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Polyunsaturated Fatty Acids (PUFAs) References
(644 References)

Yazdani, M., K. Ide, et al. (2004). "Effects of Caffeine on the Saturated and Monounsaturated Fatty Acids of the Newborn Rat Cerebellum." Ann Nutr Metab 48(2): 79-83.

            Caffeine (1,3,7-trimethylxanthine) is one of the most commonly consumed drugs in our daily life, and its use is increasing. However, very little attention has been paid to its potential effects on early growth and development. Because of the steady increase in breast feeding of infants and because caffeine diffuses readily into breast milk, the present study examined if caffeine intake by newborn rats during lactation would affect the saturated and monounsaturated fatty acids in the growing cerebellum. A total of 10 timed pregnant rats were purchased from the breeder. At birth litters were combined, and 8 pups were randomly assigned to each dam without regard to the sex of the pups. Dams with litters were divided into 2 groups. Dams of group 1 received a 20% protein diet as a control, and dams of group 2 received a 20% protein diet plus caffeine (4 mg/100 g BW). Pups were killed at day 10. The cerebellums were removed, weighed and homogenized. Gas chromatograph-mass spectrometry was used to identify and quantify free fatty acids. Chronic caffeine exposure from birth to day 10 in pups through the maternal milk resulted in a decrease in cerebellum weight, a significant increase in the saturated fatty acids, and a tendency toward an increase of monounsaturated fatty acids. In addition, there was a slight increase of some of the polyunsaturated fatty acids. However, there was no difference in food intake of the lactating dams and weight gain of the pups between the groups. These data indicate that early caffeine intake by the suckling pups alters the composition of fatty acids of the cerebellum; thus, avoidance of caffeine during lactation is critical. The risks and benefits of caffeine administration in premature infants must be carefully evaluated during this rapid period of brain growth. Copyright 2004 S. Karger AG, Basel

Yamada, S., T. Funada, et al. (2004). "Protein-bound 4-hydroxy-2-hexenal as a marker of oxidized n-3 polyunsaturated fatty acids." J Lipid Res.

            In the present study, to investigate the contribution of n-3 polyunsaturated fatty acids (n-3 PUFAs) in the oxidative modification of protein in vivo, we characterize the covalent binding of 4-hydroxy-2-hexenal (HHE), a potent cytotoxic aldehyde originating from the peroxidation of n-3 PUFAs, to protein and describe the production of this aldehyde in oxidatively modified LDL and in human atherosclerotic lesions. Upon incubation with bovine serum albumin, HHE was rapidly incorporated into the protein and generated the protein-linked carbonyl derivative, a potential marker of oxidatively modified proteins under oxidative stress. To detect the protein-bound HHE in vivo, we raised a monoclonal antibody HHE53 (mAb HHE53) directed to the HHE-modified protein and identified the Michael addition-type HHE-histidine adduct as the major epitope. This antibody reacted with copper-oxidized LDL, suggesting that HHE was produced during the oxidative modification of LDL. In addition, we demonstrated that the materials immunoreactive to mAb HHE53 indeed constituted the atherosclerotic lesions, in which intense positivity was associated primarily with macrophage-derived foam cells. The results of this study suggest that the reaction between oxidized n-3 PUFAs and protein might represent a process common to the formation of degenerative proteins during aging and its related diseases.

Tocher, D. R., J. Fonseca-Madrigal, et al. (2004). "Effects of water temperature and diets containing palm oil on fatty acid desaturation and oxidation in hepatocytes and intestinal enterocytes of rainbow trout (Oncorhynchus mykiss)." Comp Biochem Physiol B Biochem Mol Biol 137(1): 49-63.

            Food grade fisheries have reached their sustainable limits while aquaculture production has increased to meet consumer demands. However, for growth in aquaculture to continue and utilise sustainable, feeding ingredients, alternatives to fish oil (FO), the predominant lipid component of fish diets, must be developed. Therefore, there is currently considerable interest in the regulation of fatty acid metabolism in fish in order to determine strategies for the best use of plant oils in diets for commercially important cultured fish species. Plant oils are characteristically rich in C(18) polyunsaturated fatty acids (PUFA) but devoid of C(20) and C(22) highly unsaturated fatty acids (HUFA) found in FO. The fatty acyl desaturase enzyme activities involved in the biosynthesis of HUFA from PUFA are known to be under nutritional regulation and can be increased in fish fed diets rich in plant oils. However, fatty acid desaturase activity is also known to be modulated by water temperature in fish. The present study aimed to investigate the interaction between water temperature and diet in the regulation of fatty acid metabolism in rainbow trout. Trout, acclimatized to 7, 11 or 15 degrees C, were fed for 4 weeks on diets in which the FO was replaced in a graded manner by palm oil. At the end of the trial, fatty acyl desaturation/elongation and beta-oxidation activities were determined in isolated hepatocytes and intestinal enterocytes using [1-(14)C]18:3n-3 as substrate, and samples of liver were collected for analysis of lipid and fatty acid composition. The most obvious effect of temperature was that fatty acid desaturation/elongation and beta-oxidation were reduced in both hepatocytes and intestinal enterocytes from fish maintained at the highest water temperature (15 degrees C). There were differences between the two tissues with the highest desaturation/elongation and beta-oxidation activities tending to be in fish held at 11 degrees C in the case of hepatocytes, but 7 degrees C in enterocytes. Correlations between fatty acid metabolism and dietary palm oil were most clearly observed in desaturation/elongation activities in both hepatocytes and enterocytes at 11 degrees C. The highest beta-oxidation activities were generally observed in fish fed FO alone in both hepatocytes and enterocytes with palm oil having differential effects in the two cell types.

Skeaff, C. M., K. Williscroft, et al. (2004). "Replacing cows' with sheep's dairy fat lowers plasma cholesterol concentration in participants consuming dairy fat-rich diets." Eur J Clin Nutr 58(2): 250-7.

            OBJECTIVE:: To determine the effects on plasma cholesterol concentration of replacing cows' dairy fat with sheep's dairy fat. DESIGN:: Randomised crossover dietary intervention. SETTING:: General community, Dunedin, New Zealand. SUBJECTS:: Volunteer sample of 41 healthy adults with initial plasma cholesterol concentration between 4.8 and 7.8 mmol/l. INTERVENTIONS:: Participants were asked to follow a self-selected low-fat background diet throughout the study to which, during each of the 2, 3-week dairy diets, they were asked to add sheep's or cows' dairy products. MAIN OUTCOME MEASURES:: Energy and nutrient intakes, plasma triacylglycerol fatty acids, and plasma cholesterol. RESULTS:: Energy and nutrient intakes on the sheep-dairy and cow-dairy diets were very similar, with total, saturated, monounsaturated and polyunsaturated fat contributing 34, 18-19, 9, and 3% of total energy intake, respectively. Participants consumed approximately 50 g/day of dairy fat on each diet. Replacing cows' with sheep's dairy fat led to a 0.33 (0.11-0.56, 95% CI) mmol/l decrease (6%) in plasma total cholesterol concentration, from 5.53 (0.90, s.d.) to 5.20 (0.90) mmol/l. Plasma low-density lipoprotein (LDL) cholesterol was 0.18 (0.02-0.33) mmol/l lower on the sheep-dairy diet as was the concentration of plasma high-density lipoprotein (HDL) cholesterol, 0.11 (0.02-0.20) mmol/l. The LDL to HDL cholesterol ratio at the end of the sheep-dairy diet, 2.91 (1.10), was not significantly different (P>0.05) from the cow-dairy diet, 2.73 (0.83). CONCLUSIONS:: Within the context of a diet high in dairy fat (50 g/day), replacing cows' milk fat with sheep's milk fat leads to a small reduction in plasma cholesterol concentration, but no change in the ratio of LDL to HDL cholesterol. SPONSORSHIP:: Foundation for Research Science and Technology, New Zealand Government; Frontiers Group Company Limited.European Journal of Clinical Nutrition (2004) 58, 250-257. doi:10.1038/sj.ejcn.1601774

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.

Sarkadi-Nagy, E., V. Wijendran, et al. (2004). "Formula feeding potentiates docosahexaenoic and arachidonic acid biosynthesis in term and preterm baboon neonates." J Lipid Res 45(1): 71-80.

            Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula+DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 +/- 0.22%wt DHA and 0.62 +/- 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-(13)C]alpha-linolenic acid (LNA*) and [U-(13)C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was approximately 3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group. These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels.

