacylglyceride fraction. We propose that specific changes in lipid metabolism in the adrenal, as a result of hypoxia, may partly explain the increased steroidogenesis previously observed. The mechanism responsible may involve alterations in cellular signaling and/or mitochondrial function. These cellular changes may be a mechanism by which the neonate can increase circulating adrenal steroids necessary for survival, therefore bypassing a relative insensitivity to normal stimuli.
Zhang, C. W. and A. Richmond (2003). "Sustainable, high-yielding outdoor mass cultures of Chaetoceros muelleri var. subsalsum and Isochrysis galbana in vertical plate reactors." Mar Biotechnol (NY) 5(3): 302-10.
Continuous cultures of Chaetoceros muelleri and Isochrysis galbana were grown outdoors in flat plate-glass reactors in which light-path length (LPL) varied from 5 to 30 cm. High daily productivity (13 to 16 g cell mass per square meter of irradiated reactor surface) for long periods of time was obtained in reactors in which the optical path as well as cell density were optimized. 'Twenty centimeters was the optimal LPL, yielding the highest areal productivity of cell mass (g m(-2)d(-1)), eicosapentaenoic acid, and docosahexaenoic acid, which was identical with that previously found for polysaccharide production of Porphyridium and not far from the optimal LPL affecting maximal productivity in Nannochloropsis species. Relating the energy impinging on a given reactor surface area to the appropriate number of cells showed that the most efficient light dose per cell, obtained with the 20-cm LPL reactor, was approximately 2.5 times lower than the light dose available per cell in the 5-cm LPL reactor, in which a significant decline in areal cell density accompanied the lowest areal output of cell mass. The most effective harvesting regimen was in the range of 10% to 15% of culture volume harvested daily and replaced with fresh growth medium, resulting in a sustainable culture density of 24 x 10(6) and 28 x 10(6) cells/ml of C. muelleri and I. galbana, respectively.
Zackova, M., E. Skobisova, et al. (2003). "Activating omega-6 polyunsaturated fatty acids and inhibitory purine nucleotides are high affinity ligands for novel mitochondrial uncoupling proteins UCP2 and UCP3." J Biol Chem 278(23): 20761-9.
UCP2 (the lowest Km values: 20 and 29 microm, respectively) for omega-6 polyunsaturated FAs (PUFAs), all-cis-8,11,14-eicosatrienoic and all-cis-6,9,12-octadecatrienoic acids, which are also the most potent agonists of the nuclear PPARbeta receptor in the activation of UCP2 transcription. omega-3 PUFA, cis-5,8,11,14,17-eicosapentaenoic acid had lower affinity (Km, 50 microm), although as an omega-6 PUFA, arachidonic acid exhibited the same low affinity as lauric acid (Km, approximately 200 microm). These findings suggest a possible dual role of some PUFAs in activating both UCPn expression and uncoupling activity. UCP2 (UCP3)-dependent H+ translocation activated by all tested FAs was inhibited by purine nucleotides with apparent affinity to UCP2 (reciprocal Ki) decreasing in order: ADP > ATP approximately GTP > GDP >> AMP. Also [3H]GTP ([3H]ATP) binding to isolated Escherichia coli (Kd, approximately 5 microm) or yeast-expressed UCP2 (Kd, approximately 1.5 microm) or UCP3 exhibited high affinity, similar to UCP1. The estimated number of [3H]GTP high affinity (Kd, <0.4 microm) binding sites was (in pmol/mg of protein) 182 in lung mitochondria, 74 in kidney, 28 in skeletal muscle, and approximately 20 in liver mitochondria. We conclude that purine nucleotides must be the physiological inhibitors of UCPn-mediated uncoupling in vivo.
Yusufi, A. N., J. Cheng, et al. (2003). "Differential effects of low-dose docosahexaenoic acid and eicosapentaenoic acid on the regulation of mitogenic signaling pathways in mesangial cells." J Lab Clin Med 141(5): 318-29.
Although dietary fish oil supplementation has been used to prevent the progression of kidney disease in patients with IgA nephropathy, relatively few studies provide a mechanistic rationale for its use. Using an antithymocyte (ATS) model of mesangial proliferative glomerulonephritis, we recently demonstrated that fish oil inhibits mesangial cell (MC) activation and proliferation, reduces proteinuria, and decreases histologic evidence of glomerular damage. We therefore sought to define potential mechanisms underlying the antiproliferative effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the predominant omega-3 polyunsaturated fatty acids found in fish oil, in cultured MC. DHA and EPA were administered to MC as bovine serum albumin fatty-acid complexes. Low-dose (10-50 micromol/L) DHA, but not EPA, inhibited basal and epidermal growth factor (EGF)-stimulated [(3)H]-thymidine incorporation in MCs. At higher doses (100 micromol/L), EPA and DHA were equally effective in suppressing basal and EGF-stimulated MC mitogenesis. Low-dose DHA, but not EPA, decreased ERK activation by 30% (P <.01), as assessed with Western-blot analysis using phosphospecific antibodies. JNK activity was increased by low-dose DHA but not by EPA. p38 activity was not significantly altered by DHA or EPA. Cyclin E activity, as assessed with a histone H1 kinase assay, was inhibited by low-dose DHA but not by EPA. DHA increased expression of the cell cycle inhibitor p21 but not p27; EPA had no effect on p21 or p27. We propose that the differential effect of low-dose DHA vs EPA in suppressing MC mitogenesis is related to down-regulation of ERK and cyclin E activity and to induction of p21.
Yuri, T., N. Danbara, et al. (2003). "Dietary docosahexaenoic acid suppresses N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats more effectively than eicosapentaenoic acid." Nutr Cancer 45(2): 211-7.
We compared the effects of identical amounts but different proportions of dietary n-3 polyunsaturated fatty acids (PUFAs) on N-methyl-N-nitrosourea (MNU)-induced mammary cancer in a rat model. The ability of dietary docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to suppress mammary cancer was evaluated. Female Sprague-Dawley rats were randomly assigned to three groups and maintained on diets containing 10% fatty acid consisting of EPA, a 1:1 mixture of EPA-plus-DHA, or DHA. The experimental diet was started after administration of MNU at 49 days of age, and the rats were maintained on the respective diets until the largest mammary tumor reached >1 cm in diameter or until the end of the study period (20 wk after MNU). All histologically detected mammary carcinomas were evaluated, irrespective of size. The DHA diet was associated with significant suppression of the carcinogenic effect of MNU compared with the EPA and EPA-plus-DHA diets: tumor incidence decreased to 23% (3/13) compared with 73% (11/15) and 65% (12/17) (P < 0.01 and P < 0.05, respectively); tumor multiplicity decreased to 0.23 compared with 1.67 and 1.59 (P < 0.01 and P < 0.05, respectively). There was no significant difference in tumor latency among the DHA, EPA, and EPA-plus-DHA groups (119, 105, and 117 days, respectively). Over 20 wk, the fatty acid composition of serum and mammary fat tissue reflected differences in the dietary n-3 PUFAs. Although DHA suppressed MNU-induced mammary carcinogenesis more effectively than EPA, generalized steatosis including mammary fat tissue appeared in all three groups.
Yokoyama, M. and H. Origasa (2003). "Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS)." Am Heart J 146(4): 613-20.
HYPOTHESIS: The principle aim of the current study is to test the hypothesis that the long-term use of highly purified EPA (eicosapentaenoic acid: 1800 mg/day), in addition to HMG-CoA reductase inhibitor, is effective in preventing cardiovascular events in Japanese patients with hypercholesterolemia. BACKGROUND: Epidemiological and clinical evidence suggest that intake of long-chain polyunsaturated n-3 fatty acids (PUFAs), which are abundant in fish, might have a significant role in the prevention of coronary artery disease, as marine PUFAs have multiple biological functions through lipid-dependent and lipid-independent mechanisms. METHODS: The Japan EPA Lipid Intervention Study (JELIS) is a prospective, randomized, open-label, blinded end point trial including both primary and secondary prevention strata, with a maximum follow-up of 5 years. Its main purpose is to examine the clinical effectiveness of EPA oil given as an additional treatment to patients taking HMG-CoA reductase inhibitors for hypercholesterolemia. A primary end point is major coronary events: sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina pectoris including hospitalization for documented ischemic episodes, and events of angioplasty/stenting or coronary artery bypass grafting. Secondary end points include all-cause mortality, stroke, peripheral artery disease, and cancer. Baseline study composition comprises 15,000 participants (4204 men and 10,796 women) in the primary prevention stratum and 3645 (1656 men and 1989 women) in the secondary stratum. The minimum age is 40 years for men, women are required to be postmenopausal, and all patients must be < or =75 years of age. The mean age of participants is 61 years, and 69% are female. The schedule for plasma fatty acid composition measurement is as follows: at baseline, at 6 month, and yearly thereafter. The mean baseline total and low-density lipoprotein cholesterol levels were 275 mg/dL (7.1 mmol/L) and 180 mg/dL (4.6 mmol/L). RESULTS: Results are expected in 2005. CONCLUSION: JELIS is a large clinical trial that will evaluate whether EPA can make an additional improvement in mortality and morbidity of coronary artery disease beyond that of HMG-CoA reductase inhibitor treatment.
