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Aim: To study the effects of eicosapentaenoic acid (EPA) on prostate-specific antigen (PSA) failure in prostate cancer patients who underwent prostatectomy., Patients and Methods: Sixty-two prostate cancer patients whose PSA levels were less than 0.2 ng/ml 3 months after surgery were randomized to either an EPA group (n=32) or a control group (n=30). EPA (2.4 g/day) was administered in the EPA group for 2 years. PSA was measured every two months., Results: The EPA concentration increased but the docosahexaenoic acid concentration decreased significantly (P<0.001) in erythrocytes. The PSA recurrence rates during a mean follow-up of 53.8 months were not different between the two groups (p=0.16)., Conclusion: A longer and/or larger intervention or docosahexaenoic acid supplementation might be necessary to identify significant preventive effects of mega-3 polyunsaturated fatty acids on PSA recurrence.

Background: Soy protein ameliorates rat polycystic kidney disease with concomitant renal enrichment of omega3-polyunsaturated fatty acids. A study was conducted to examine the effects of eicosapentaenoic acids (EPA) on renal volume and function in patients with autosomal dominant polycystic kidney disease (ADPKD)., Methods: Non-azotemic patients were randomized to either a control group (n = 20) or an EPA group (n = 21). EPA capsules (2.4 g/day) were administered in the EPA group for 2 years. Twenty-four hours of urine was collected for the creatinine clearance (Ccr) measurement every year. At baseline and 24 months, fatty acid compositions in erythrocytes were measured and computerized tomographies were obtained for calculation of renal volume by the modified ellipsoid and volumetric methods., Results: In the EPA group, the EPA concentration (1.80 +/- 0.99 versus 4.40 +/- 1.79 area%, P < 0.001) and the omega3/omega6 ratio in the erythrocyte increased, but docosahexaenoic acid (DHA) (6.76 +/- 1.19 versus 5.64 +/- 1.45 area%, P < 0.010) concentration decreased. Ccr decreased by 8.5 +/- 9.5 and 9.0 +/- 13.0 ml/min/1.73 m(2)/2 years in the control and EPA groups, respectively (NS). The increases in renal volume calculated by either method were not significantly different between the two groups., Conclusions: A beneficial effect of EPA on renal function and kidney volume in ADPKD patients could not be confirmed in the present study. Administration of EPA with DHA supplementation and/or longer intervention might be necessary to demonstrate preventive effects of omega3-polyunsaturated fatty acids on progression of ADPKD.

The blood eicosapentaenoic and docosahexaenoic acid (EPA+DHA) concentration is an important inverse risk factor for sudden cardiac death. However, it is not known what kinds of factors influence the EPA+DHA levels in the total phospholipid fraction in red blood cells (RBC EPA+DHA) in Japan, who regularly eat more fish with increasing age. Four hundred and fifty-six healthy individuals (320 men and 136 women, 18 to 70 years old) were recruited between 2002 and 2005. RBC EPA+DHA were measured by gas chromatography and questionnaires were administered. Multivariate analysis indicated that there were significant correlations between RBC EPA+DHA and (i) dietary EPA+DHA (beta=0.31), (ii) age (beta=0.33), (iii) gender (beta=-0.15) and (iv) physical activity (beta=-0.11) but not with body mass index or smoking.

Epidemiological studies showed that habitual fish intakes were associated with lower blood inflammatory markers. In the present study the effects of a fish oil-containing food on inflammatory markers were investigated in healthy, mostly middle-aged subjects (59 men and 82 women) with normal to mildly elevated triglyceride levels. Study subjects were randomly allocated to two groups in a double-blind manner; one group ingested an eicosapentaenoic acid (EPA)-rich fish oil-fortified drink (0.60 g EPA+0.26 g docosahexaenoic acid/d. EPA group, n=68) for 12 wk. The rest of the subjects took a placebo (control group, n=73). Plasma levels of high sensitivity C-reactive protein (hs-CRP) and soluble tumor necrosis factor-receptors 1 and 2 (sTNF-Rs 1 and 2) were measured at the start and end of intervention. EPA concentrations in the total RBC phospholipid fraction significantly increased by 79% in the EPA group at the end of the study, and they changed very little in the control group (+0.68%). The inflammatory markers did not change in either group. It is likely that fish oil does not change hs-CRP or sTNF-Rs 1 or 2 in subjects without active inflammation.