Rasanen, M., S. Keskinen, et al. (2004). "Impact of nutrition counselling on nutrition knowledge and nutrient intake of 7- to 9-y-old children in an atherosclerosis prevention project." Eur J Clin Nutr 58(1): 162-72.

            OBJECTIVE:: To assess the impact of nutrition counselling given to 7.5- to 9-y-old children and their parents on children's nutrition knowledge and nutrient intakes. DESIGN AND SUBJECTS:: The study children are participants in a prospective, randomised STRIP study (Special Turku Coronary Risk Factor Intervention Project for Children), whose aim was to decrease the intakes of saturated fat and cholesterol while increasing the intake of unsaturated fat in the intervention children from the age of 7 months onwards. Nutrition counselling was given only to the parents until the child's age of 7 y. Nutrition knowledge and nutrient intakes (total energy, total fat, saturated fat, unsaturated fat and sodium) were studied in a time-restricted cohort of 47, 7-y-old intervention and 51 control children. Thereafter, nutrition counselling was given both to the children and parents. Children's nutrition knowledge and nutrient intakes were measured again at the age of 9 y. RESULTS:: Biannual nutrition counselling given to the intervention children and the parents maintained the differences in saturated fatty acid intake attained during the intervention given to the parents alone (11.5 vs 13.3 E% (percent of energy intake), at the age of 7 y, P<0.01; 11.1 vs 13.4 E% at the age of 9 y, respectively; P<0.01). The intervention children used more polyunsaturated fatty acids at the age of 9 y than the control children (5.7 vs 5.1 E%, P=0.05). At 7 y, the intervention and control children had similar nutrition knowledge scores (total knowledge score 12.9 vs 12.0, respectively, P=0.13). After 1.5 y of nutrition intervention, at 9 y, the intervention children's nutrition knowledge was higher than that of the controls (total nutrition score 16.5 vs 13.2, respectively, P<0.001) and the ability to explain the reasons for their picture choices in the nutrition knowledge test had increased. CONCLUSION:: This study showed that only a relatively short period of counselling with low input is needed to increase in children's nutrition knowledge and ability to explain nutrition-related subjects if advice has first been given to the parents and if the parents have received reinforcement and concrete help with parent-child communication after their children have been involved in the counselling. The differences attained in nutrient intake could also be maintained.European Journal of Clinical Nutrition (2004) 58, 162-172. doi:10.1038/sj.ejcn.1601763

Pitkanen, O. M., P. Luukkainen, et al. (2004). "Attenuated Lipid Peroxidation in Preterm Infants during Subsequent Doses of Intravenous Lipids." Biol Neonate 85(3): 184-187.

            The aim of this study was to determine whether the administration of a lipid emulsion containing less polyunsaturated fatty acids but rich in monounsaturated fatty acids causes less in vivo lipid peroxidation in preterm infants. The prospective intervention study included 13 infants with birth weights and gestational ages ranging between 1,100 and 2,660 g and from 28.4 to 32.9 weeks. All were in a stable condition and randomly allocated for a 3-hour infusion (0.16 g/kg/h) of an olive oil-based and a soybean oil + medium chain fatty acid (MCT) emulsion on 2 consecutive days. Expired pentane and plasma triglycerides (TGs) were measured before, during, and after the 3-hour infusion. Basal exhaled pentane averaged 9.4 +/- 7.0 pmol/kg/min (mean +/- SD). During the olive oil-based emulsion, exhaled pentane increased to 95.2 +/- 56.7, and during soybean oil + MCT it increased to 110 +/- 93.9 pmol/kg/min (p < 0.05 both from basal, n.s. between preparations). One hour after discontinuation of the infusion, exhaled pentane returned to 21.1 +/- 12.6 pmol/kg/min (p < 0.05 vs. basal). Combined data on expired pentane measurements demonstrated that on day 1 pentane peaked at 124 +/- 87.0 pmol/kg/min which was significantly attenuated to 57.5 +/- 24.4 pmol/kg/min after an identical dose of lipid on day 2 (p < 0.05). No difference in peak TGs was detected between the two preparations or the study days. Infusion of a constant dose of intravenous lipids on 2 subsequent days to the newborn infants is associated with a reduction in lipid peroxidation. This finding may be dependent on normal postnatal maturation or may represent an appropriate adaptive response aiming at a reduction in oxidative stress. Peroxidation of soybean oil + MCT and olive oil-based lipid emulsions was similar in the newborn infants. Copyright 2004 S. Karger AG, Basel

O'Keefe, J. H., Jr. and L. Cordain (2004). "Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer." Mayo Clin Proc 79(1): 101-8.

            Our genetic make-up, shaped through millions of years of evolution, determines our nutritional and activity needs. Although the human genome has remained primarily unchanged since the agricultural revolution 10,000 years ago, our diet and lifestyle have become progressively more divergent from those of our ancient ancestors. Accumulating evidence suggests that this mismatch between our modern diet and lifestyle and our Paleolithic genome is playing a substantial role in the ongoing epidemics of obesity, hypertension, diabetes, and atherosclerotic cardiovascular disease. Until 500 generations ago, all humans consumed only wild and unprocessed food foraged and hunted from their environment. These circumstances provided a diet high in lean protein, polyunsaturated fats (especially omega-3 [omega-3] fatty acids), monounsaturated fats, fiber, vitamins, minerals, antioxidants, and other beneficial phytochemicals. Historical and anthropological studies show hunter-gatherers generally to be healthy, fit, and largely free of the degenerative cardiovascular diseases common in modern societies. This review outlines the essence of our hunter-gatherer genetic legacy and suggests practical steps to re-align our modern milieu with our ancient genome in an effort to improve cardiovascular health.

Murthy, S., E. Born, et al. (2004). "Liver-X-receptor-mediated increase in ATP-binding cassette transporter A1 expression is attenuated by fatty acids in CaCo-2 cells: effect on cholesterol efflux to high-density lipoprotein." Biochem J 377(Pt 3): 545-52.

            The effect of fatty acids on LXR (liver X receptors)-mediated enhancement of ABCA1 (ATP-binding cassette transporter A1) expression and cholesterol efflux was investigated in human intestinal cells CaCo-2. LXR activation by T0901317 increased basolateral cholesterol efflux to lipoprotein particles isolated at a density of 1.21 g/ml or higher. Oleic and arachidonic acids attenuated the amount of cholesterol isolated from these particles. Stearic, linoleic and docosahexaenoic acids also decreased cholesterol efflux from basolateral membranes, with the polyunsaturated fatty acids being the most potent. Although oleic, arachidonic and docosahexaenoic acids modestly decreased ABCA1 mRNA levels in response to LXR activation, stearic and linoleic acids did not. Except for oleic acid, all fatty acids substantially attenuated an increase in ABCA1 mass secondary to LXR activation. Inhibiting acyl-CoA:cholesterol acyltransferase activity prevented the decrease in cholesterol efflux caused by oleic acid. Thus, in response to LXR activation, all fatty acids decreased the efflux of cholesterol from the basolateral membrane of CaCo-2 cells. Although modest suppression of ABCA1 gene expression by oleic, arachidonic and docosahexaenoic acids cannot be completely excluded as a mechanism, the predominant effect of fatty acids on ABCA1 expression and cholesterol efflux is at a post-transcriptional level.

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.

Morise, A., C. Serougne, et al. (2004). "Effects of dietary alpha linolenic acid on cholesterol metabolism in male and female hamsters of the LPN strain." J Nutr Biochem 15(1): 51-61.

            N-3 polyunsaturated fatty acids and estrogens are recognized as protective factors of atherosclerosis, however their interactions on cholesterol metabolism remain unclear. Male and female hamsters were fed for 9 weeks diets containing 12.5% lipids and rich in either alpha-linolenic acid ("linseed" diet) or saturated fatty acids ("butter" diet). Hamsters fed the "linseed" diet exhibited lower plasma concentrations of cholesterol (-29%), total LDL (-35%) and HDL (-17%), glucose (-20%), insulin (-40%) and of the LDL-cholesterol/HDL-cholesterol ratio (-27%) than those fed the "butter" diet. In the liver, cholesterol content was 2.7-fold lower in response to the "linseed" diet, whereas the concentration of HDL receptor (SR-BI) and the activities of HMGCoA reductase and cholesterol 7alpha-hydroxylase were 30 to 50% higher than with the "butter" diet. By contrast, the LDL receptor concentration did not vary with the diet. Females exhibited higher concentration of LDL (+24%), lower concentration of plasma triglycerides (-34%), total VLDL (-46%) and VLDL-cholesterol (-37%) and of biliary phospholipids (-19%). Besides, there was also an interaction between gender and diet: in males fed the "butter" diet, plasma triglycerides and VLDL concentration, were 2 to 4 fold higher than in the other groups. These data suggest that gene and/or metabolic regulations by fatty acids could interact with that of sex hormones and explain why males are more sensitive to dietary fatty acids.