Yamagata, K., M. Tagami, et al. (2003). "Polyunsaturated fatty acids induce tight junctions to form in brain capillary endothelial cells." Neuroscience 116(3): 649-56.
Tight junctions create a rate-limiting barrier to the diffusion of solutes between vertebrate epithelial cells and endothelial cells. They are also controlled within individual cells by a variety of physiologically relevant signals. We investigated the effects of polyunsaturated fatty acids on the formation of tight junctions in brain capillary endothelial cells, monitoring the transepithelial electrical resistance, and analyzed the expression of occludin messenger RNA. Brain-capillary endothelial cells were grown to confluence on filters and exposed to eicosapentaenoic acids, gamma linolenic acid and linoleic acid. Transepithelial electrical resistance was determined with voltage-measuring electrodes. The messenger RNA expression of occludin was quantitated by real-time quantitative reverse transcriptase-polymerase chain reaction. The basal resistance across monolayers of porcine brain capillary endothelial cells was 83+/-8.1 Omega cm(2). Cells cultured in eicosapentaenoic acids and gamma linolenic acid, but not linolenic acid, displayed a 2.7-fold increase in transepithelial electrical resistance at 10 microM in brain capillary endothelial cells. The expression level of occludin messenger RNA increased markedly immediately after the exposure to eicosapentaenoic acids or gamma linolenic acid. Following an 8 h exposure to exogenous eicosapentaenoic acids or gamma linolenic acid, occludin messenger RNA levels were significantly increased. In addition, the rise in transepithelial electrical resistance induced by eicosapentaenoic acids and gamma linolenic acid was markedly inhibited by the tyrosine kinase inhibitors genistein and PP2 and protein kinase C inhibitor, calphostin C. In contrast, the rise in transepithelial electrical resistance induced by eicosapentaenoic acids and gamma linolenic acid was not inhibited by the PI 3-kinase inhibitor, LY294002.We conclude that eicosapentaenoic acids and gamma linolenic acid increased the transepithelial electrical resistance and the expression of occludin messenger RNA in brain capillary endothelial cells. This gamma linolenic acid and eicosapentaenoic acid induced assembly of tight junction is likely to be regulated by protein kinase C and tyrosine kinase activity.
Yakimov, M. M., L. Giuliano, et al. (2003). "Oleispira antarctica gen. nov., sp. nov., a novel hydrocarbonoclastic marine bacterium isolated from Antarctic coastal sea water." Int J Syst Evol Microbiol 53(Pt 3): 779-85.
The taxonomic characteristics of two bacterial strains, RB-8(T) and RB-9, isolated from hydrocarbon-degrading enrichment cultures obtained from Antarctic coastal marine environments (Rod Bay, Ross Sea), were determined. These bacteria were psychrophilic, aerobic and Gram-negative with polar flagella. Growth was not observed in the absence of NaCl, occurred only at concentrations of Na+ above 20 mM and was optimal at an NaCl concentration of 3-5% (w/v). The major cellular fatty acids were monounsaturated straight-chain fatty acids. The strains were able to synthesize the polyunsaturated fatty acid eicosapentaenoic acid (20: 5omega3) at low temperatures. The DNA G + C contents were 41-42 mol%. The strains formed a distinct phyletic line within the gamma-Proteobacteria, with less than 89.6% sequence identity to their closest relatives within the Bacteria with validly published names. Both isolates exhibited a restricted substrate profile, with a preference for aliphatic hydrocarbons, that is typical of marine hydrocarbonoclastic micro-organisms such as Alcanivorax, Marinobacter and Oleiphilus. On the basis of ecophysiological properties, G + C content, 16S rRNA gene sequences and fatty acid composition, a novel genus and species within the gamma-Proteobacteria are proposed, Oleispira antarctica gen. nov., sp. nov.; strain RB-8(T) (= DSM 14852(T) = LMG 21398(T)) is the type strain.
Yajima, M., M. Takada, et al. (2003). "A newly established in vitro culture using transgenic Drosophila reveals functional coupling between the phospholipase A2-generated fatty acid cascade and lipopolysaccharide-dependent activation of the immune deficiency (imd) pathway in insect immunity." Biochem J 371(Pt 1): 205-10.
Innate immunity is the first line of defence against infectious micro-organisms, and the basic mechanisms of pathogen recognition and response activation are evolutionarily conserved. In mammals, the innate immune response in combination with antigen-specific recognition is required for the activation of adaptive immunity. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Here, for the purpose of pharmaceutical screening, we established an in vitro culture based on the innate immune response of Drosophila. The in vitro system is capable of measuring lipopolysaccharide (LPS)-dependent activation of the immune deficiency (imd) pathway, which is similar to the tumour necrosis factor signalling pathway in mammals. Screening revealed that well-known inhibitors of phospholipase A(2) (PLA(2)), dexamethasone (Dex) and p-bromophenacyl bromide (BPB) inhibit LPS-dependent activation of the imd pathway. The inhibitory effects of Dex and BPB were suppressed by the addition of an excess of three (arachidonic acid, eicosapentaenoic acid and gamma-linolenic acid) of the fatty acids so far tested. Arachidonic acid, however, did not activate the imd pathway when used as the sole agonist. These findings indicate that PLA(2) participates in LPS-dependent activation of the imd pathway via the generation of arachidonic acid and other mediators, but requires additional signalling from LPS stimulation. Moreover, PLA(2) was activated in response to bacterial infection in Sarcophaga. These results suggest a functional link between the PLA(2)-generated fatty acid cascade and the LPS-stimulated imd pathway in insect immunity.
Wu, F. C., Y. Y. Ting, et al. (2003). "Dietary docosahexaenoic acid is more optimal than eicosapentaenoic acid affecting the level of cellular defence responses of the juvenile grouper Epinephelus malabaricus." Fish Shellfish Immunol 14(3): 223-38.
The combined effects of dietary docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids on phagocytic, respiratory burst, and leucocyte proliferative activities of the juvenile grouper, Epinephelus malabaricus, were investigated. The test fish were fed for 12wk on test diets containing 1g 100g(-1) diet of DHA and EPA in combinations (DHA/EPA: 3/1, 2/1, 1/1, 0.7/1, 0.3/1). In addition to promoting fish growth, high dietary DHA/EPA ratio significantly enhanced phagocytic and respiratory burst activities of grouper head-kidney leucocytes compared with low ratio. Significant correlations were found between leucocyte phagocytic or respiratory burst activities and concentrations of 20:3(n-3), DHA and EPA in fish liver and muscle tissues. Leucocyte proliferation was significantly higher (P< 0.05) when the diets were high in DHA/EPA ratio than low in DHA/EPA ratio, when stimulated by Con A and PHA-P, but not by LPS. Tissue DHA concentrations and leucocyte proliferation were significantly and positively correlated. Fortification of dietary DHA, thus increased T-cell proliferation and phagocytic function of grouper leucocytes. DHA is the only member in the (n-3) highly unsaturated fatty acid family that stimulated phagocytic functions of leucocytes and T-cell proliferation, and is more optimal than EPA affecting the cellular defence responses of the E. malabaricus juveniles.
Wiesenfeld, P. W., U. S. Babu, et al. (2003). "Flaxseed increased alpha-linolenic and eicosapentaenoic acid and decreased arachidonic acid in serum and tissues of rat dams and offspring." Food Chem Toxicol 41(6): 841-55.
The effects of dietary flaxseed (FS), and defatted flaxseed meal (FLM) on serum and tissue fatty acid profiles were investigated. Pregnant Sprague-Dawley rats were fed AIN-93 based diets balanced in calories, fat, nitrogen, and fiber. Diets contained 0, 20%, 40% FS or 13% or 26% FLM by weight. The control, FS and FLM diets differed in linoleic acid to alpha-linolenic acid (ALA) fatty acid ratio. These diets were fed continuously during gestation, suckling period and 8 weeks post-weaning (F(1)). FS fatty acids were bioavailable and metabolized by pregnant and F(1) rats. ALA and eicosapentaenoic acid increased; linoleic and arachidonic acid decreased; and docosahexaeonic acid was unchanged in serum, 'gastric milk' and liver of FS and FLM-fed pregnant and F(1) rats. FS more than FLM, changed fatty acids profiles, but FLM and 40% FS significantly reduced serum cholesterol. Dietary 40% FS may have increased oxidative stress as evidenced by a reduction in liver vitamin E.
Whitehouse, A. S., J. Khal, et al. (2003). "Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin-proteasome pathway." Br J Cancer 89(4): 737-45.