The "Study of EPA Effects on Prostate Cancer" (SEEPC) Group has been conducting a clinical trial with patients who underwent radical prostatectomy. The main purpose of the SEEPC is to evaluate whether eicosapentaenoic acid (EPA) prevents prostate cancer (PC) recurrence. As the surrogate marker of recurrence, the prostate-specific antigen (PSA) level was measured. However, if EPA affects the PSA values independently of PC, PSA may not be a good marker of recurrence in the event of EPA treatment. Thus, in the present study, whether EPA affected the PSA values was investigated using non-PC volunteers. Twenty men, of at least 50 years of age, were recruited, mostly from hospital staff The volunteers were randomly allocated either to the EPA group or the control. The subjects in the EPA group were administered EPA-ethyl ester a dose of 2400 mg/day for 12 weeks, whereas the controls were administered none. Fasting blood samples were obtained before the start of EPA administration and 4 and 12 weeks later. The EPA concentrations in erythrocytes increased in all the subjects in the EPA group (174+/-96%) with no significant changes in the control group (8.5+/-14.0%). There were no significant differences between the two groups in the serum PSA levels, allowing the conclusion that the PSA is an appropriate surrogate marker of recurrence in prostate cancer.

Eicosapentaenoic acid (EPA) is one of the major components of fish oil, which was reported to have antiatherogenic, anti-inflammatory and immune suppressive effects. In the present study, highly purified EPA was administered to patients with lupus nephritis and the effects of EPA on urinary 8-isoprostane, a reliable marker of oxidative stress, were investigated in these patients. Six outpatients (1 man and 5 women), with lupus nephritis diagnosed by renal biopsy, were entered in the study. We administered 1800 mg EPA ethyl-ester (purity > 95%) daily and examined the urinary 8-isoprostane levels and plasma fatty acid composition before and 3 months after EPA treatment. The urinary 8-isoprostane levels were significantly decreased after the treatment compared with those before the treatment (from 530 +/- 113 pg/mg x Cr to 235 +/- 49 pg/mg x Cr, p = 0.02). The EPA levels in the plasma phospholipid (PL) fraction were significantly increased after the treatment (from 3.30 +/- 0.64 mol% to 8.01 +/- 0.47 mol%, p < 0.001). Arachidonic acid (AA) levels in the plasma PL fraction were significantly decreased after the treatment (from 9.47 +/- 0.28 mol% to 7.33 +/- 0.43 mol%, p < 0.001). The ratios of EPA to AA were significantly increased after the treatment (from 0.35 +/- 0.07 to 1.14 +/- 0.16, p < 0.001). Thus, this preliminary study indicated that EPA might exert beneficial effects on lupus nephritis by decreasing the oxidative stress.