Meyer, B. J., T. A. Larkin, et al. (2004). "Limited Lipid-Lowering Effects of Regular Consumption of Whole Soybean Foods." Ann Nutr Metab 48(2): 67-78.

            AIM: To examine cardiovascular health benefits of foods containing a whole soybean extract. METHODS: The study design was a randomized, placebo-controlled crossover trial of consuming soy-based milk and yoghurt (treatment) or equivalent dairy products (control) for 5 weeks each. Twenty-six mildly hypercholesterolaemic and/or hypertensive volunteers were recruited from the community as study volunteers, of which 23 completed. Main outcome measures included clinic and ambulatory blood pressure, arterial compliance, lipids, fatty acids and isoflavones in fasted blood and 24-hour urinary isoflavone excretion. Nutrient intakes were assessed initially and after each 5-week period. Multiple regression analyses were used to determine predictor variables in statistical models; order effects were tested by repeated measures ANOVA. Changes in Lp(a) were determined by Wilcoxon signed ranks tests; other differences between treatment and control were assessed by t tests. RESULTS: Plasma and urinary isoflavones were markedly increased by whole soy supplementation but there were no overall differences in plasma lipids, blood pressure or arterial compliance between the soy and dairy diets. However, in 8 equol-positive subjects (equol detected in either plasma or urine), retrospective analysis revealed significant reductions in total cholesterol (8.5%), LDL cholesterol (10%), LDL:HDL ratio (13.5%), plasma triglycerides (21%) and lipoprotein(a) (11%) with the soy diet. These reductions were independent of changes in polyunsaturated fat and other macronutrient intakes. CONCLUSIONS: Regular consumption of whole soybean milk and yogurt products had no effect on plasma lipids, blood pressure or arterial compliance in at-risk subjects, despite substantially increasing isoflavone levels in blood and urine. Retrospective analysis suggests that improvement of plasma lipids may have been limited to equol-positive subjects. Copyright 2004 S. Karger AG, Basel

Macdonald, H. M., S. A. New, et al. (2004). "Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids." Am J Clin Nutr 79(1): 155-65.

            BACKGROUND: The menopausal transition is characterized by rapid bone loss. Few data exist on the role of nutrition. OBJECTIVE: The objective of the study was to ascertain which dietary factors influence perimenopausal skeletal loss. DESIGN: A longitudinal study was conducted of 891 women aged 45-55 y at baseline and 50-59 y at follow-up 5-7 y later. Bone mineral density (BMD) was measured by using dual-energy X-ray absorptiometry at the lumbar spine and femoral neck (FN). Nutrient intakes were assessed after the baseline visit and 5 y later, by using the same food-frequency questionnaire. RESULTS: After adjustment for energy intake and other confounders, higher intakes of calcium were correlated with change in FN BMD (ie, reduced loss) (r = 0.073, P < 0.05), and the intake of modest amounts of alcohol was associated with less lumbar spine bone loss (P < 0.01 for quartile of alcohol intake). Greater FN BMD loss was associated with increased intake of polyunsaturated fatty acids (r = -0.110, P < 0.01), monounsaturated fatty acids (r = -0.069, P < 0.05), retinol (r = -0.067; P < 0.05), and vitamin E (r = -0.110; P < 0.01). The latter 2 nutrients were highly correlated with polyunsaturated fatty acids. For premenopausal women, calcium and nutrients found in fruit and vegetables (vitamin C, magnesium, and potassium) were associated with FN BMD, and calcium, vitamin C, and magnesium were associated with change in FN BMD. CONCLUSIONS: Although menopausal status and hormone replacement therapy use dominate women's bone health, diet may influence early postmenopausal bone loss. Fruit and vegetable intake may protect against premenopausal bone loss.

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.

Iribarren, C., J. H. Markovitz, et al. (2004). "Dietary intake of n-3, n-6 fatty acids and fish: Relationship with hostility in young adults-the CARDIA study." Eur J Clin Nutr 58(1): 24-31.

            BACKGROUND:: Hostility has been shown to predict both the development and manifestation of coronary disease. Examining the inter-relation of dietary intake of fish and of polyunsaturated (n-3 and n-6) essential fatty acids with hostility may provide additional insights into the cardioprotective effect of dietary fish and polyunsaturated fatty acids. OBJECTIVE:: To examine the association of dietary n-3, n-6 fatty acids and fish with level of hostility in a sample of 3581 urban white and black young adults. DESIGN:: Cross-sectional observational study as part of an ongoing cohort study. A dietary assessment in 1992-1993 and measurement of hostility and other covariates in 1990-1991 were used in the analysis. RESULTS:: The multivariate odds ratios of scoring in the upper quartile of hostility (adjusting for age, sex, race, field center, educational attainment, marital status, body mass index, smoking, alcohol consumption and physical activity) associated with one standard deviation increase in docosahexaenoic acid (DHA, 22:6) intake was 0.90 (95% CI=0.82-0.98; P=0.02). Consumption of any fish rich in n-3 fatty acids, compared to no consumption, was also independently associated with lower odds of high hostility (OR=0.82; 95% CI=0.69-0.97; P=0.02). CONCLUSIONS:: These results suggest that high dietary intake of DHA and consumption of fish rich in n-3 fatty acids may be related to lower likelihood of high hostility in young adulthood. The association between dietary n-3 fatty acids and hostile personality merits further research.European Journal of Clinical Nutrition (2004) 58, 24-31. doi:10.1038/sj.ejcn.1601739

Huang, X. F., X. Xin, et al. (2004). "Role of fat amount and type in ameliorating diet-induced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor, neuropeptide Y and pro-opiomelanocortin mRNA expression." Diabetes Obes Metab 6(1): 35-44.

            AIMS: Dietary fatty acid profile, independent of caloric percent of fat, is a major regulator of body adiposity. This study examined the effects of dietary fat amount and types on fat storage and hypothalamic gene expression in the mouse model of chronic diet-induced obesity. METHODS: The dietary interventions were in twofold: (1) the obesity was induced by a 13-week obesogenic fat diet compared with a low-fat (LF) diet, and (2) the reversibility was tested by using high n-3 polyunsaturated fat (PUFA) and LF diets. Fifty-four C57Bl/6 mice were fed a high-fat (59% in kcal) diet for 13 weeks and then classified as diet-induced obese (DIO) or diet-resistant (DR) mice according to upper and lower tertiles of body weight gain. The DIO mice were then subdivided into three groups for a 6-week secondary dietary intervention. Two of the groups were switched to either a high n-3 PUFA (DIO-n3) or a low-fat (10% in kcal, DIO-LF) diet, whereas the third (controls) and DR mice continued on the initial high-fat diet. Food efficiency was calculated as weekly body weight gain per gram of food intake. RESULTS: After switching the DIO mice to the n-3 PUFA or LF diet, their body weights were reduced to the level of the DR and LF mice. The food efficiencies were, from the highest to lowest, in the order: DIO > LF > DR > DIO-LF > DIO-n3. Using quantitative in situ hybridization, we found that the DIO mice had higher levels of leptin receptor (LR, +290%, p < 0.005) and neuropeptide Y (NPY, +25%, p < 0.05) mRNA expression in the hypothalamic arcuate nucleus (Arc) than the DR mice, whereas the level of pro-opiomelanocortin (POMC) mRNA expression was significantly reduced (-45%, p < 0.01). All effects that were essentially returned to DR levels by the change to the n-3 PUFA diet and, with the exception of a failure to normalize Arc NPY mRNA levels, by the change to LF diet. CONCLUSIONS: Taken together, the present results show that both change in level and quality of dietary fat can potently alter hypothalamic neuropeptide expression and result in effective amelioration of diet-induced obesity. Interestingly, the n-3 PUFA diet when fed to already obese mice produced a pattern of hypothalamic gene expression similar to that in obesity resistant (DR) mice. It remains to be determined if the effects of n-3 fatty acids on brain neuropeptide gene expression are direct or indirect.

Hammad, H., H. J. de Heer, et al. (2004). "Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma." Am J Pathol 164(1): 263-71.

            Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. In the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-specific T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (IL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.

Guillou, H., S. D'Andrea, et al. (2004). "The surprising diversity of Delta6-desaturase substrates." Biochem Soc Trans 32(Pt 1): 86-7.