The potential role of 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) as an intracellular signal for increased protein catabolism and induction of the expression of key components of the ubiquitin-proteasome proteolytic pathway induced by a tumour cachectic factor, proteolysis-inducing factor has been studied in murine C(2)C(12) myotubes. 15(S)-HETE induced protein degradation in these cells with a maximal effect at concentrations between 78 and 312 nM. The effect was attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA). There was an increase in 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the proteasome, in the same concentration range as that inducing total protein degradation, and this effect was also attenuated by EPA. 15(S)-hydroxyeicosatetraenoic acid also increased maximal expression of mRNA for proteasome subunits C2 and C5, as well as the ubiquitin-conjugating enzyme, E2(14k), after 4 h incubation, as determined by quantitative competitive RT-PCR. The concentrations of 15-HETE affecting gene expression were the same as those inducing protein degradation. Western blotting of cellular supernatants of myotubes treated with 15(S)-HETE for 24 h showed increased expression of p42, an ATPase subunit of the regulatory complex at similar concentrations, as well as a decrease in expression of myosin in the same concentration range. 15(S)-hydroxyeicosatetraenoic acid activated binding of nuclear factor-kappaB (NF-kappaB) in the myotube nucleus and stimulated degradation of I-kappaBalpha. The effect on the NF-kappaB/I-kappaBalpha system was attenuated by EPA. In addition, the NF-kappaB inhibitor peptide SN50 attenuated the increased chymotrypsin-like enzyme activity in the presence of 15(S)-HETE. These results suggest that 15(S)-HETE induces degradation of myofibrillar proteins in differentiated myotubes through an induction of an increased expression of the regulatory components of the ubiquitin-proteasome proteolytic pathway possibly through the intervention of the nuclear transcription factor NF-kappaB, and that this process is inhibited by EPA.
Whitehouse, A. S. and M. J. Tisdale (2003). "Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB." Br J Cancer 89(6): 1116-22.
Proteolysis-inducing factor (PIF), isolated from a cachexia-inducing murine tumour, has been shown to stimulate protein breakdown in C(2)C(12) myotubes. The effect was attenuated by the specific proteasome inhibitor lactacystin and there was an elevation of proteasome 'chymotrypsin-like' enzyme activity and expression of 20S proteasome alpha-subunits at concentrations of PIF between 2 and 16 nM. Higher concentrations of PIF had no effect. The action of PIF was attenuated by eicosapentaenoic acid (EPA) (50 microM). At a concentration of 4 nM, PIF induced a transient decrease in IkappaBalpha levels after 30 min incubation, while no effect was seen at 20 nM PIF. The level of IkappaBalpha, an NF-kappaB inhibitory protein, returned to normal after 60 min. Depletion of IkappaBalpha from the cytosol was not seen in myotubes pretreated with EPA, suggesting that the NF-kappaB/IkappaB complex was stabilised. At concentrations between 2 and 8 nM, PIF stimulated an increased nuclear migration of NF-kappaB, which was not seen in myotubes pretreated with EPA. The PIF-induced increase in chymotrypsin-like enzyme activity was also attenuated by the NF-kappaB inhibitor peptide SN50, suggesting that NF-kappaB may be involved in the PIF-induced increase in proteasome expression. The results further suggest that EPA may attenuate protein degradation induced by PIF, at least partly, by preventing NF-kappaB accumulation in the nucleus.
Wen, B., E. Deutsch, et al. (2003). "n-3 polyunsaturated fatty acids decrease mucosal/epidermal reactions and enhance antitumour effect of ionising radiation with inhibition of tumour angiogenesis." Br J Cancer 89(6): 1102-7.
The purpose of this study was to evaluate the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on normal tissue (lip mucosa) and tumour growth when combined with ionising radiation. The oral region (snout) of C57 black mice was irradiated with 16.5 Gy and n-3 PUFAs (100 microl) were injected intravenously for 2 weeks. After exposure to irradiation, the degree and duration of the acute reactions decreased significantly when mice were treated with n-3 PUFAs as compared to the control group. Interestingly, the range of the reactions in the n-3 PUFAs-treated group compared favourably to the group receiving amifostine (27.5 mg/kg i.v.). the effect of n-3 PUFAs was further evaluated in HEP-2 human carcinoma xenograft transplanted in nude mice. An inhibition of tumour growth was observed when mice were treated with n-3 PUFAs alone and this effect was maximal when combined with irradiation. Similar results were obtained using eicosapentaenoic acid. The effect of n-3 PUFAs was associated with inhibition of angiogenesis and tumour proliferation, and significantly decreased expression of cyclooxygenase-2. In conclusion, n-3 PUFAs administration decrease mucosal response, while moderately enhancing the antitumour effect of irradiation. The magnitude of the differential effect suggests that n-3 PUFAs need to be further investigated in the clinic.
Wen, Z. Y. and F. Chen (2003). "Heterotrophic production of eicosapentaenoic acid by microalgae." Biotechnol Adv 21(4): 273-94.
Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid that plays an important role in the regulation of biological functions and prevention and treatment of a number of human diseases such as heart and inflammatory diseases. As fish oil fails to meet the increasing demand for purified EPA, alternative sources are being sought. Microalgae contain large quantities of high-quality EPA and they are considered a potential source of this important fatty acid. Some microalgae can be grown heterotrophically on cheap organic substrate without light. This mode of cultivation can be well controlled and provides the possibility to maximize EPA production on a large scale. Numerous strategies have been investigated for commercial production of EPA by microalgae. These include screening of high EPA-yielding microalgal strains, improvement of strains by genetic manipulation, optimization of culture conditions, and development of efficient cultivation systems. This paper reviews recent advances in heterotrophic production of EPA by microalgae with an emphasis on the use of diatoms as producing organisms.
Wang, Y., M. A. Crawford, et al. (2003). "Fish consumption, blood docosahexaenoic acid and chronic diseases in Chinese rural populations." Comp Biochem Physiol A Mol Integr Physiol 136(1): 127-40.
The Chinese traditional diet is low in fat. However, there is regional variability in the amount, type of fat consumed and the pattern of chronic diseases. An epidemiological survey of 65 rural counties in China (6500 subjects) was conducted in the 1980s. We have re-examined the red blood cell fatty acid and antioxidant composition, with fish consumption. Fish consumption correlated significantly with the levels of docosahexaenoic acid (DHA) in red blood cells (RBC) (r=0.640, P<0.001), selenium (r=0.467, P<0.001) and glutathione peroxidase (r=0.333, P<0.01) in plasma. The proportion of DHA in RBC was inversely associated with total plasma triglyceride concentrations. A strong inverse correlation between DHA in RBC and cardiovascular disease (CVD) was found. The strongest correlation was the combination of DHA and oleic acid. RBC docosahexaenoic acid itself also correlated negatively and significantly with most chronic diseases and appeared to be more protective than either eicosapentaenoic or the omega3 docosapenataenoic acids. These results demonstrate the protective nature of fish consumption and DHA, found in high fat Western diets, operates at a low level of fat. This finding suggests the protective effect of fish consumption as validated by red cell DHA is universal. The protective effect is, therefore, most likely to be due to the fundamental properties of docosahexaenoic acid in cell function.
Wallace, F. A., E. A. Miles, et al. (2003). "Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects." Br J Nutr 89(5): 679-89.
Studies on animal and human subjects have shown that greatly increasing the amount of linseed (also known as flaxseed) oil (rich in the n-3 polyunsaturated fatty acid (PUFA) alpha-linolenic acid (ALNA)) or fish oil (FO; rich in the long-chain n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) in the diet can decrease a number of markers of immune function. The immunological effects of more modest doses of n-3 PUFA in human subjects are unclear, dose-response relationships between n-3 PUFA supply and immune function have not been established and whether ALNA has the same effects as its long-chain derivatives is not known. Therefore, the objective of the present study was to determine the effect of enriching the diet with different doses of FO or with a modest dose of ALNA on a range of functional responses of human monocytes and lymphocytes. In a randomised, placebo-controlled, double-blind, parallel study, forty healthy males aged 18-39 years were randomised to receive placebo or 3.5 g ALNA/d or 0.44, 0.94 or 1.9 g (EPA+DHA)/d in capsules for 12 weeks. The EPA:DHA ratio in the FO used was 1.0:2.5. ALNA supplementation increased the proportion of EPA but not DHA in plasma phospholipids. FO supplementation decreased the proportions of linoleic acid and arachidonic acid and increased the proportions of EPA and DHA in plasma phospholipids. The interventions did not alter circulating mononuclear cell subsets or the production of tumour necrosis factor-alpha, interleukin (IL) 1beta, IL-2, IL-4, IL-10 or interferon-gamma by stimulated mononuclear cells. There was little effect of the interventions on lymphocyte proliferation. The two higher doses of FO resulted in a significant decrease in IL-6 production by stimulated mononuclear cells. It is concluded that, with the exception of IL-6 production, a modest increase in intake of either ALNA or EPA+DHA does not influence the functional activity of mononuclear cells. The threshold of EPA+DHA intake that results in decreased IL-6 production is between 0.44 and 0.94 g/d.
von Schacky, C. (2003). "The role of omega-3 fatty acids in cardiovascular disease." Curr Atheroscler Rep 5(2): 139-45.
Plant-derived alpha-linolenic acid has been studied in a limited number of investigations. So far, some epidemiologic and a few mechanistic studies suggest a potential of protection from cardiovascular disease, but this potential remains to be proven in intervention studies. In contrast, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are prevalent in fish and fish oils, have been studied in thousands of investigations. A consistent body of evidence has been elaborated in various types of investigations, ultimately demonstrating reduction in total mortality, cardiovascular mortality, and morbidity by ingestion of roughly 1 g/d of EPA plus DHA. Current guidelines, however, do not discern between the omega-3 fatty acids mentioned; in fact, most even do not differentiate polyunsaturated fatty acids at all. Unfortunately, this complicates efficient implementation of an effective means of prophylaxis of atherosclerosis.