Objective: We previously reported that administration of fish oil rich in docosahexaenoic acid (DHA) increased the plasma ratio of epinephrine to norepinephrine (NE) at rest in young adults who were under chronic stress and that this effect was achieved mainly through depression of NE. However, not many reports have documented the effects of eicosapentaenoic acid (EPA) and DHA on blood catecholamine levels in healthy humans. Therefore, we performed another intervention study to test their effect on catecholamines with healthy subjects under no chronic stress., Methods: Twenty-one healthy young adults (15 men and 6 women) were randomly assigned to an omega-3 group (n = 9) or a control group (n = 12) in a double-blind manner. Twenty capsules of shellfish-derived lipids containing 762 mg of EPA plus DHA per day were administered to the omega-3 group for 2 mo. The controls took the same amount of placebo capsules. Fasting blood samples after a 30-min rest with a catheter in a forearm vein were obtained at the start and the end of the study for catecholamine measurements., Results: EPA but not DHA concentrations in red blood cells significantly increased in the omega-3 group compared with the control group (P < 0.001). Plasma NE concentrations were significantly decreased in the omega-3 group (from 1.49 +/- 0.39 nmol/L to 1.05 +/- 0.14 nmol/L) compared with the control group (from 1.12 +/- 0.24 nmol/L to 1.39 +/- 0.32 nmol/L) with analysis of covariance (P < 0.001). The differences remained significant (P = 0.01) even after deletion of three subjects in the omega-3 group who had the highest baseline NE values and one in the control group who had the lowest baseline NE value to nullify a significant baseline differences in NE between groups., Conclusion: This study demonstrated that EPA plus DHA supplementation lowered plasma NE concentrations in normal volunteers even at the small dose of 762 mg of EPA plus DHA per day. This effect of EPA plus DHA to lower plasma NE concentrations may be important to understand some of the effects of fish oils on diseases.

Background: Epidemiologic studies show that low fish intake is a risk factor of suicidality; however, there are no case-control studies investigating suicide attempt risk and tissue n-3 fatty acid levels., Methods: We recruited 100 suicide-attempt cases and another 100 control patients injured by accidents who were admitted to three hospitals affiliated with Dalian Medical University in Dalian, China. Case and control subjects were matched for age, gender, and smoking status. Those who were inebriated at the time of hospitalization were excluded. Blood was sampled immediately after admission to a hospital. Washed red blood cells (RBCs) were obtained, and the fatty acid composition of the total RBC phospholipid fraction was analyzed by gas chromatography., Results: Eicosapentaenoic acid (EPA) levels in RBC in the case subjects were significantly lower than those of the control subjects (.74 +/-.52% vs. 1.06 +/-.62%, p <.0001). When the highest and lowest quartiles of EPA in RBC were compared, the odds ratios of suicide attempt was.12 in the highest quartile (95% confidence interval:.04-.36, p for trend =.0001) after adjustment for possible confounding factors, Conclusions: Our findings suggest that low n-3 fatty acid levels in tissues were a risk factor of suicide attempt. Further studies including intervention with fish oil are warranted.

Mice were fed a diet supplemented either with beef tallow (BT), BT plus ethyl eicosapentaenoate (EPA) or BT plus ethyl docosahexaenoate (DHA) for 9 weeks. EPA and DHA supplementation increased the content of the respective fatty acid in spleen leukocyte lipids, which was associated with the reduction in the arachidonate content. IL-1beta mRNA induction upon lipopolysaccharide (LPS) stimulation in spleen leukocytes in the DHA diet group was significantly lower than in the BT diet group, but the EPA diet was without any significant effect. The amount of prostaglandin E2 (PGE2) released from LPS-stimulated spleen leukocytes was significantly lower in both the EPA and DHA groups than in the BT group. Thus, dietary EPA and DHA inhibited arachidonate metabolism similarly but had different effects on IL-1beta mRNA induction in mouse spleen leukocytes.