            A single gene encoding a Delta6-desaturase (FADS2) has been isolated and characterized in mammalian species. This Delta6-desaturase plays a major role in the biosynthesis of PUFAs (polyunsaturated fatty acids). It catalyses the rate-limiting desaturation of linoleic acid (C(18:2) n -6) and alpha-linolenic acid (C(18:3) n -3) required for the biosynthesis of long-chain PUFAs. Moreover, recent studies have provided strong evidence that this Delta6-desaturase also acts on 24-carbon PUFAs of both the n -6 and n -3 series. Another substrate of this Delta6-desaturase has been identified through complementary works from different investigators. This Delta6-desaturase acts on a saturated fatty acid, palmitic acid (C(16:0)), leading to the newly characterized biosynthesis of hexadecenoic acid (C(16:1) n -10) or sapienate.

Goodfriend, T. L., D. L. Ball, et al. (2004). "Epoxy-Keto Derivative of Linoleic Acid Stimulates Aldosterone Secretion." Hypertension.

            Plasma levels of aldosterone are not always predictable from the activity of renin and the concentration of potassium. Among the unexplained are elevated levels of aldosterone in some obese humans. Obesity is characterized by increased plasma fatty acids and oxidative stress. We postulated that oxidized fatty acids stimulate aldosteronogenesis. The most readily oxidized fatty acids are the polyunsaturated, and the most abundant of those is linoleic acid. We tested oxidized derivatives of linoleic acid for effects on rat adrenal cells. One derivative, 12,13-epoxy-9-keto-10(trans)-octadecenoic acid (EKODE), was particularly potent. EKODE stimulated aldosteronogenesis at concentrations from 0.5 to 5 micro mol/L, and inhibited aldosteronogenesis at higher doses. EKODE's stimulatory effect was most prominent when angiotensin and potassium effects were submaximal. The lipid's mechanism of action was on the early pathway leading to pregnenolone; its action was inhibited by atrial natriuretic peptide. Plasma EKODE was measured by liquid chromatography/mass spectrometry. All human plasmas tested contained EKODE in concentrations ranging from 10(-9) to 5x10(-7) mol/L. In samples from 24 adults, levels of EKODE correlated directly with aldosterone (r=0.53, P=0.007). In the 12 blacks in that cohort, EKODE also correlated with body mass index and systolic pressure. Those other correlations were not seen in white subjects. The results suggest that oxidized derivatives of polyunsaturated fatty acids other than arachidonic are biologically active. Compounds like EKODE, derived from linoleic acid, may affect adrenal steroid production in humans and mediate some of the deleterious effects of obesity and oxidative stress, especially in blacks.

Ferreri, C., A. Samadi, et al. (2004). "Regioselective cis-trans isomerization of arachidonic double bonds by thiyl radicals: the influence of phospholipid supramolecular organization." J Am Chem Soc 126(4): 1063-72.

            Trans unsaturated fatty acids in humans may be originated by two different contributions. The exogenous track is due to dietary supplementation of trans fats and the endogenous path deals with free-radical-catalyzed cis-trans isomerization of fatty acids. Arachidonic acid residue (5c,8c,11c,14c-20:4), which has only two out of the four double bonds deriving from the diet, was used to differentiate the two paths and to assess the importance of a radical reaction. A detailed study on the formation of trans phospholipids catalyzed by the HOCH(2)CH(2)S(*) radical was carried out on l-alpha-phosphatidylcholine from egg lecithin and 1-stearoyl-2-arachidonoyl-l-alpha-phosphatidylcholine (SAPC) in homogeneous solution or in large unilamellar vesicles (LUVET). Thiyl radicals were generated from the corresponding thiol by either gamma-irradiation or UV photolysis, and the reaction course was followed by GC, Ag/TLC, and (13)C NMR analyses. The isomerization was found to be independent of cis double bond location (random process) in i-PrOH solution. In the case of vesicles, the supramolecular organization of lipids produced a dramatic change of the isomerization outcome: (i) in egg lecithin, the reactivity of arachidonate moieties is higher than that of oleate and linoleate residues, (ii) in the linoleate residues of egg lecithin, the 9t,12c-18:2 isomer prevailed on the 9c,12t-18:2 isomer (3:1 ratio), and (iii) a regioselective isomerization of SAPC arachidonate residues occurred in the 5 and 8 positions. This effect of "positional preference" indicates that thiyl radicals entering the hydrophobic region of the membrane bilayer start to isomerize polyunsaturated fatty acid residues having the double bonds nearest to the membrane surfaces. We propose that arachidonic acid and its trans isomers can function as biomarkers in membranes for distinguishing the two trans fatty acid-forming pathways.

Engelmann, B. (2004). "Plasmalogens: targets for oxidants and major lipophilic antioxidants." Biochem Soc Trans 32(Pt 1): 147-50.

            Cellular membranes and plasma lipoproteins are less efficiently protected against oxidative stress than the various aqueous compartments of mammalian organisms. Here, previous results on the role of plasmalogens in lipid oxidation are evaluated on the basis of criteria required for an antioxidant. The plasmalogen-specific enol ether double bond is targeted by a vast variety of oxidants, including peroxyl radicals, metal ions, singlet oxygen and halogenating species. Oxidation of the vinyl ether markedly prevents the oxidation of highly polyunsaturated fatty acids, and products of plasmalogen degradation do not propagate lipid oxidation. This protection is also demonstrated intramolecularly, thus ascertaining the function of plasmalogens as a major storage pool for polyunsaturated fatty acids. Although cells rapidly incorporate and synthesize plasmalogens de novo, their plasmalogen contents can be deliberately increased by supplementation with precursors. Thus plasmalogens terminate lipid-oxidation processes, are present in adequate locations at sufficient concentrations, and are rapidly regenerated, classifying them as efficient antioxidants in vitro. Future work should address the in vivo role of plasmalogens in lipid oxidation and the biological function of plasmalogen interactions with oxidants.

Dwyer, J. H., H. Allayee, et al. (2004). "Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis." N Engl J Med 350(1): 29-37.

            BACKGROUND: Leukotrienes are inflammatory mediators generated from arachidonic acid (polyunsaturated n-6 fatty acid) by the enzyme 5-lipoxygenase. Since atherosclerosis involves arterial inflammation, we hypothesized that a polymorphism in the 5-lipoxygenase gene promoter could relate to atherosclerosis in humans and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates. METHODS: We determined 5-lipoxygenase genotypes, carotid-artery intima-media thickness, and markers of inflammation in a randomly sampled cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis Study. Dietary arachidonic acid and marine n-3 fatty acids (including a competing 5-lipoxygenase substrate that reduces the production of inflammatory leukotrienes) were measured with the use of six 24-hour recalls of food intake. RESULTS: Variant 5-lipoxygenase genotypes (lacking the common allele) were found in 6.0 percent of the cohort. Mean (+/-SE) intima-media thickness adjusted for age, sex, height, and racial or ethnic group was increased by 80+/-19 microm (95 percent confidence interval, 43 to 116; P<0.001) among carriers of two variant alleles, as compared with carriers of the common (wild-type) allele. In multivariate analysis, the increase in intima-media thickness among carriers of two variant alleles (62 microm, P<0.001) was similar in this cohort to that associated with diabetes (64 microm, P=0.01), the strongest common cardiovascular risk factor. Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of genotype, whereas increased dietary intake of n-3 fatty acids blunted the effect. Finally, the plasma level of C-reactive protein, a marker of inflammation, was increased by a factor of 2 among carriers of two variant alleles as compared with that among carriers of the common allele. CONCLUSIONS: Variant 5-lipoxygenase genotypes identify a subpopulation with increased atherosclerosis. The observed diet-gene interactions further suggest that dietary n-6 polyunsaturated fatty acids promote, whereas marine n-3 fatty acids inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation.

Dixon, G., J. Nolan, et al. (2004). "Arachidonic acid, palmitic acid and glucose are important for the modulation of clonal pancreatic beta-cell insulin secretion, growth and functional integrity." Clin Sci (Lond) 106(2): 191-9.