Vogan, C. L., B. H. Maskrey, et al. (2003). "Hepoxilins and trioxilins in barnacles: an analysis of their potential roles in egg hatching and larval settlement." J Exp Biol 206(Pt 18): 3219-26.
The barnacle life cycle has two key stages at which eicosanoids are believed to be involved in cellular communication pathways, namely the hatching of nauplii and the settlement of cypris larvae. Barnacle egg-hatching activity has previously been reported to reside in a variety of eicosanoids, including 8-hydroxyeicosapentaenoic acid and a number of tri-hydroxylated polyunsaturated fatty acid derivatives, the trioxilins. The production of the eicosapentaenoic acid metabolite trioxilin A4 (8,11,12-trihydroxy-5,9,14,17-eicosatetraenoic acid) by the barnacles Balanus amphitrite and Elminius modestus was confirmed using a combination of high-performance liquid chromatography and gas chromatography, both linked to mass spectrometry. In addition, both species also generated trioxilin A3 (8,11,12-trihydroxy-5,9,14-eicosatrienoic acid; an arachidonic acid-derived product), 8,11,12-trihydroxy-9,14,17-eicosatrienoic acid (a omega3 analogue of trioxilin A3; derived from omega3 arachidonic acid) and 10,13,14-trihydroxy-4,7,11,16,19-docosapentaenoic acid (a docosahexaenoic acid-derived product). In contrast to earlier reports, trioxilin A3 had no E. modestus egg-hatching activity at any of the concentrations tested (10(-9)-10(-6) mol l(-1)). The unstable epoxide precursor hepoxilin A3, however, caused significant levels of hatching at 10(-6) mol l(-1). Furthermore, the stable hepoxilin B3 analogue PBT-3 stimulated hatching at 10(-7) mol l(-1). Neither trioxilin A3, hepoxilin A3 or PBT-3 at 0.25-30 micromol l(-1) served as settlement cues for B. amphitrite cypris larvae.
Vecera, R., N. Skottova, et al. (2003). "Antioxidant status, lipoprotein profile and liver lipids in rats fed on high-cholesterol diet containing currant oil rich in n-3 and n-6 polyunsaturated fatty acids." Physiol Res 52(2): 177-87.
Plant-based n-3 polyunsaturated fatty acids (PUFA) possess a prospective antiatherogenic potential. Currant oil from Ribes nigrum L. is one of the few plant oils containing PUFAn-3 (15.3 mol%) in addition to PUFAn-6 (60.5 mol%). This study was aimed at comparing the effects of currant oil with those of lard fat, rich in saturated (43.8 mol%) and monounsaturated (47.0 mol%) fatty acids, on antioxidant parameters, the lipoprotein profile and liver lipids in rats fed on 1 % (w/w) cholesterol diets containing either 10 % of currant oil (COD) or lard fat (LFD). After 3 weeks of feeding, the COD induced a significant decrease in blood glutathione (GSH) and an increase in Cu(2+) induced oxidizability of serum lipids, but did not affect liver GSH and t-butyl hydroperoxide-induced lipoperoxidation of liver microsomes. Although the COD did not cause accumulation of liver triacylglycerols as LFD, the lipoprotein profile (VLDL, LDL, HDL) was not significantly improved after COD. The consumption of PUFAn-3 was reflected in LDL as an increase in eicosapentaenoic and docosahexaenoic acid. These results suggest that currant oil affects positively the lipid metabolism in the liver, above all it does not cause the development of a fatty liver. However, adverse effects of currant oil on the antioxidant status in the blood still remain of concern.
VanderJagt, D. J., M. R. Trujillo, et al. (2003). "Phase angle correlates with n-3 fatty acids and cholesterol in red cells of Nigerian children with sickle cell disease." Lipids Health Dis 2(1): 2.
OBJECTIVE: To determine the cholesterol content and fatty acid composition of red cell membrane phospholipids (PL) of children with sickle cell disease (SCD) and to correlate these levels with whole body phase angle that is related to the integrity and function of cell membranes. STUDY DESIGN: Blood samples were obtained from 69 children with SCD and 72 healthy age- and gender-matched controls in Nigeria for the determination of the cholesterol content and proportions of fatty acids in red cell PL. Bioelectrical impedance analysis was used to obtain resistance (R) and reactance (Xc) from which phase angle was calculated as arctan Xc/R. Cholesterol (normalized to lipid phosphorus) and the proportions of individual fatty acids were correlated with phase angle. RESULTS: The proportions of palmitic (p < 0.001), stearic acid (p = 0.003) and cholesterol (p < 0.001) were significantly higher in the red cells of children with SCD, whereas the proportions of arachidonic acid and docosahexaenoic acid were reduced (p = 0.03 and < 0.001, respectively) compared to controls. The phase angle was inversely correlated with the proportions of palmitic acid (p = 0.03) and oleic acid (p < 0.001) and cholesterol (p = 0.003). Three n-3 polyunsaturated fatty acids-eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid- were positively correlated with phase angle (p < 0.001). CONCLUSIONS: The fatty acid composition and cholesterol content of tissue membranes in SCD correlate with the phase shift measured by bioelectrical impedance analysis. Phase angle measurements may provide a non-invasive method for monitoring interventions aimed at altering the lipid composition of membranes.
Usami, M., T. Komurasaki, et al. (2003). "Effect of gamma-linolenic acid or docosahexaenoic acid on tight junction permeability in intestinal monolayer cells and their mechanism by protein kinase C activation and/or eicosanoid formation." Nutrition 19(2): 150-6.
OBJECTIVE: Polyunsaturated fatty acids have been characterized as immunonutrients, but the effect of gamma-linolenic acid (GLA) or docosahexaenoic acid (DHA) on intestinal permeability has rarely been reported. METHODS: Confluent Caco-2 cells on porous filter were used to measure tight junction function by fluorescein sulfonic acid permeability and transepithelial electrical resistance. Treatments with 0, 10, 50, and 100 microM of GLA or DHA during 24 h were compared. Then the effects of butylated hydroxytoluene (antioxidant), 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (protein kinase C antagonist), and inhibitors of enzymatic degradation to the eicosanoids, indomethacin (cyclooxygenase inhibitor) and 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone (lipoxygenase inhibitor), on GLA or DHA were examined. RESULTS: GLA and DHA enhanced fluorescein sulfonic acid permeability to 8.7- and 1.4-fold, respectively, and lowered transepithelial electrical resistance to 0.52- and 0.73-fold, respectively, versus the control in a concentration-dependent manner without cell injury (P < 0.001 to 0.05). Indomethacin and 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone enhanced the changes mediated by GLA but did not alter the DHA effect. Butylated hydroxytoluene was ineffective. 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine facilitated the changes mediated by GLA, DHA, and eicosapentaenoic acid. The results indicated that the mechanism to change tight junction permeability via protein kinase C regulation is common but that via eicosanoid formation differs among GLA, DHA, and eicosapentaenoic acid. CONCLUSIONS: GLA and DHA affect tight junction permeability in intestinal monolayer cells specifically and in a concentration-dependent manner.
Ursin, V. M. (2003). "Modification of plant lipids for human health: development of functional land-based omega-3 fatty acids." J Nutr 133(12): 4271-4.
We have remodeled canola seeds to accumulate the omega-3 fatty acid, stearidonic acid (SDA). In doing so, we have demonstrated the feasibility of developing a land-based source of functional omega-3 fatty acids on a large scale. Land-based omega-3 fatty acids represent a sustainable source of omega-3 fatty acids that can be produced on large acreages and delivered to consumers in a wide variety of functional foods. And unlike alpha-linolenic acid, SDA can provide eicosapentaenoic acid equivalence at moderate intakes. Widely applied, SDA-enriched foods could become a valuable tool for delivering recommended levels of omega-3 fatty acids to large portions of the population. By obviating the need for dietary changes, SDA-enriched foods may facilitate increased compliance with recommendations for daily omega-3 intakes.
Tully, A. M., H. M. Roche, et al. (2003). "Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study." Br J Nutr 89(4): 483-9.