HMG-CoA reductase inhibitors reduce serum total cholesterol concentrations and the risk of coronary heart disease in patients with hypercholesterolemia. Recently, it has been reported that patients with combined hyperlipidemia are also at risk of coronary heart disease. However, HMG-CoA reductase inhibitor therapy alone does not sufficiently reduce serum triglyceride concentrations. Epidemiological and clinical evidence has shown that fish oil can lower plasma lipid levels, especially triglycerides. Consequently, we investigated the effects of the combination of HMG-CoA reductase inhibitors and eicosapentaenoic acid, a major component of fish oil, on hyperlipidemia. We administered 900-1,800 mg/day of the ethyl ester of eicosapentaenoic acid to patients with hyperlipidemia who had been treated with HMG-CoA reductase inhibitors for 30 +/- 6 months (means +/- SE). Serum total cholesterol and triglyceride concentrations were significantly decreased 3 months after the administration of eicosapentaenoic acid (from 5.63 +/- 0.23 mmol/l to 5.02 +/- 0.20 mmol/l, P < 0.05; from 2.07 +/- 0.41 mmol/l to 1.08 +/- 0.17 mmol/l, P < 0.01, respectively). Serum high-density lipoprotein-cholesterol concentrations were significantly increased after the treatment (from 1.23 +/- 0.12 mmol/l to 1.34 +/- 0.13 mmol/l, P < 0.05). Plasma eicosapentaenoic acid concentrations and the ratio to arachidonic acid in plasma were also significantly increased 3 months after the treatment (from 101.9 +/- 8.1 mg/l to 181.8 +/- 23.9 mg/l, P < 0.001; from 0.640 +/- 0.075 to 1.211 +/- 0.170, P < 0.001, respectively). These results suggested that the combination therapy of HMG-CoA reductase inhibitors and eicosapentaenoic acid was effective for patients with hyperlipidemia.

Remnant lipoproteins are transient metabolites from chylomicron and/or very low density lipoproteins (VLDL), and remnant hyperlipoproteinemia has recently been reported to be a risk factor for atherosclerosis. Eicosapentaenoic acid (EPA), a major component of fish oil, has the following effects: anti-platelet aggregation, vaso-dilation, anti-inflammation, hypotriglyceridemia, and therefore has potential anti-atherosclerotic effects. We measured serum of remnant-like particle cholesterol (RLP-C) concentrations, and investigated the effects of EPA on serum RLP-C concentrations in patients with diabetes mellitus. Ten patients with non-insulin dependent diabetes mellitus were treated with 900-1800 mg EPA ethyl-ester daily for 3 months. We investigated serum RLP-C concentrations and plasma fatty acid composition before and after the administration of EPA. Serum RLP-C concentrations were significantly decreased 3 months after the administration of EPA (from 14.5 +/- 5.3 mg/dL to 3.3 +/- 0.8 mg/dL, P < 0.01). Plasma EPA concentrations and the ratios of EPA to arachidonic acids (AA) were significantly increased during the same period (from 86.2 +/- 12.4 mg/L to 194.6 +/- 27.3 mg/L, P < 0.01, from 0.571 +/- 0.074 to 1.242 +/- 0.163. P < 0.01, respectively). Serum RLP-C concentrations were inversely correlated with the ratios of EPA to AA in plasma (r = -.516, P < 0.05). These results suggested that administration of EPA was effective on remnant hyperlipoproteinemia which was a risk factor for atherosclerosis.

There is a significant interest in the interrelationship between long-chain n-3 and n-6 fatty acids due to their ability to modulate eicosanoid production. In general, the intake of arachidonic acid (AA) results in enhanced eicosanoid production, whereas n-3 polyunsaturated fatty acids (PUFA) decrease the production of eicosanoids from AA. The purpose of this study was to investigate whether the effects of dietary AA on eicosanoid production in the rat were correlated with the AA and EPA levels in platelets and aorta (eicosanoid-producing tissues). Four groups of male Sprague-Dawley rats were fed a high-fat diet enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (approximately 100 mg/day of EPA + DHA) for 24 d. During the last 10 d, the four groups were orally supplemented with 0, 30, 60, and 90 mg/day of ethyl arachidonate. A further group of rats was fed a control diet (without long-chain n-3 PUFA) for 24 d. In vitro aorta prostacyclin (PGI2) production, serum thromboxane A2 (TxA2) production and plasma, and platelet and aorta phospholipid (PL) fatty acids were measured. Enriching the diet with n-3 PUFA resulted in significant reductions in tissue AA levels and an increase in the n-3 PUFA, particularly EPA. On this diet, the AA to EPA ratio was 1:1 in platelet PL, and it was 2:1 in the aorta PL. There were significant decreases in the in vitro PGI2 and TxA2 production compared with the control animals. The inclusion of AA in the diet resulted in marked increases in AA levels in the platelet and aorta PL with corresponding decreases in EPA. The lowest dose of AA (30 mg/rat) reversed the effects of 100 mg/day of n-3 PUFA on AA levels in platelet and aortic PL and on in vitro aorta PGI2 and serum TxA2 production. The dietary AA caused a differential (twofold) increase in TxA2 relative to PGI2 for all three levels of AA supplementation. There were greater changes in the levels of AA and/or EPA in platelet PL compared with the aorta PL, which might have accounted for the differential effects of these PUFA on thromboxane production compared with PGI2 production in this study.