            Insulin-resistant states such as obesity can result in an increase in the function and mass of pancreatic beta-cells, so that insulin secretion is up-regulated and Type II diabetes does not develop. However, expansion of beta-cell mass is not indefinite and may well decrease with time. Changes in circulating concentrations of nutritional factors, such as fatty acids and/or glucose, may lead to a reduction in beta-cell mass in vivo. Few previous studies have attempted to explore the interplay between glucose, amino acids and fatty acids with respect to beta-cell mass and functional integrity. In the present study, we demonstrate that culture of clonal BRIN-BD11 cells for 24 h with the polyunsaturated fatty acid arachidonic acid (AA) increased beta-cell proliferation and enhanced alanine-stimulated insulin secretion. These effects of AA were associated with significant decreases in the cellular consumption of D-glucose and L-alanine as well as decreased rates of production of nitric oxide and ammonia. Conversely 24 h exposure to the saturated fatty acid palmitic acid (PA) was found to decrease beta-cell viability (by increasing apoptosis), increase the intracellular concentration of triacylglycerol (triglyceride), while inhibiting alanine-stimulated insulin secretion. These effects of PA were associated with significant increases in D-glucose and L-glutamine consumption as well as nitric oxide and ammonia production. However, L-alanine consumption was decreased in the presence of PA. The effects of AA, but not PA, were additionally dependent on glucose concentration. These studies indicate that AA may have a critical role in maintaining the appropriate mass and function of islet beta-cells by influencing rates of cell proliferation and insulin secretion. This regulatory effect may be compromised by high circulating levels of glucose and/or PA, both of which are elevated in Type II diabetes and may impact upon dysfunctional and apoptotic intracellular events in the beta-cell.

Ding, J. L., E. H. Lim, et al. (2004). "Expression of recombinant vitellogenin in the yeast Pichia pastoris." Biotechnol Bioeng 85(3): 330-9.

            Vitellogenin (Vtg) plays vital roles as precursor to the yolk proteins and as carrier for lipids, carbohydrates, phosphates, metal ions, vitamins, and hormones into the oocytes during the massive deposition of yolk nutrients for subsequent nourishment of the developing embryos. Reproductive success is highly sensitive to the nutritional quality of the broodstock diet, which greatly affects the egg and larval viability. We present a novel strategy for genetically engineering a Pichia pastoris yeast strain that constitutively produces recombinant Vtg (rVtg), for application as an enriched feed. The tilapia Oreochromis aureus Vtg (OaVtg) cDNA (5.3 kb) was cloned into a nonsecretory pGAPZA vector. Clones containing up to 31 copies of glyceraldehyde-3-phosphate dehydrogenase (GAP)-promoter-driven Vtg expression cassettes were isolated. These clones expressed a membrane-associated intracellular rVtg protein of 194 kDa, constituting up to 1.16% of total protein. To facilitate future purification of rVtg, we explored the possibility of secreting rVtg using the native Vtg secretion signal and the alpha-factor secretion signal of Saccharomyces cerevisiae. However, neither signal promoted the secretion of rVtg. The clones maximally expressed rVtg at 23 degrees C, reaching a peak at 22 h in shake flasks and 16 h in a fermentor. The clones exhibited a significant increase in essential amino acids and long-chain polyunsaturated fatty acids, which are important for its application as a high-quality nutrient feed.

Das, U. N. (2004). "Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-beta to prevent human essential hypertension." Eur J Clin Nutr 58(2): 195-203.

            Patients with uncontrolled essential hypertension have elevated concentrations of superoxide anion (O(2)(-*)), hydrogen peroxide (H(2)O(2)), lipid peroxides, endothelin, and transforming growth factor-beta (TGF-beta) with a simultaneous decrease in endothelial nitric oxide (eNO), superoxide dismutase (SOD), vitamin E, and long-chain polyunsaturated fatty acids (LCPUFAs). Physiological concentrations of angiotensin II activate NAD(P)H oxidase and trigger free radical generation (especially that of O(2)(-*)). Normally, angiotensin II-induced oxidative stress is abrogated by adequate production and release of eNO, which quenches O(2)(-*) to restore normotension. Angiotensin II also stimulates the production of endothelin and TGF-beta. TGF-beta enhances NO generation, which in turn suppresses TGF-beta production. Thus, NO has a regulatory role on TGF-beta production and is also a physiological antagonist of endothelin. Antihypertensive drugs suppress the production of O(2)(-*) and TGF-beta and enhance eNO synthesis to bring about their beneficial actions. LCPUFAs suppress angiotensin-converting enzyme (ACE) activity, reduce angiotensin II formation, enhance eNO generation, and suppress TGF-beta expression. Perinatal supplementation of LCPUFAs decreases insulin resistance and prevents the development of hypertension in adult life, whereas deficiency of LCPUFAs in the perinatal period results in raised blood pressure later in life. Patients with essential hypertension have low concentrations of various LCPUFAs in their plasma phospholipid fraction. Based on this, it is proposed that LCPUFAs serve as endogenous regulators of ACE activity, O(2)(-*), eNO generation, and TGF-beta expression. Further, LCPUFAs have actions similar to statins, inhibit (especially omega-3 fatty acids) cyclooxygenase activity and suppress the synthesis of proinflammatory cytokines, and activate the parasympathetic nervous system, all actions that reduce the risk of major vascular events. Hence, it is proposed that availability of adequate amounts of LCPUFAs during the critical periods of growth prevents the development of hypertension in adulthood.European Journal of Clinical Nutrition (2004) 58, 195-203. doi:10.1038/sj.ejcn.1601766

Cho, S. H., M. L. Jahncke, et al. (2004). "Nutritional composition and microflora of the fresh and fermented skate (Raja Kenojei) skins." Int J Food Sci Nutr 55(1): 45-51.

            The proximate compositions of fresh and fermented skate skin were each 75.95% and 74.5% moisture, 22.7% and 21.8% protein, 0.5% and 0.7% lipid and 0.6% and 0.9% ash, respectively. The predominant minerals were potassium and phosphorus (i.e. 53.5 and 33.0 mg/100 g in fresh skin, and 10.46 and 10.51 mg/100 g in fermented skin, respectively). Amino acid concentrations were lower in the fermented skin compared with the fresh skin. Histidine, glycine, alanine and glutamic acid were the major free amino acids in both skins. Palmitic acid (C16:0) was the major fatty acid in both fresh (16.68%) and fermented (20.38%) skate skin. Omega-3 polyunsaturated fatty acids were higher in fresh skin (22.17%) and fermented skin (24.54%) compared with omega-6 polyunsaturated fatty acids. The predominant microflora present in the both fresh and fermented skin were Photobacterium sp. and Vibrio sp. Total plate counts for the fresh and fermented skin were 2.4x10(4) CFU/g and 7.7x10(7) CFU/g, respectively.

Caro, A. A. and A. I. Cederbaum (2004). "Oxidative stress, toxicology, and pharmacology of cyp2e1 *." Annu Rev Pharmacol Toxicol 44: 27-42.

            This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.

Cabre, A., J. Girona, et al. (2004). "Aldehydes mediate tissue factor induction: a possible mechanism linking lipid peroxidation to thrombotic events." J Cell Physiol 198(2): 230-6.

            Tissue factor (TF), which is expressed in atherosclerotic plaques and colocalizes with oxidized lipids, initiates the thrombogenic process. We have analyzed the effect of aldehydes derived from peroxidation of polyunsaturated fatty acids on TF expression in human vascular smooth muscle cells (HVSMC). Our results demonstrate that hexanal and 2,4-decadienal (2,4-DDE), two apolar aldehydes, increase TF expression. Exposure of HVSMC to hexanal for 2 h led to TF protein levels up to seven times higher than untreated cells whereas 2,4-DDE for 30 min led to them being up to 2.2 times higher. This induction of TF antigen by aldehydes correlates with an increase in TF mRNA levels. Electrophoretic mobility shift assays (EMSAs) showed that the binding activity of the transcription factor AP-1 (c-Fos/c-Jun) to TF promoter was elevated in response to these oxidation products. This enhancement was associated to an increase of c-fos transcriptional activity, which was reversible by pretreatment with simvastatin. We conclude that the induction of TF by aldehydes might contribute to the severity of atherogenesis.

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.

Blesbois, E., V. Douard, et al. (2004). "Effects of n-3 polyunsaturated dietary supplementation on the reproductive capacity of male turkeys." Theriogenology 61(2-3): 537-49.