Low n-3 polyunsaturated fatty acid (PUFA) status may be associated with neuro-degenerative disorders, in particular Alzheimer's disease, which has been associated with poor dietary fish or n-3 PUFA intake, and low docosahexaenoic acid (DHA) status. The present case-control study used an established biomarker of n-3 PUFA intake (serum cholesteryl ester-fatty acid composition) to determine n-3 PUFA status in patients with Alzheimer's disease, who were free-living in the community. All cases fulfilled the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria for Alzheimer's disease. Detailed neuropsychological testing and neuroimaging established the diagnosis in all cases. The subjects (119 females and twenty-nine males) aged 76.5 (SD 6.6) years had a clinical dementia rating (CDR) of 1 (SD 0.62) and a mini mental state examination (MMSE) score of 19.5 (SD 4.8). The control subjects (thirty-six females and nine males) aged 70 (SD 6.0) years were not cognitively impaired (defined as MMSE score <24): they had a mean MMSE score of 28.9 (SD 1.1). Serum cholesteryl ester-eicosapentaenoic acid and DHA levels were significantly lower (P<0.05 and P<0.001 respectively) in all MMSE score quartiles of patients with Alzheimer's disease compared with control values. Serum cholesteryl ester-DHA levels were progressively reduced with severity of clinical dementia. DHA levels did not differ in patients with Alzheimer's disease across age quartiles: all were consistently lower than in control subjects. Step-wise multiple regression analysis showed that cholesteryl ester-DHA and total saturated fatty acid levels were the important determinants of MMSE score and CDR. It remains to be determined whether low DHA status in Alzheimer's disease is a casual factor in the pathogenesis and progression of Alzheimer's disease.
Tsuji, M., S. I. Murota, et al. (2003). "Docosapentaenoic acid (22:5, n-3) suppressed tube-forming activity in endothelial cells induced by vascular endothelial growth factor." Prostaglandins Leukot Essent Fatty Acids 68(5): 337-42.
It is generally accepted that n-3 polyunsaturated fatty acids have beneficial effects on vascular homeostasis. Among the several functions of endothelial cells, angiogenesis contributes to tumor growth, inflammation, and microangiopathy. We have already demonstrated that eicosapentaenoic acid (EPA, 20:5, n-3) suppressed angiogenesis. In this paper, we examined the effect of docosapentaenoic acid (DPA, 22:5, n-3), an elongated metabolite of EPA, on tube-forming activity in bovine aortic endothelial cells (BAE cells) incubated between type I collagen gels. The pretreatment of BAE cells with DPA suppressed tube-forming activity induced by vascular endothelial growth factor (VEGF). The effect of DPA was stronger than those of EPA and docosahexaenoic acid (22:6, n-3). The migrating activity of endothelial cells stimulated with VEGF was also suppressed by DPA pretreatment. The treatment of BAE cells with DPA caused the suppression of VEGF receptor-2 (VEGFR-2, the kinase insert domain-containing receptor, KDR) expression in both plastic dish and collagen gel cultures. These data indicate that DPA has a potent inhibitory effect on angiogenesis through the suppression of VEGFR-2 expression.
Trebble, T., N. K. Arden, et al. (2003). "Inhibition of tumour necrosis factor-alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation." Br J Nutr 90(2): 405-12.
Increased dietary consumption of the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (20 : 5n-3; EPA) and docosahexaenoic acid (22 : 6n-6; DHA) is associated with their incorporation into circulating phospholipid and increased production of lipid peroxide metabolites. The relationship between peripheral blood mononuclear cell (PBMC) function, n-3 PUFA intake and antioxidant co-supplementation is poorly defined. We therefore investigated tumour necrosis factor (TNF)-alpha and interleukin (IL) 6 production by PBMC and phospholipid fatty acid composition in plasma and erythrocytes of healthy male subjects (n 16) receiving supplemental intakes of 0.3, 1.0 and 2.0 g EPA+DHA/d, as consecutive 4-week courses. All subjects were randomised in a double-blind manner to receive a concurrent antioxidant supplement (200 microg Se, 3 mg Mn, 30 mg D-alpha-tocopheryl succinate, 90 mg ascorbic acid, 450 microg vitamin A (beta-carotene and retinol)) or placebo. There was a positive dose-dependent relationship between dietary n-3 PUFA intake and EPA and DHA incorporation into plasma phosphatidylcholine and erythrocyte phosphatidylethanolamine, with a tendency towards a plateau at higher levels of intake. Production of TNF-alpha and IL-6 by PBMC decreased with increasing n-3 PUFA intake but tended towards a 'U-shaped' dose response. Both responses appeared to be augmented by antioxidant co-supplementation at intermediate supplementary n-3 PUFA intakes. Thus, increased dietary n-3 PUFA consumption resulted in defined but contrasting patterns of modulation of phospholipid fatty acid composition and PBMC function, which were further influenced by antioxidant intake.
Trebble, T. M., S. A. Wootton, et al. (2003). "Prostaglandin E2 production and T cell function after fish-oil supplementation: response to antioxidant cosupplementation." Am J Clin Nutr 78(3): 376-82.
BACKGROUND: Prostaglandin E(2) (PGE(2)) inhibits lymphocyte proliferation and the production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells, but the effect of PGE(2) on interleukin 4 (IL-4) production is unclear. Fish oil, which contains eicosapentaenoic and docosahexaenoic acids, inhibits production of PGE(2). The effects of fish oil on lymphocyte proliferation and production of IFN-gamma and IL-4 are unclear and may be influenced by the availability of antioxidants. OBJECTIVE: We investigated the effect of dietary fish oil with and without antioxidant cosupplementation on lymphocyte proliferation and the production of PGE(2), IFN-gamma, and IL-4 by peripheral blood mononuclear cells. DESIGN: Sixteen healthy men received dietary fish-oil supplements providing 0.3, 1, and 2 g eicosapentaenoic acid plus docosahexaenoic acid/d for 4 consecutive weeks each (total of 12 wk). All subjects were randomly assigned to daily cosupplementation with either antioxidants (200 microg Se, 3 mg Mn, 30 mg RRR-alpha-tocopheryl succinate, 90 mg ascorbic acid, 450 micro g vitamin A) or placebo. RESULTS: Fish-oil supplementation decreased PGE(2) production and increased IFN-gamma production and lymphocyte proliferation from baseline values. Cosupplementation with antioxidants did not affect cytokine production or lymphocyte proliferation. CONCLUSION: Dietary fish oil modulates production of IFN-gamma and lymphocyte proliferation in a manner consistent with decreased production of PGE(2), but this effect is not modified by antioxidant cosupplementation.
Trebble, T. M., S. A. Wootton, et al. (2003). "Essential fatty acid status in paediatric Crohn's disease: relationship with disease activity and nutritional status." Aliment Pharmacol Ther 18(4): 433-42.
BACKGROUND: Active paediatric Crohn's disease is associated with nutritional deficiencies and altered nutrient intake. The availability of essential fatty acids (linoleic and alpha-linolenic acids) or their derivatives (arachidonic and eicosapentaenoic acids) may alter in plasma and cell membrane phospholipid in protein-energy malnutrition in children and in Crohn's disease in adults. AIM: To investigate the relationship of fatty acid phospholipid profiles with disease activity and nutritional status in paediatric Crohn's disease. METHODS: The fatty acid (proportionate) composition of plasma and erythrocyte phosphatidylcholine was determined in 30 patients (10.3-17.0 years) stratified into active and quiescent Crohn's disease (paediatric Crohn's disease activity index) and high and low body mass (body mass index centile). RESULTS: In plasma phosphatidylcholine, active disease activity was associated with a lower level of alpha-linolenic acid compared with that in quiescent disease (P < 0.05). A body mass index below the 50th centile was associated with active Crohn's disease, low linoleic and alpha-linolenic acids and high arachidonic acid (P < 0.05) in plasma phosphatidylcholine, and low alpha-linolenic acid in erythrocyte phosphatidylcholine. These findings could not be explained through differences in habitual dietary fat intake. CONCLUSION: In paediatric Crohn's disease, a low body mass index centile and high disease activity are associated with altered profiles of essential fatty acids and their derivatives, which may reflect altered metabolic demand.
Tonon, T., D. Harvey, et al. (2003). "Identification of a very long chain polyunsaturated fatty acid Delta4-desaturase from the microalga Pavlova lutheri." FEBS Lett 553(3): 440-4.
Pavlova lutheri, a marine microalga, is rich in the very long chain polyunsaturated fatty acids (VLCPUFAs) eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids. Using an expressed sequence tag approach, we isolated a cDNA designated Pldes1, and encoding an amino acid sequence showing high similarity with polyunsaturated fatty acid front-end desaturases. Heterologous expression in yeast demonstrated that PlDES1 desaturated 22:5n-3 and 22:4n-6 into 22:6n-3 and 22:5n-6 respectively, and was equally active on both substrates. Thus, PlDES1 is a novel VLCPUFA Delta4-desaturase. Pldes1 expression is four-fold higher during the mid-exponential phase of growth compared to late exponential and stationary phases.
Tokudome, Y., K. Kuriki, et al. (2003). "Seasonal variation in consumption and plasma concentrations of fatty acids in Japanese female dietitians." Eur J Epidemiol 18(10): 945-53.