To investigate effects of eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) on acute inflammation, we fed rats either of the following four diets: an EPA-rich diet for 5 or 15 days, a DHA-rich diet for 5 or 15 days, a control diet for 5 or 15 days, and standard chow for 15 days. At the end of diets, the carrageenan-induced swelling of footpads was measured. Peritoneal cells were analyzed for their fatty acids in the phospholipid fraction. The swelling was similarly reduced in the EPA and DHA groups (p < 0.05, if fed for 15 days) compared with rats fed the control diet for 15 days. The mean proportion of arachidonic acid (AA) to the sum of highly unsaturated fatty acids was correlated (r = 0.87) to the mean degree of swelling among all dietary groups (n = 7). Effects of EPA and DHA might be explained by the reduced availability of AA for eicosanoid formation represented by the proportion of AA.

Wistar rats (4-week-old) were administered with streptozotocin (45 mg/kg) through tail veins. After 3 months, diabetic rats were divided into 2 groups. One group (EPA group, n = 16) was fed a lipid-free diet (90%, w/w) plus lard (8%) and 90% pure eicosapentaenoic acid ethyl ester (2%) for 6 months. The other group (control group, n = 16) was fed in the same way except that eicosapentaenoic acid ethyl ester was replaced by safflower oil. Twenty-four-hour urine was collected just before starting the experimental diets and during the 6-month experimental period at monthly intervals. There were no differences in food intake and body weight between the two groups throughout the experiment. The mean microalbuminuria of the EPA group became significantly lower than that of the control group after 4 months on the diets through the end of the study (6 months). The mean microalbuminuria levels at the end of the study were 1.38 mg/day in the EPA group (n = 9) and 5.19 mg/day in the control group (n = 6) (p < 0.01). Eicosapentaenoic acid administration might retard the progression of diabetic nephropathy by reducing microalbuminuria.

The aim of the present study was to examine the effect of acute infusion of lipid emulsions enriched with either docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) on heart lipids, tolerance to infusion and to ischaemia-reperfusion. Isolated rat hearts were subjected to a 10 min lipid infusion period prior to 25 min of total global ischaemia and 30 min of reperfusion. Effects on physiology and metabolism were recorded during infusion and reperfusion. A more than doubled increase of DHA and a 12-fold increase of EPA in terms of relative concentration was demonstrated in the free fatty acid fraction after infusion with the respective triglyceride emulsions, without any profound change in physiology. High levels of DHA were associated with a reduced recovery of left ventricular developed pressure (LVDP) and increased release of lactate dehydrogenase (LDH) during reperfusion, while the hearts infused with the EPA-emulsion showed a recovery comparable to the control group. Heart lipid peroxidation, evaluated by release of thiobarbituric acid reactive substances (TBARS) in effluate, was about 4-fold higher in the DHA-group compared to the EPA-group during start of reperfusion and may in part explain the reduced recovery observed in these hearts. The present study demonstrates enrichment of DHA and EPA in the free fatty acid fraction after a short period of infusion. Protective effects of the emulsions were not found, instead the data indicate harmful effects of DHA during ischaemia-reperfusion. However, the presence of TBARS in this emulsion could have influenced the results.