            To measure the effects of dietary n-3 polyunsaturated fatty acid (PUFA) supplementation on the reproductive capacity of adult male turkeys in industrial flocks, the males of 22 commercial farms were fed either a standard diet or a fish oil diet enriched in n-3 PUFAs. The fatty acid composition of the spermatozoa and reproductive performance were measured throughout the reproductive period. The fish oil diet very effectively increased the percentage of n-3 fatty acids (FA) (22:5n-3 and 22:6n-3) in spermatozoa and correspondingly decreased the percentage of n-6 PUFAs (20:4-6 and 22:4n-6): the n-3/n-6 ratio in spermatozoa fatty acids were 0.04-0.07 with the standard diet and 0.32-0.4 with the fish oil diet. These changes did not affect the spermatozoa content of n-9 PUFAs, particularly of 22:3n-9 which is abundant in turkey spermatozoa (9-12% of the total fatty acids). The supplementation was effective in the middle as at the end of the reproductive period. The reproductive capacity of males was modified by the diet and the positive effect of the n-3 supplemented diet increased with age (increase in hatching rates of nearly 2 points at 48-58 weeks for males fed fish oil diet). These results indicate that an increase in the dietary ratio of n-3/n-6 PUFAs is valuable to sustain the reproductive capacity of male turkeys especially when they are getting older.

Artwohl, M., M. Roden, et al. (2004). "Free fatty acids trigger apoptosis and inhibit cell cycle progression in human vascular endothelial cells." Faseb J 18(1): 146-8.

            Plasma free fatty acid (FFA) concentrations are increased in states of insulin resistance and impair endothelial function. Because the underlying mechanisms are largely unknown, we examined selected, purified FFAs' (100-300 micromol/l, 24-48 h) action on apoptosis, cell cycle distribution, and associated gene/protein expression in human umbilical vein endothelial cells (HUVECs). Stearic acid, but not oleic acid, time and concentration dependently increased endothelial apoptosis by fivefold (n=6, P<0.01), whereas polyunsaturated FFAs (PUFAs; linoleic, gamma-linolenic, and arachidonic acid) exerted proapoptotic activity only at 300 micromol/l (P<0.05). Proapoptotic FFA action increased with FFAs' number of double bonds and with protein expression of the apoptosis promotor bak. The G0/G1 cell cycle arrest (n=6, P<0.05) induced by stearic acid (+14%) and PUFAs (+30%) is reflected by up-regulation of p21(WAF-1/Cip1). In addition, all FFAs concentration dependently reduced (P<0.05) gene/protein expression of clusterin (-54%), NF-kappaB's inhibitor, IkappaBalpha (-50%), endothelin-1 (-44%), and endothelial NO synthase (-44%). Plasma samples obtained from individuals with elevated plasma FFAs (372+/-22 micromol/l) increased endothelial apoptosis by 4.2-fold (P<0.001, n=10) compared with intra-individually matched low plasma FFA (56+/-21 micromol/l) conditions, underlining the results obtained by defined FFA stimulation. In conclusion, FFA structure differently affects endothelial cell proliferation and apoptosis, both representing key factors in the development of micro- and macrovascular dysfunction.

Araya, J., R. Rodrigo, et al. (2004). "Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in non-alcoholic fatty liver disease patients." Clin Sci (Lond).

            Hepatic steatosis is a major feature associated with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to assess the levels of polyunsaturated fatty acids (PUFA) in liver total lipids, triacylglycerols and phospholipids of NAFLD patients, in relation to those in adipose tissue and hepatic indexes related to oxidative stress, as factors contributing to hepatic steatosis. Eleven control subjects and nineteen patients with NAFLD were studied. Analysis of liver and abdominal adipose tissue fatty acids was carried out by gas liquid chromatography. The liver content of protein carbonyl groups and malondialdehyde were taken an indexes related to oxidative stress. NAFLD patients showed depletion of long-chain PUFA (LCPUFA) of the n-6 and n-3 series in liver triacylglycerols, with reduced 20:4n-6/18:2n-6 and (20:5n-3 + 22:6n-3):18:3n-3 ratios, whereas liver phospholipids contained higher n-6 and lower n-3 LCPUFA. These findings were accompanied by an enhancement of (i) n-6/n-3 ratio in liver and adipose tissue, (ii) 18:1n-9 trans levels in adipose tissue, and (iii) hepatic lipid peroxidation and protein oxidation indexes. It is concluded that a marked enhancement in LCPUFA n-6/n-3 ratio occurs in the liver of NAFLD patients, a condition that may favor lipid synthesis over oxidation and secretion, thereby leading to steatosis. Depletion of hepatic LCPUFA may result from both a defective PUFA desaturation, due to inadequate intake of precursors such as 18:3n-3 and higher intake of the 18:1n-9 trans isomer leading to desaturase inhibition, and from a higher peroxidation of LCPUFA due to oxidative stress.

Alexander Leaf, D., M. T. Kleinman, et al. (2004). "The effects of exercise on markers of lipid peroxidation in renal dialysis patients compared with control subjects." Am J Med Sci 327(1): 9-14.

            SUMMARY: ABSTRACT Purpose:The purpose of this study was to compare the susceptibility to exercise-induced lipid peroxidation of patients on chronic maintenance dialysis (CMD) and non-CMD control subjects.Design:Cross-sectional comparison of exercise-induced changes in breath ethane and pentane flux between patients on CMD (group A) and an age-, gender-, medical diagnosis-, smoking-, and ethanol consumption-matched comparison group (group B). Breath ethane and pentane were measured at rest before exercise, during cardiopulmonary exercise stress testing (CPX) at lactic acidosis threshold (Vo2lat), and 5 minutes after CPX.Results:Group comparisons of clinical characteristics reveal that the groups were similar in terms of age, ethnicity, comorbid diagnoses, prevalence of medication use, BMI, measurements of aerobic exercise capacity, cigarette smoking and ethanol consumption behaviors. All subjects successfully completed the CPX protocol achieving Vo2lat. There were significant differences in breath ethane flux between group A and B subjects, with greater pre-exercise, Vo2lat, and postexercise ethane levels in group A compared with group B subjects, and significant group differences, with lower breath ethane/pentane flux ratios at rest, Vo2lat, and recovery with lower ratios in group B than group A subjects.Discussion/Conclusions:This study shows that patients on CMD have greater lipid peroxidation compared with control subjects at rest and during and after physical exercise. In addition, compared with control subjects, patients on CMD preferentially peroxidize n-3 polyunsaturated fatty acids at rest and during physical exercise and recovery. The lipid peroxidation profile may result in an unfavorable endoperoxide shift and should be evaluated further, along with modalities to reduce oxidative stress among patients on CMD.

Agostoni, C. and W. Heird (2004). "Long chain polyunsaturated fatty acids in chronic childhood disorders: panacea, promising, or placebo." J Pediatr Gastroenterol Nutr 38(1): 2-3.

Zolfaghari, R. and A. C. Ross (2003). "Recent advances in molecular cloning of fatty acid desaturase genes and the regulation of their expression by dietary vitamin A and retinoic acid." Prostaglandins Leukot Essent Fatty Acids 68(2): 171-9.

            Vitamin A, as an essential micronutrient, is involved in higher animals in embryonic development and postnatal growth, reproduction and maintenance of normal skin, immunity and vision. Recently, studies in vivo and in cell lines have shown that vitamin A and its active metabolite, retinoic acid, regulate the expression of fatty acid desaturases including stearoyl-CoA desaturase and delta-5 desaturase. Whereas the former desaturase catalyzes the formation of monounsaturated from saturated fatty acids, the latter enzyme is involved in the desaturation pathway of dietary essential fatty acids for production of polyunsaturated fatty acids. The reaction products of these desaturases serve as critical regulators in a wide range of physiological processes which include fetal growth and development, reproduction, cell differentiation, immune and inflammatory responses.

Zeyda, M., A. B. Szekeres, et al. (2003). "Suppression of T cell signaling by polyunsaturated fatty acids: selectivity in inhibition of mitogen-activated protein kinase and nuclear factor activation." J Immunol 170(12): 6033-9.

            Polyunsaturated fatty acids (PUFAs) are known to suppress inflammatory and autoimmune responses and, therefore, clinical applications of PUFAs as immunomodulatory substances are extensively studied. PUFAs are known to inhibit T cell responses, but with respect to TCR/CD3-mediated signal transduction only a block in CD3-induced phospholipase Cgamma1/calcium signaling has been shown so far. In this study, we investigated PUFA-mediated changes in downstream T cell signal transduction. We show that among the mitogen-activated protein kinase families activation of c-Jun NH(2)-terminal kinase, but not phosphorylation of extracellular signal-regulated kinase-1/-2 or p38 is inhibited. CD3/CD28-induced activity of NF-AT was markedly reduced by PUFA treatment, while activation of other nuclear receptors (AP-1 and NF-kappaB) remained unaltered. Furthermore, IL-2 promoter activity, IL-2 and IL-13 mRNA levels, IL-2 secretion, and IL-2R alpha-chain expression were significantly diminished by PUFA treatment, whereas the expression of IFN-gamma, IL-4, IL-10, and CD69 remained essentially unaffected by PUFAs. In conclusion, PUFA treatment of T cells inhibits selectively c-Jun NH(2)-terminal kinase and NF-AT activation, resulting in diminished production of IL-2 and IL-13.