OBJECTIVE: To study seasonal variation in intake and plasma concentrations of fatty acids (FAs) in Japanese female dietitians. SUBJECTS AND METHODS: We assessed consumption of FAs based on four season 7 consecutive day weighed diet records from 71 Japanese female dietitians in 1996-1997. Using overnight fasting venous blood, plasma concentrations of FAs were analyzed by gas chromatography. Seasonal variation in consumption and plasma concentrations was examined by ANOVA for repeated values, followed by Tukey's multiple t-test. We calculated Spearman's partial rank correlation coefficients (CCs) between intake and plasma concentrations of FAs. Furthermore, we computed inter-seasonal Spearman's partial rank CCs for consumption and plasma concentrations of FAs. RESULTS: Statistically significant seasonal differences were observed in consumption for most FAs, except for myristic acid, monounsaturated FAs, oleic acid, n-6 polyunsaturated FAs (PUFAs), linoleic acid, gamma-linolenic acid, alpha-linolenic acid, PUFAs/saturated FAs, and n-6 PUFAs/n-3 PUFAs, and for most plasma concentrations, except for stearic acid, gamma-linolenic acid, n-3 PUFAs, alpha-linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and n-3 highly unsaturated FAs (HUFAs). However, statistically significant Spearman's partial rank CCs between intake and plasma concentrations were observed for EPA, DHA, n-3 HUFAs, n-6 PUFAs/n-3 PUFAs and n-6 PUFAs/n-3 HUFAs for almost all seasons. CONCLUSIONS: Seasonal variation exists in consumption and plasma concentrations of FAs, so that this should be taken into account in epidemiological analyses, including case-control and cohort studies.
Tisdale, M. J. (2003). "The 'cancer cachectic factor'." Support Care Cancer 11(2): 73-8.
The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month(-1). They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month(-1). Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E2(14k)), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.
Terry, P. D., T. E. Rohan, et al. (2003). "Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone-related cancers: a review of the epidemiologic evidence." Am J Clin Nutr 77(3): 532-43.
Marine fatty acids, particularly the long-chain eicosapentaenoic and docosahexaenoic acids, have been consistently shown to inhibit the proliferation of breast and prostate cancer cell lines in vitro and to reduce the risk and progression of these tumors in animal experiments. However, whether a high consumption of marine fatty acids can reduce the risk of these cancers or other hormone-dependent cancers in human populations is unclear. Focusing primarily on the results of cohort and case-control studies, we reviewed the current epidemiologic literature on the intake of fish and marine fatty acids in relation to the major hormone-dependent cancers. Despite the many epidemiologic studies that have been published, the evidence from those studies remains unclear. Most of the studies did not show an association between fish consumption or marine fatty acid intake and the risk of hormone-related cancers. Future epidemiologic studies will probably benefit from the assessment of specific fatty acids in the diet, including eicosapentaenoic and docosahexaenoic acids, and of the ratio of these to n-6 fatty acids, dietary constituents that have not been examined individually very often.
Tanaka, Y., M. Hashimoto, et al. (2003). "Effects of exercise on platelet and aortic functions in aged rats." Acta Physiol Scand 179(2): 155-65.
AIM AND METHODS: To assess age- and exercise-related changes in platelet aggregation, we measured the magnitude of platelet aggregation with a four-channel aggregometer, plasma and aortic polyunsaturated fatty acids by gas chromatography and related prostanoids with a reagent kit in young and aged non-exercised and in aged exercised rats. RESULTS: Platelet aggregation in platelet-rich plasma induced by ADP (5 microm) in the primary wave increased with age. In the non-exercised groups, the basal levels of thromboxane B2 in platelet-rich plasma increased in aged rats compared with young rats. In aged exercised rats, the basal levels of 6-keto-prostaglandin F1alpha in platelet-rich plasma were stimulated and those of thromboxane B2 were depressed, compared with non-exercised aged rats. The plasma levels of eicosapentaenoic acid and docosahexaenoic acid increased with age. Only aortic eicosapentaenoic acid in the aged group increased by exercise. In the aged non-exercised and exercised groups, the aortic, but not the plasma, levels of eicosapentaenoic acid correlated inversely with the basal levels of thromboxane B2 in platelet-rich plasma (r = -0.53, P < 0.05) and associated negatively with the magnitudes of platelet aggregation induced by ADP (5 microm) (r = -0.47, P < 0.05). CONCLUSION: These findings suggest that exercise in aged rats increases aortic eicosapentaenoic acid concentrations, which in turn depress the basal levels of thromboxane, B2 in platelet-rich plasma to modulate platelet aggregation.
Szabo, A., F. Husveth, et al. (2003). "Effects of transcutaneous electrical nerve stimulation on the fatty acid profile of rabbit longissimus dorsi muscle (preliminary report)." J Anim Physiol Anim Nutr (Berl) 87(9-10): 309-14.
This study was designed to investigate whether transcutaneous electrical nerve stimulation (TENS) of the longissimus dorsi muscle (MLD) of rabbits induces specific proportional changes in the muscle fatty acid composition. Ten 4-week-old Pannon White rabbits were exposed to TENS treatment two times a day, with the following settings: 30 Hz, 20 micros impulse length, 10 mA, 2 x 20 min. After a treatment period of 50 days rabbits were slaughtered and the fatty acid composition of the MLD was determined by gas chromatography. The TENS treatment increased the proportions of linoleic (C18:2 n-6), linolenic (C18:3 n-3) and gondoic acids (C20:1 n-9), compared with the control group. The level of palmitic (C16:0), stearic (C18:0), oleic (C18:1 n-9) and eicosapentaenoic (C20:5 n-3) acids significantly decreased. The proportion of total unsaturated fatty acids significantly increased. On the basis of the results obtained, TENS may have similar effects on the muscle fatty acid profile like physical training. Based on the supposal that the composition of membrane structure was also affected, the electrical stimulation of muscles may have further consequences, e.g. on membrane properties.
Swan, J. S., K. Dibb, et al. (2003). "Effects of eicosapentaenoic acid on cardiac SR Ca(2+)-release and ryanodine receptor function." Cardiovasc Res 60(2): 337-46.
n-3 polyunsaturated fatty acids (PUFAs) can prevent life-threatening arrhythmias but the mechanisms responsible have not been established. There is strong evidence that part of the antiarrhythmic action of PUFAs is mediated through inhibition of the Ca(2+)-release mechanism of the sarcoplasmic reticulum (SR). It has also been shown that PUFAs activate protein kinase A (PKA) and produce effects in the cardiac cell similar to beta-adrenergic stimulation. We have investigated whether the inhibitory effect of PUFAs on the Ca(2+)-release mechanism is caused by direct inhibition of the SR Ca(2+)-release channel/ryanodine receptor (RyR) or requires activation of PKA. Experiments in intact cells under voltage-clamp show that the n-3 PUFA eicosapentaenoic acid (EPA) is able to reduce the frequency of spontaneous waves of Ca(2+)-release while increasing SR Ca(2+) content even when PKA activity is inhibited with H-89. This suggests that the EPA-induced inhibition of SR Ca(2+)-release is not dependent on activation of PKA. Consistent with this, single-channel studies demonstrate that EPA (10-100 microM), but not saturated fatty acids, reduce the open probability (Po) of the cardiac RyR incorporated into phospholipid bilayers. EPA also inhibited the binding of [3H]ryanodine to isolated heavy SR. Our results indicate that direct inhibition of RyR channel gating by PUFAs play an important role in the overall antiarrhythmic properties of these compounds.
Suzuki, T., K. Fukuo, et al. (2003). "Eicosapentaenoic acid protects endothelial cells against anoikis through restoration of cFLIP." Hypertension 42(3): 342-8.
Dietary supplementation with eicosapentaenoic acid (EPA) improves the prognosis of chronic inflammatory diseases, including atherosclerosis. The mechanism underlying these beneficial effects, however, remains to be elucidated. Here we show that EPA protects endothelial cells from anoikis through upregulation of the cellular FLICE (Fas-associating protein with death domain-like interleukin-1-converting enzyme)-inhibitory protein (cFLIP), an endogenous inhibitor of caspase-8. EPA-induced upregulation of cFLIP expression was partially suppressed by the phosphatidylinositol-3-kinase inhibitor wortmannin. Conversely, treatment with insulinlike growth factor-1 (IGF-1), an activator of phosphatidylinositol-3-kinase/Akt signaling, or infection with an adenoviral construct expressing the constitutively active Akt gene induced upregulation of cFLIP expression. In addition, pretreatment of endothelial cells with either EPA or IGF-1 protected them from anoikis, suggesting that EPA-induced protection against anoikis is partially mediated through activation of Akt. On the other hand, when endothelial cells were already detached, treatment of these cells with EPA but not with IGF-1 protected them against anoikis. Importantly, EPA restored cFLIP expression without activating Akt signaling in detached endothelial cells, whereas IGF-1 had no effect. Additionally, exogenously restored expression of cFLIP by the tetracycline-regulated adenovirus system protected endothelial cells against anoikis. Furthermore, EPA was protective against the loss of endothelium in an organ culture of rat aortas. These findings suggest that EPA protects against endothelial cell anoikis through restoration of cFLIP expression, which might contribute to the mechanism underlying the beneficial effects of EPA in patients with hypertension.
Surh, J., J. S. Ryu, et al. (2003). "Seasonal variations of fatty acid compositions in various Korean shellfish." J Agric Food Chem 51(6): 1617-22.