Leukotriene (LT) B4 is a major chemical activator of PMN. Inhibitory effects of oral administration of docosahexaenoic acid (DHA) on LTB4 synthesis by PMN are known. We intravenously infused tridocosahexaenoyl-glycerol (DHA-TG) emulsion into rabbits in three different doses, namely 0.8, 0.4, or 0.2 g DHA/kg, and investigated the changes in LTB4/5 production by ionophore-activated PMN. The averaged LTB4 production by PMN was significantly reduced to 57 and 59% of baseline at 6 h after the infusion of 0.8 and 0.4 g DHA/kg, respectively (P < 0.05), but not after the infusion of 0.2 g DHA/kg or 0.8 g soybean oil/kg. The combined concentrations of both DHA and eicosapentaenoic acid in the PMN phospholipid fraction were significantly increased at 6 h after the infusion of 0.8 or 0.4 g DHA/kg but not after the infusion of 0.2 g DHA/kg or 0.8 g soybean oil/kg. Oral administration of 0.8 g DHA/kg did not increase DHA or eicosapentaenoic acid in the PMN phospholipid fraction and did not decrease LTB4 production by PMN at 6 h after administration. We suggest that the infusion of 0.4-0.8 g DHA/kg might be beneficial to patients who suffer from diseases that are related to the acute elevation of LTB4 production.

An infusible emulsion of 10% eicosapentaenoic acid ethyl ester (EPA-EE, 99.2% pure) was prepared. Three ml of the emulsion was infused into tail veins of 20 Wistar rats weighing approx. 300 g. They were killed 1 h, 6 h, 24 h, 3 d and 7 d after the infusion, and fatty acid composition of various organs and plasma was analyzed along with that of control rats. There was no lipidosis in any organs of any rats. It was estimated that not less than 98% of infused EPA was cleared from plasma during the first hour after the infusion. EPA concentrations reached their peaks within 6 h after EPA infusion in plasma lipid fractions and in the phospholipid fraction of liver, heart, lung, kidney and spleen. The fatty acid composition of the phospholipid fraction of heart was very stable, and was not altered by EPA infusion except for a very slight increase in EPA at 1 h after the infusion (0.18% at 0 h to 0.56%). However, EPA concentrations increased markedly in the free fatty acid fraction of heart at 1 h after the infusion (0.15% at 0 h to 4.23%). Arachidonic acid concentrations decreased significantly within 24 h in the phospholipid fraction of organs except for heart. EPA emulsion might be useful for patients in whom a rapid increment in EPA in tissues is beneficial.

During myocardial infarction leukotriene B4 (LTB4) is probably a major determining factor of tissue damage because it can amplify the inflammatory reaction by recruiting leukocytes and degranulating them. Oral administration of eicosapentaenoic acid (EPA) is known to reduce LTB4 production by polymorphonuclear leukocytes (PMNL). However, it takes several weeks for EPA to take effect. In this study, we formulated a trieicosapentaenoyl-glycerol emulsion and infused it into rabbits (0.8 g EPA/kg). In the ex vivo study, the inhibition of LTB4 production by PMNL from EPA-infused rabbits was maximal (32-60% of preinfusion values, P less than 0.01) 6 h after the infusion. There was also a tendency toward reduced LTB4 production 1, 24, and 168 h after the infusion. A lower dose (0.2 g EPA/kg) also reduced LTB4 production (45% of preinfusion values, P less than 0.02) 6 h after the infusion. There was no significant change in LTB4 production in control groups in which soybean oil emulsion was infused instead of EPA. EPA infusion might be useful for reduction of tissue damage in the acute phase of LTB4-related diseases such as acute myocardial infarction.