Zeitlin, L., E. Segev, et al. (2003). "Effects of long-term administration of N-3 polyunsaturated fatty acids (PUFA) and selective estrogen receptor modulator (SERM) derivatives in ovariectomized (OVX) mice." J Cell Biochem 90(2): 347-60.

            We studied the beneficial effects of dietary consumption of n-3 polyunsaturated fatty acids (PUFA) and two selective estrogen receptor modulator (SERM) derivatives (SERM-I and SERM-II) and their combined effect on serum lipids, skin dermis and adipose layers, bone marrow adipogenesis, and cytokine secretion in mice. Two different ovariectomized (OVX) models were studied: treatment began immediately post-OVX in one and 3 months post-OVX in the other. Our results showed that n-3 PUFA and both SERMs decreased triglyceride levels in the serum, and that SERMs also decreased serum cholesterol levels while n-3 PUFA had no similar effect. SERMs had no effect on IL-6, IL-1 beta, or IL-10 levels, but they decreased ex vivo tumor necrosis factor (TNF-alpha). N-3 PUFA decreased secretion of non-induced IL-6 and TNF-alpha from cultured BMC and IL-1 beta levels in vivo (i.e., in bone marrow plasma), but its main effect was a significant elevation in the secretion of IL-10, a known anti-inflammatory cytokine. OVX-induced B-lymphopoiesis was not affected by LY-139481 (SERM-I) while LY-353381 (SERM-II) exhibited an estrogen-antagonistic effect in sham and OVX mice and elevated the amount of B-cells in bone marrow. Fish oil consumption prevented the elevation in B-lymphopoiesis caused by OVX, but had no curative effect on established augmented B-lymphopoiesis. This activity could be mediated via the elevation of IL-10 which was shown to suppress B-lymphopoiesis. Both SERMs and n-3 PUFA inhibited the increase in adipose tissue thickness caused by OVX in mice. Our results showed that n-3 PUFA, could prevent some of the deleterious outcomes of estrogen deficiency that were not affected by SERMs. We observed no significant beneficial effects of the combined administration of SERM-I, SERM-II, and PUFA on the studied parameters.The exact mechanism by which polyunsaturated fatty acids exert their activities is still not clear, but peroxisome proliferator-activated receptors (PPARs) might be involved in processes which are modulated by n-3 PUFA.

Zeh, N., S. S. Rossi, et al. (2003). "The effect of extracorporeal albumin dialysis on plasma phospholipid fatty acids in patients with end-stage liver disease." Liver Int 23 Suppl 3: 34-8.

            The effect of extracorporeal albumin dialysis (ECAD) using the MARS device on plasma phospholipid fatty acids (PLFA) in patients with end-stage liver disease (ESLD) was examined. Phospholipids were isolated from plasma and the fatty acid (FA) composition of non-sphingomyelin PL determined using capillary gas chromatography (GC). Plasma samples were also obtained from six patients with ESLD undergoing ECAD and from five patients with similar ESLD who were not treated, as well as from non-fasting healthy subjects. PLFA were much lower [506 +/- 62 microg/mL (M +/- SD)] in patients with ESLD than in healthy subjects (2709 +/- 688 microg/mL). In addition, the proportion of n3 and n6 polyunsaturated FA was much lower in patients with ESLD (n3, 1.7 +/- 0.1%, n6, 19.6 +/- 1.4%) than in healthy controls (n3, 4.1 +/- 2.4%, n6, 31.9 +/- 6.2%) ECAD caused an immediate increase in PLFA, averaging 56% in all patients, but PLFA levels decreased some hours later after treatment. ECAD also caused a small increase in the proportion of n3 and n6 of PLFA. During the 5 days of the study, PLFA rose in both ECAD-treated and untreated patients, but the increase was significantly greater in ECAD treated patient. It is concluded that patients with ESLD have markedly decreased PLFA; these PLFA have a lower proportion of the polyunsaturated n3 and n6 FA with the result that the plasma level of these essential polyunsaturated PLFA is extremely low compared to that of healthy subjects. ECAD causes a transient increase in PLFA toward normal levels and also increases the proportion of n3 and n6 FA.

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.

Young, J. F., K. Rosenvold, et al. (2003). "Significance of preslaughter stress and different tissue PUFA levels on the oxidative status and stability of porcine muscle and meat." J Agric Food Chem 51(23): 6877-81.

            Polyunsaturated fatty acids (PUFAs) and exercise-induced stress are known to increase the oxidative susceptibility of lipids in muscle tissue. In contrast, antioxidative enzymes, e.g., catalase, superoxide dismutase, and glutathione peroxidase, are known to help sustain the delicate oxidative balance in biological tissue upon the application of stressors. The present study investigates the combined effect of different diet-induced muscle PUFA contents and preslaughter stress on the activity of antioxidative muscle enzymes and the oxidative stability of cooked meat. An increased content of unsaturated fatty acids in the tissue led to a decreased activity of lactate dehydrogenase in the plasma, indicating increased cell integrity. Catalase activity in the muscle tissue increased with increasing PUFA levels. However, this upregulation in antioxidative status of the muscle could not counteract the subsequent development of accelerated lipid oxidation in cooked meat as measured in terms of thiobarbituric acid reactive substances. Moreover, preslaughter stress induced increasing oxidative changes with elevated PUFA levels in the muscle tissue.

Yoshida, H., H. Soh, et al. (2003). "Beneficial effects of n-9 eicosatrienoic acid on experimental bowel lesions." Surg Today 33(8): 600-5.

            PURPOSE: Dietary fortification of n-9 polyunsaturated fatty acids (PUFA) or 5,8,11-eicosatrienoic acid (ETrA) as well as n-3 PUFA might contribute to the suppression of leukotriene B4 (LTB4) synthesis and thereby reduce inflammatory bowel lesions. As a result, the effect of an ETrA-enriched diet on experimental bowel lesions was examined in this study. METHODS: In Expt. 1, rats were freely fed either an ETrA-enriched or a standard diet. After 7 days of feeding, acute bowel lesions were induced by the subcutaneous injection of 10 mg/kg indomethacin. In Expt. 2, chronic bowel lesions were made by performing subcutaneous injections of 7.5 mg/kg indomethacin twice. After the first injection, the rats were freely fed either an ETrA-enriched or a standard diet for 7 days. RESULTS: In both experiments, the rats fed an ETrA-enriched diet showed increased levels of ETrA in the plasma and intestinal mucosa, and a decreased inflammation score. However, there was no significant decrease in plasma and intestinal mucosal LTB4 in the ETrA-enriched diet-fed rats. CONCLUSION: These results suggest that the dietary supplementation of ETrA may have both prophylactic and therapeutic effects on experimentally produced bowel lesions. Further investigations are necessary to clarify the effects of ETrA on bowel lesions and its mechanisms.

Yoshida, S. and H. Yoshida (2003). "Nondestructive analyses of unsaturated fatty acid species in dietary oils by attenuated total reflectance with Fourier transform IR spectroscopy." Biopolymers 70(4): 604-13.

            The aim of this study was to develop a nondestructive method to quantitate relative amounts of n-3 and n-6 polyunsaturated fatty acid (PUFA) species in vegetable oils and oil seeds using Fourier transform IR spectroscopy (FTIR). The alkene Cbond;H stretching vibrations of unsaturated fatty acids in oils showed IR absorption bands with various peak positions and intensities at around 3010 cm(-1), depending on the extent of unsaturation and PUFA species. With the aid of partial least-squares regression analysis, the FTIR measurement could practically predict the content of each PUFA species in the oil to be tested. A calculation method was also presented to directly find PUFA species in oils from the FTIR spectra. This technique was applied to dried soybean seeds to demonstrate a nonhomogenous distribution of saturated fatty acids and PUFAs, as well as glycans, in soybean cross sections.

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.

Yin, H. and N. A. Porter (2003). "Specificity of the ferrous oxidation of xylenol orange assay: analysis of autoxidation products of cholesteryl arachidonate." Anal Biochem 313(2): 319-26.