Seasonal variations of fatty acids in various Korean shellfish were investigated in relation to the changes in total fatty acids contents, the ratio of polyunsaturated fatty acids to saturated fatty acids (P/S), and that of n-3 fatty acids to n-6 fatty acids (n-3/n-6). A distinct seasonal pattern was found in total fatty acids contents with maximal values in early summer and minimal values in late summer. The percentage of monounsaturated fatty acids was lowest in most species throughout the year. In summer months, the proportion of polyunsaturated fatty acids decreased while that of saturated fatty acids increased. The major contributing factor to the seasonal variation of polyunsaturated fatty acids was n-3 fatty acids. These results led to the lowest levels of P/S and n-3/n-6 in summer. Nevertheless, the data suggest that bivalve shellfish would be excellent sources of n-3 fatty acids, especially eicosapentaenoic acid and docosahexaenoic acid.
Surette, M. E., I. L. Koumenis, et al. (2003). "Inhibition of leukotriene synthesis, pharmacokinetics, and tolerability of a novel dietary fatty acid formulation in healthy adult subjects." Clin Ther 25(3): 948-71.
BACKGROUND: Numerous studies have explored dietary-management strategies for decreasing leukotriene synthesis by inflammatory cells through supplementation with polyunsaturated fatty acids such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA). OBJECTIVES: This study sought to determine the optimal daily intake, ratios, and formulation of dietary GLA and EPA required to safely reduce leukotriene biosynthesis in healthy individuals, and to evaluate the pharmacokinetics and safety profile of such a formulation. METHODS: Two preliminary trials were conducted to determine the minimum effective levels of GLA and EPA intake needed to reduce leukotriene biosynthesis and prevent increases in plasma arachidonic acid (AA) concentrations. These preliminary trials were followed by a single-center, randomized, double-blind, placebo-controlled, parallel-group, escalating-intake inpatient trial of a dietary GLA/EPA emulsion (PLT 3514) in healthy adult subjects. Subjects consumed either 10, 20, or 100 g of the PLT 3514 emulsion (respectively containing 0.75 g GLA + 0.5 g EPA, 1.5 g GLA + 1 g EPA, and 7.5 g GLA + 5 g EPA), or a placebo emulsion containing olive oil daily for 14 days. Plasma fatty acids were measured by gas chromatography Stimulated whole blood leukotrienes were measured by high-performance liquid chromatography with ultraviolet detection. RESULTS: Thirty subjects were included in the preliminary trials; 47 subjects were enrolled in the escalating-intake trial, of whom 42 completed the study. In the preliminary trials, intake of GLA 1.5 g/d in gelatin capsules decreased the capacity to synthesize leukotrienes but increased plasma levels of AA (both, P < 0.05). Inclusion of 0.25 or 1 g of dietary EPA prevented the increase in plasma AA concentrations. Dietary GLA and EPA showed significantly enhanced bioavailability when consumed in 20 g PLT 3514 emulsion compared with consumption in gelatin capsules (P < 0.05), resulting in a reduction in the amount of intake required to block leukotriene biosynthesis. Pharmacokinetic analyses indicated that fasting plasma GLA and EPA levels plateaued within 7 days' daily consumption at all levels of intake, whereas the time to maximum plasma concentration (Tmax) was shorter for GLA than for EPA. The Tmax was similar on days 1 and 14 for both GLA and EPA. There were no clinically significant between-group differences in changes in vital signs, mean clinical laboratory values, or abbreviated hematology laboratory tests, or significant differences in the occurrence of treatment-emergent adverse events between the group consuming up to 20 g/d of the GLA/EPA emulsion and the group consuming placebo. CONCLUSION: Consumption of specific proportions and intake levels of dietary GLA and EPA in a novel emulsion formulation inhibited leukotriene biosynthesis and appeared to be well tolerated in this population of healthy adult subjects.
Surette, M. E., I. L. Koumenis, et al. (2003). "Inhibition of leukotriene biosynthesis by a novel dietary fatty acid formulation in patients with atopic asthma: a randomized, placebo-controlled, parallel-group, prospective trial." Clin Ther 25(3): 972-9.
BACKGROUND: Leukotriene inhibitors and leukotriene-receptor antagonists are effective in the treatment of inflammatory diseases such as asthma. A search of the entirety of MEDLINE using the terms diet plus leukotrienes identified numerous studies that have explored dietary-management strategies to reduce leukotriene levels through supplementation with polyunsaturated fatty acids such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA). However, the search found no studies on the use of combinations of these fatty acids in patients with asthma. OBJECTIVE: The goal of this study was to determine the effect of daily intake of an emulsion (PLT 3514) containing dietary GLA and EPA on ex vivo stimulated whole blood leukotriene biosynthesis in patients with atopic asthma. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, prospective trial in patients with mild to moderate atopic asthma. Patients consumed 10 g PLT 3514 emulsion (containing 0.75 g GLA + 0.5 g EPA), 15 g PLT 3514 emulsion (containing 1.13 g GLA + 0.75 g EPA), or placebo (olive oil) emulsion daily for 4 weeks. Plasma fatty acids were measured by gas chromatography, and stimulated whole blood leukotrienes were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection using a diode array detector. RESULTS: Forty-three patients (33 women, 10 men) participated in the study. Leukotriene biosynthesis was significantly decreased in patients consuming 10 or 15 g PLT 3514 compared with placebo (P < 0.05, analysis of covariance). No clinically significant changes in vital signs were observed throughout the study, and there were no significant between-group differences in treatment-emergent adverse events or mean clinical laboratory values. CONCLUSION: Daily consumption of dietary GLA and EPA in a novel emulsion formulation inhibited leukotriene biosynthesis in this population of patients with atopic asthma and was well tolerated.
Suresh, Y. and U. N. Das (2003). "Long-chain polyunsaturated fatty acids and chemically induced diabetes mellitus: effect of omega-6 fatty acids." Nutrition 19(2): 93-114.
OBJECTIVE: We previously showed that prior oral supplementation of oils rich in omega-3, eicosapentaenoic acid and docosahexaenoic acid, and omega-6, gamma-linolenic acid and arachidonic acid, can prevent the development of alloxan-induced diabetes mellitus in experimental animals. But the effect of individual fatty acids on chemically induced diabetes mellitus is not known. We report the results of our studies with omega-6 fatty acids. METHODS: Alloxan-induced in vitro cytotoxicity and apoptosis in an insulin-secreting rat insulinoma cell line, RIN, was prevented by prior exposure of these cells to linoleic acid, gamma-linolenic acid, and arachidonic acid (AA) but not to dihomo-gamma-linolenic acid. Cyclo-oxygenase and lipoxygenase inhibitors did not block this protective action of AA. Prior oral supplementation with gamma-linolenic acid and pre- and simultaneous treatments with AA prevented alloxan-induced diabetes mellitus. RESULTS: Even though pretreatment with linoleic acid and dihomo-gamma-linolenic acid and simultaneous treatment with linoleic acid, gamma-linolenic acid, and dihomo-gamma-linolenic acid did not prevent the development of diabetes mellitus, the severity of diabetes was much less. The saturated fatty acid stearic acid and the monounsaturated fatty acid oleic acid were ineffective in preventing alloxan-induced diabetes mellitus. gamma-Linolenic acid and AA not only attenuated chemically induced diabetes mellitus but also restored the antioxidant status to normal range in various tissues. Changes in the concentrations of various fatty acids of the phospholipid fraction of plasma that occurred as a result of alloxan-induced diabetes mellitus also reverted to normal in the AA-treated animals. CONCLUSIONS: These results suggest that polyunsaturated fatty acids can prevent chemically induced diabetes in experimental animals and attenuate the oxidant stress that occurs in diabetes mellitus.
Suresh, Y. and U. N. Das (2003). "Long-chain polyunsaturated fatty acids and chemically induced diabetes mellitus. Effect of omega-3 fatty acids." Nutrition 19(3): 213-28.
In a previous study, we showed that prior oral feeding of oils rich in omega-3 eicosapentaenoic acid and docosahexaenoic acid and omega-6 gamma-linolenic acid and arachidonic acid prevent the development of alloxan-induced diabetes mellitus in experimental animals. We also observed that 99% pure omega-6 fatty acids gamma-linolenic acid and arachidonic acid protect against chemically induced diabetes mellitus. Here we report the results of our studies with omega-3 fatty acids. Alloxan-induced in vitro cytotoxicity and apoptosis in an insulin-secreting rat insulinoma cell line, RIN, was prevented by prior exposure of these cells to alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. Prior oral supplementation with alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid prevented alloxan-induced diabetes mellitus. alpha-Linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid not only attenuated chemical-induced diabetes mellitus but also restored the anti-oxidant status to normal range in various tissues. These results suggested that omega-3 fatty acids can abrogate chemically induced diabetes in experimental animals and attenuate the oxidant stress that occurs in diabetes mellitus.
Sun, D., A. Krishnan, et al. (2003). "Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice." J Bone Miner Res 18(7): 1206-16.