Recently, many investigators have studied the effects of eicosapentaenoic acid (EPA)-rich fish oil on immune function and immune disease. However, effects of dietary supplementation of fish oil or EPA on the immune system are still unclear. In the present study, the effects of EPA on antigen presentation were investigated. We have used antigen-specific helper T-cell clones that proliferate in the presence of antigen [keyhole limpet haemocyanin (KLH)] and spleen cells as antigen-presenting cells (APC). Mice were divided into two groups and fed an experimental diet or a control diet for 4 weeks ad libitum. In mice fed the experimental diet, the arachidonic acid (AA) content of spleen cells was decreased and that of EPA and docosapentaenoic acid was increased markedly compared to those of the control diet. Dietary enrichment with EPA inhibited the ability of accessory cells to present antigen to murine helper T-cell clones. This effect was observed for two distinct helper T-cell clones, Th1 and Th2. We also examined the effects of EPA-TG emulsion on APC function. The direct addition of EPA-TG emulsion to a T-cell proliferation assay system suppressed APC function. The inhibition was proportional to the concentration of EPA-TG emulsion. Pretreatment of splenocytes with EPA-TG emulsion resulted in inhibition of APC function. Inhibition of antigen presentation by dietary supplementation with EPA might depress immune reactivity.

Eicosapentaenoic acid (EPA) ethyl ester (1.8 g/d) was administered to 16 diabetic patients (5 insulin-dependent and 11 noninsulin-dependent diabetics) for 6 mon. EPA in total plasma fatty acids increased from 4.0 +/- 2.4 mol% (mean +/- SD) to 7.5 +/- 3.1 mol% (p less than 0.001). Albumin excretion, measured with spot urine, was significantly reduced from 65 to 36 mg/g creatinine (geometric means, p less than 0.001). Fasting blood sugar levels, glycohemogloblin, body weight and blood pressure did not change significantly during the study. There were also no significant changes in serum levels of creatinine, urea nitrogen, total cholesterol and triglycerides. Although no overt hemorrhage was observed in the patients, hematocrit was reduced from 42.6 +/- 2.8% to 41.0 +/- 3.9% (p less than 0.02). Ten other similar diabetic patients (4 insulin-dependent and 6 noninsulin-dependent diabetics) were followed as a reference group, not concomitantly, for 6 mon with neither EPA ethyl ester nor placebo. The parameters mentioned above were not changed significantly in this group during 6 mon. EPA administration might retard the appearance of overt diabetic nephropathy.

The effect of eicosapentaenoic acid (EPA) on natural killer (NK) cell activity of human lymphocytes was examined. The addition of an emulsion of trieicosapentaenoyl-glycerol (EPA-TG) emulsified with purified phosphatidylcholine from krill to a cytotoxicity assay system resulted in a marked depression of NK activity. The inhibition was proportional to the concentration of EPA-TG emulsion, and was observed as early as the first one hour of incubation at various effector to target cell ratios. Pretreatment of effector cells with EPA-TG emulsion resulted in significant suppression of their NK activity. Inhibition of cytotoxicity was not due to direct toxicity to effector cells or decreased target cell binding. These results indicate that EPA is a potent inhibitor of NK activity in vitro.

The ethyl ester of eicosapentaenoic acid (EPA) is the only pure EPA-containing lipid available in bulk for oral administration. However, there is doubt as to whether EPA ethyl ester can efficiently increase the plasma levels of EPA in comparison with the ability of other kinds of EPA-containing lipids to do so. Therefore, two other kinds of EPA-containing lipids were prepared to study the efficiency of oral administration of those lipids for increasing the EPA content in plasma phospholipids and cholesteryl esters. EPA-containing lipids which were investigated were [A] 1,2,3-trieicosapentaenoyl-glycerol, [B] 2-eicosapentaenoyl-phosphatidylcholine and [C] ethyl ester of EPA. An adjusted amount of lipids [A], [B] and [C] was administered to rats through a gastric tube for 4 days (the first experiment) or for 10 days (the second experiment), and the fatty acid composition of plasma phospholipids and cholesteryl esters was determined. In the first experiment, there were no significant differences in the efficiency for increasing EPA levels in either phospholipids or cholesteryl esters among the lipids. In the second experiment, the EPA levels of both plasma phospholipids and cholesteryl esters of rats administered ethyl ester of EPA were significantly higher than those of rats administered 2-eicosapentaenoyl-phosphatidylcholine. The EPA levels of the rats administered 1,2,3-trieicosapentaenoyl-glycerol were between the levels of the two groups mentioned above, but the differences in the EPA levels were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