            Autoxidation of polyunsaturated fatty acids and esters leads to a complex mixture containing hydroperoxides and cyclic peroxides. The oxidation mixture of cholesteryl arachidonate, which has been characterized by a variety of mass spectrometry techniques, was subject to analysis by conventional thiobarbituric acid-reactive substance (TBARS) and ferrous oxidation in xylenol orange (FOX) assays. Our results indicate that the FOX assay is not specific for hydroperoxides. Cyclic peroxides, such as monocyclic peroxides and serial-cyclic peroxides, give a positive FOX response even after triphenylphosphine reduction. We suggest that bicyclic endoperoxides are the major TBARS active compounds present in cholesteryl arachidonate oxidation mixtures. These compounds give a positive FOX assay before reaction with triphenylphosphine but negative TBARS and FOX assays after this reaction. Caution should be exercised when the FOX assay is used to analyze highly oxidized lipids, especially arachidonyl-containing lipids.

Yatsuya, H., A. Ohwaki, et al. (2003). "Reproducibility and validity of a simple checklist-type questionnaire for food intake and dietary behavior." J Epidemiol 13(5): 235-45.

            BACKGROUND: A simple, reliable, and valid food questionnaire is needed in clinical dietary assessments, community health education, and multi-purpose epidemiologic studies to obtain a crude measure of dietary intake. METHODS: To assess the validity and reproducibility of a simple 4-point scale food intake and behavior checklist, it was compared to two 3-day weighed dietary records. The FBC was administered to 47 students of a dietician course and their parents (n = 94) over a 9-month interval to assess the reproducibility. The mean intakes of selected food groups assessed by the two dietary records completed between food intake and behavior checklists were compared to the responses to the food intake and behavior checklist to assess its validity. RESULTS: The kappa statistics for reproducibility ranged from 0.25 for confectionaries to 0.63 for a preference for fatty foods (median, 0.39). There was a reasonable level of correlation between the dietary record and the food intake and behavior checklist in the intake of eggs, milk, and fruits (r = 0.53, 0.56, and 0.50, respectively). There was a weaker but still significant correlation in the intake of vegetables, and alcohol (r = 0.31 and 0.45, respectively). No significant correlation was observed in the intake of meat, fish, confectionaries, and soft drinks. However, those who reported consuming mainly fish rather than meat were found to eat significantly less meat and animal fat. Similarly, those who did not prefer fatty foods consumed significantly less meat, animal fat, and polyunsaturated fatty acids. CONCLUSIONS: This simple food checklist was useful in collecting data on egg, milk, and fruit consumption. Assessing intake frequency of vegetables, meat or fish with the FBC may be useful in screening high- or low-intake individuals.

Yaqoob, P. and P. C. Calder (2003). "N-3 polyunsaturated fatty acids and inflammation in the arterial wall." Eur J Med Res 8(8): 337-54.

            Atherosclerosis, leading to cardiovascular disease, is a chronic condition involving a strong inflammatory component. There is evidence that the n-3 polyunsaturated fatty acids (PUFA) present in oily fish and fish oils protect against cardiovascular disease. While these fatty acids have well-recognised effects on plasma triacylglycerol concentrations, it is likely that they exert beneficial effects through other mechanisms in addition. A large body of evidence suggests that the n-3 PUFA have anti-inflammatory properties, some of which may be manifested in the arterial wall, either directly or indirectly, to modulate the progression of atherosclerosis. This review critically evaluates the evidence for the anti-inflammatory effects of the n-3 PUFA in cells and on pathways which have a direct influence on atherogenesis in the arterial wall.

Yao, J. K., C. G. Sistilli, et al. (2003). "Membrane polyunsaturated fatty acids and CSF cytokines in patients with schizophrenia." Prostaglandins Leukot Essent Fatty Acids 69(6): 429-36.

            Findings to date provide evidence that altered membrane structure and function are present in patients with either first-episode or chronic schizophrenia, suggesting defects in phospholipid metabolism and cell signaling in schizophrenia. The purpose of this investigation is to test whether decreased membrane polyunsaturated fatty acids (PUFAs) were associated with an increased secretion of proinflammatory cytokines. Thus, we measured interleukin 6 (IL-6) and interleukin 10 (IL-10) in cerebrospinal fluid (CSF) of patients with chronic schizophrenia as well as PUFAs of red blood cell (RBC) membranes from the same individuals. A significant and inverse correlation was found between CSF IL-6 (not IL-10) and RBC membrane PUFAs levels in both haloperidol-treated and medication-free patients with schizophrenia. Specifically, such an association was found in the n-6 (18:2, 20:4, and 22:4) and, to a lesser extent, the n-3 fatty acids. Taken together, the present findings suggest that decreased membrane PUFAs may be related to an immune disturbance in schizophrenia, possibly resulting from an increased phospholipase A2 activity mediated through the proinflammatory cytokines.

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.

Xian, M., J. Nie, et al. (2003). "Production of gamma-linolenic acid by disrupted mycelia of Mortierella isabellina." Lett Appl Microbiol 36(3): 182-5.

            AIMS: To optimize the production of linolenic acid by disrupted mycelia of Mortierella isabellina. METHODS AND RESULTS: Effects of incubation conditions such as incubation time, pH of reaction mixture, concentration of Mg2+ or malate and incubation temperature on production of linolenic acid were studied. The production of gamma-linolenic acid reached 224 mg g-1 dry cells when the reaction mixture was composed of 1.0 g (dry mycelial mass) of disrupted mycelia of M. isabellina, 50 ml (50 mmol l(-1)) potassium phosphate buffer supplemented with 0.312 mmol l(-1) of Mg2+ and 10 mmol l(-1) of malate, pH 7.0 and incubated at 5 degrees C for 1 day. CONCLUSIONS: Incubation temperature, concentration of Mg2+ and malate showed major effects on the increased linolenic acid production. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights conditions for increasing gamma-linolenic acid production by cell-free mycelia of M. isabellina and an insight into rapidly gaining high production of polyunsaturated fatty acids.

Wood, L. G., D. A. Fitzgerald, et al. (2003). "Hypothesis: vitamin E complements polyunsaturated fatty acids in essential fatty acid deficiency in cystic fibrosis." J Am Coll Nutr 22(4): 253-7.

            While several studies have demonstrated essential fatty acid (EFA) deficiency in plasma and tissue lipids of cystic fibrosis (CF) patients, the reasons for this deficiency are not well established. It is believed that reduced EFA intake, malabsorption of fat, altered desaturase/lipase activity and defective cystic fibrosis transmembrane conductance regulator (CFTR) altering utilisation of EFA in epithelial cells contribute to the development of EFA deficiency in CF. It is likely that increased metabolism of arachidonic acid to eicosanoids such as leukotrienes, thromboxane and prostaglandins may also be a contributing factor. Evidence is presented that elevated oxidative damage to EFA and impaired antioxidant defences, in particular vitamin E, may contribute to the development of EFA deficiency in CF. Furthermore, antioxidant supplementation in CF may improve EFA status.

Wolfram, G. (2003). "Dietary fatty acids and coronary heart disease." Eur J Med Res 8(8): 321-4.

            Epidemiological studies have confirmed a strong association between fat intake, especially saturated and trans fatty acids, plasma cholesterol levels and rate of coronary heart disease (CHD) mortality. Meanwhile it is clear, that early atherosclerosis is largely preventable by modifying nutritional behaviour and lifestyle. There is clear evidence that a diet moderate in total fat (25-35 % energy) is superior to extremes in dietary fat. Because fat is energy dense moderation in fat intake is also essential for weight control. Saturated fatty acids are very potent in increasing LDL-cholesterol concentration in plasma a dangerous risk factor for early CHD. Unsaturated fatty acids have numerous beneficial health effects. The results of prospective cohort studies fit well to the experimental experience of the antihypercholesterolemic action of Omega-6 fatty acids and the antithrombotic, vasodilatory and antiarrhythmic properties of Omega-3 fatty acids, while the optimistic rating of Omega-9 fatty acids is less supported by epidemiologic studies. The results of prospective cohort studies are confirmed by intervention trials revealing that saturated fatty acids enhance early development of CHD whereas polyunsaturated fatty acids, especially of the Omega-3 type, significantly preserve from CHD. In context with a prudent diet pattern favourable dietary fatty acid composition offers the best chance for a reduced risk of CHD.

Wijendran, V., A. Pronczuk, et al. (2003). "Dietary trans-18:1 raises plasma triglycerides and VLDL cholesterol when replacing either 16:0 or 18:0 in gerbils." J Nutr Biochem 14(10): 584-90.

            To compare the relative impact of trans-18:1 with the two main dietary saturated fatty acids it replaces, plasma lipid response was assessed in Mongol