The mechanisms of action of dietary fish oil (FO) on osteoporosis are not fully understood. This study showed FO decreased bone loss in ovariectomized mice because of inhibition of osteoclastogenesis. This finding supports a beneficial effect of FO on the attenuation of osteoporosis. INTRODUCTION: Consumption of fish or n-3 fatty acids protects against cardiovascular and autoimmune disorders. Beneficial effects on bone mineral density have also been reported in rats and humans, but the precise mechanisms involved have not been described. METHODS: Sham and ovariectomized (OVX) mice were fed diets containing either 5% corn oil (CO) or 5% fish oil (FO). Bone mineral density was analyzed by DXA. The serum lipid profile was analyzed by gas chromatography. Receptor activator of NF-kappaB ligand (RANKL) expression and cytokine production in activated T-cells were analyzed by flow cytometry and ELISA, respectively. Osteoclasts were generated by culturing bone marrow (BM) cells with 1,25(OH)2D3. NF-kappaB activation in BM macrophages was measured by an electrophoretic mobility shift assay. RESULTS AND CONCLUSION: Plasma lipid C16:1n6, C20:5n3, and C22:6n3 were significantly increased and C20:4n6 and C18:2n6 decreased in FO-fed mice. Significantly increased bone mineral density loss (20% in distal left femur and 22.6% in lumbar vertebrae) was observed in OVX mice fed CO, whereas FO-fed mice showed only 10% and no change, respectively. Bone mineral density loss was correlated with increased RANKL expression in activated CD4+ T-cells from CO-fed OVX mice, but there was no change in FO-fed mice. Selected n-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) added in vitro caused a significant decrease in TRACP activity and TRACP+ multinuclear cell formation from BM cells compared with selected n-6 fatty acids (linoleic acid [LA] and arachidonic acid [AA]). DHA and EPA also inhibited BM macrophage NF-kappaB activation induced by RANKL in vitro. TNF-alpha, interleukin (IL)-2, and interferon (IFN)-gamma concentrations from both sham and OVX FO-fed mice were decreased in the culture medium of splenocytes, and interleukin-6 was decreased in sham-operated FO-fed mice. In conclusion, inhibition of osteoclast generation and activation may be one of the mechanisms by which dietary n-3 fatty acids reduce bone loss in OVX mice.
Sumino, H., S. Ichikawa, et al. (2003). "Effects of hormone replacement therapy on circulating docosahexaenoic acid and eicosapentaenoic acid levels in postmenopausal women." Endocr J 50(1): 51-9.
Hormone replacement therapy (HRT) has antiatherosclerotic effects of which the mechanism remains unclear. The ingestion of fish oil or other sources of n-3 polyunsaturated fatty acids has been included in comprehensive strategies to prevent atherosclerosis. Many epidemiologic studies have shown that the dietary intake of docosahexaenoic acid and eicosapentaenoic acid has antiatherosclerotic effects. We investigated the effect of HRT on plasma docosahexaenoic acid and eicosapentaenoic acid concentrations in postmenopausal women. Fifty-nine postmenopausal women, who received conjugated estrogens (0.625 mg/day) and medroxyprogesterone (2.5 mg/day) for 12 months, and 45 control postmenopausal women, who did not receive HRT, volunteered to participate in this study. Plasma docosahexaenoic acid and eicosapentaenoic acid concentrations were measured at baseline and at 6 and 12 months after the start of HRT. HRT significantly increased the plasma docosahexaenoic acid and eicosapentaenoic acid concentrations from 134 +/- 5 microg/ml and 69 +/- 4 microg/ml at baseline to 156 +/- 7 microg/ml and 85 +/- 7 microg/ml after 12 months (both p<0.01). However, the control group showed no significant change in their plasma docosahexaenoic acid and eicosapentaenoic acid levels during the study. HRT increased plasma docosahexaenoic acid and eicosapentaenoic acid levels in postmenopausal women. We propose that the increase in docosahexaenoic acid and eicosapentaenoic acid may be partially responsible for the beneficial mechanisms by which HRT induces an antiatherosclerotic effect in postmenopausal women.
Su, K. P., S. Y. Huang, et al. (2003). "Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial." Eur Neuropsychopharmacol 13(4): 267-71.
Patients with depression have been extensively reported to be associated with the abnormality of omega-3 polyunsaturated fatty acids (PUFAs), including significantly low eicosapentaenoic acid and docosahexaenoic acid in cell tissue contents (red blood cell membrane, plasma, etc.) and dietary intake. However, more evidence is needed to support its relation. In this study, we conducted an 8-week, double-blind, placebo-controlled trial, comparing omega-3 PUFAs (9.6 g/day) with placebo, on the top of the usual treatment, in 28 patients with major depressive disorder. Patients in the omega-3 PUFA group had a significantly decreased score on the 21-item Hamilton Rating Scale for Depression than those in the placebo group (P < 0.001). From the preliminary findings in this study, omega-3 PUFAs could improve the short-term course of illness and were well tolerated in patients with major depressive disorder.
Stene, L. C. and G. Joner (2003). "Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study." Am J Clin Nutr 78(6): 1128-34.
BACKGROUND: In Norway, cod liver oil is an important source of dietary vitamin D and the long-chain n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid, all of which have biological properties of potential relevance for the prevention of type 1 diabetes. OBJECTIVE: The main objective was to investigate whether the use of dietary cod liver oil or other vitamin D supplements, either by the mother during pregnancy or by the child during the first year of life, is associated with a lower risk of type 1 diabetes among children. DESIGN: We designed a nationwide case-control study in Norway with 545 cases of childhood-onset type 1 diabetes and 1668 population control subjects. Families were contacted by mail, and they completed a questionnaire on the frequency of use of cod liver oil and other vitamin D supplements and other relevant factors. RESULTS: Use of cod liver oil in the first year of life was associated with a significantly lower risk of type 1 diabetes (adjusted odds ratio: 0.74; 95% CI: 0.56, 0.99). Use of other vitamin D supplements during the first year of life and maternal use of cod liver oil or other vitamin D supplements during pregnancy were not associated with type 1 diabetes. CONCLUSION: Cod liver oil may reduce the risk of type 1 diabetes, perhaps through the antiinflammatory effects of long-chain n-3 fatty acids.
Spector, S. L. and M. E. Surette (2003). "Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma?" Ann Allergy Asthma Immunol 90(4): 371-7; quiz 377-8, 421.
OBJECTIVE: This article discusses the role of diet in the management of asthma. Readers will gain an understanding of how evolution of the western diet has contributed to increased asthma prevalence and how dietary modification that includes management of dietary lipids may reduce symptoms of asthma. DATA SOURCES: Relevant studies published in English were reviewed. STUDY SELECTION: Medline search to identify peer-reviewed abstracts and journal articles. RESULTS: Asthma and obesity, which often occur together, have increased in prevalence in recent years. Studies suggest adaption of a western diet has not only contributed to obesity, but that increased intake of specific nutrients can cause changes in the frequency and severity of asthma. Increased asthma prevalence has also been proposed to arise from increased exposure to diesel particles or lack of exposure to infectious agents or endotoxins during childhood, generating a biased Th2 immune response, and increased cytokine and leukotriene production. Antagonists directed against these pro-inflammatory mediators include anticytokines and antileukotrienes. A reduction in the levels of inflammatory mediators associated with asthma has also been seen with dietary interventions, such as the administration of oils containing gamma-linolenic acid and eicosapentaenoic acid. CONCLUSIONS: Evidence suggests elevated body mass index and dietary patterns, especially intake of dietary lipids, contribute to symptoms of asthma. Dietary modification may help patients manage their asthma as well as contribute to their overall health.
Song, C., X. Li, et al. (2003). "Effects of dietary n-3 or n-6 fatty acids on interleukin-1beta-induced anxiety, stress, and inflammatory responses in rats." J Lipid Res 44(10): 1984-91.
The present study demonstrated that an omega (n)-3 fatty acid, ethyl-eicosapentaenoic acid (ethyl-EPA), supplemented diet significantly attenuated the stress/anxiety behavior of rats in the "open field" and elevated plus maze, which was induced by subchronic intracerebroventricular administration of proinflammatory cytokine interleukin (IL)-1beta. Ethyl-EPA also reduced the rise in serum corticosterone induced by IL-1. The n-6 fatty acid ethyl-gamma-linolenic acid (ethyl-GLA) had little effect on the IL-1-induced changes in behavior and the corticosterone concentration. Following IL-1beta administration, ethyl-EPA reduced the elevated prostaglandin (PG) E2 secretion and increased the secretion of antiinflammatory cytokine IL-10 from whole blood cells. Ethyl-GLA showed a similar antiinflammatory effect to ethyl-EPA. By contrast, n-6 fatty acid arachidonic acid (AA) had no effect on the behavior, immune, and endocrine changes induced by IL-1. AA alone enhanced the basal inflammatory response, raised serum corticosterone concentrations, and induced anxiety behavior in the elevated plus maze. The reduced growth rates of rats following the administration of IL-1 was attenuated by ethyl-EPA, and to a greater extent by ethyl-EPA plus ethyl-GLA, but not by AA alone or in combination with ethyl-EPA. Thus, ethyl-EPA would appear to antagonise the endocrine, immune, and behavioral effects of subchronic IL-1 administration. Ethyl-GLA only antagonised IL-1-induced inflammatory changes, whereas AA caused an increase in the secretion of corticosterone and PGE2, and induced anxiety-like behavior without enhancing the effects of IL-1.
Song, C., A. G. Phillips, et al. (2003). "Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by cen