A highly purified ethyl ester of EPA (EPAEE) (74%) was manufactured from sardine oil. Sixty mg/kg/day of EPAEE was given orally to male Wistar rats for 8 weeks. No side effect or toxicity from the administration of EPAEE was observed. Plasma EPA concentration and the ratio of EPA to arachidonic acid were significantly increased, compared with control Wistar rats. An enhancement of PGI2-like substance production by aortas obtained from rats fed EPAEE was noted. Conversion of EPA to delta 17-6-keto-PGF1 alpha, a stable metabolite of PGI3, could not be detected by an incubation study of 14C-EPA and aortas either from rats fed EPAEE or from control rats. Therefore, PGI2-like substance produced by rat aorta is most likely to be PGI2 itself and not PGI3.

To examine the effects of in vivo eicosapentaenoic acid (EPA) on natural killer (NK) cell activity, C3H/He mice each received a single intraperitoneal bolus of an emulsion of trieicosapentaenoyl-glycerol (EPA-TG). Spleen cells were tested for NK activity using 51Chromium-release assays against YAC-1 target cells. Forty eight hours after injection, NK activity was inhibited in a dose-dependent manner. EPA-TG emulsion also inhibited the NK activity of NK-enriched effector cells. Decreased cytotoxicity was first noted 24 hr after injection; it resumed the baseline by 7 days. The addition of EPA-TG emulsion to a cytotoxicity assay system resulted in moderate depression of NK activity. These results demonstrate that EPA has significant immunomodulatory effects on NK activity.

The effect of age on eicosapentaenoic acid (20:5 n-3; EPA) incorporation into plasma lipids was investigated in young volunteers (8 males, 19 +/- 1 yr) and middle-aged volunteers (6 males, 53 +/- 7 yr). They were asked to take 5.4 g fish oil per day for one week. The increment in EPA in the cholesteryl ester fraction after the supplementation was significantly greater in the middle-aged group (delta = 1.69%) than in the young group (delta = 0.44%) (p less than 0.05). The food intake analyzed for 3 consecutive days just before the supplementation revealed that the young group took more linoleate (17 vs. 10 g) than the middle-aged group. There was a significant inverse correlation between the increment in EPA in the cholesteryl ester fraction after the supplementation and daily linoleate intake among all the volunteers combined (r = -0.63, p less than 0.02). The higher increment in EPA in cholesteryl ester in the middle-aged group might be due to less intake of linoleate and not due to the difference in age itself.

Abstract: Introduction: Cartilage contains high levels of n-9 eicosatrienoic acid (20:3n-9) but no blood vessels. 20:3n-9 might inhibit angiogenesis. Materials and methods: Angiogenesis was measured in human umbilical vein endothelial cells and diploid fibroblasts. Co-culture was performed with vascular endothelial growth factor-A (VEGF-A, 10ng/mL) and fatty acids (0.1–10μmol/L). After 10 days of incubation and immunostaining for endothelial cells, vessel areas were calculated with image analyser software. Results: Addition of 20:3n-9 and n-3 eicosatrienoic acid (20:3n-3) dose dependently inhibited VEGF-A-stimulated angiogenesis (more than the positive control suramin). Arachidonic, eicosapentaenoic, dihomo-γ-linolenic (20:3n-6) and oleic acids did not affect VEGF-A-stimulated angiogenesis even at 10μmol/L. Arachidonic and dihomo-γ-linolenic acids enhanced angiogenesis without VEGF-A. Discussion and conclusions: We suggest that the presence of 20:3n-9 in cartilage may be related to its vessel-free status and that 20:3n-9 may be useful for the treatment of disorders with excessive vasculature. Acknowledgements: This work was partly supported by Polyene Project, Inc. [Copyright &y& Elsevier]