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Long-term effects of eicosapentaenoic acid on diabetic peripheral neuropathy and serum lipids in patients with type II diabetes mellitus
Journal of Diabetes and its Complications (USA),, 1996, 10/5 (280-287)
The present study was undertaken to investigate the efficacy of a new, highly purified (purity greater than 91%), ethyl esterification product from natural eicosapentaenoic acid (EPA-E, C20:5 omega3) in patients with type II diabetes mellitus (NIDDM). Hemodynamic changes were assessed at the level of the dorsalis pedis artery using an ultrasonic color Doppler duplex system before and after oral administration of EPA-E at a dose of 1800 mg/day for 48 weeks. The cross-sectional area of the dorsalis pedis artery increased significantly from 2.5 plus or minus 0.2 to 3.9 plus or minus 0.4 mm2 (48 weeks, mean plus or minus SE, p < 0.05). Moreover, EPA-E improved the clinical symptom (coldness, numbness) as well as the vibration perception threshold sense of the lower extremities (from 32.1 plus or minus 8.5 to 16.1 plus or minus 4.8 (48 weeks) microm). A significant decrease of serum triglycerides was also noted by EPA-E administration. Furthermore, significant decrease of the excretion of albumin in urine (from 24.4 plus or minus 3.3 to 13.9 plus or minus 1.8 (48 weeks) mg/g.Cr, p < 0.05). The results of this study suggest that EPA-E has significant beneficial effects on diabetic neuropathy and serum lipids as well as other diabetic complications such as nephropathy and macroangiopathy.
Red blood cell and adipose tissue fatty acids in mild inactive multiple sclerosis.
Acta Neurol Scand (DENMARK) Jul 1990, 82 (1) p43-50
The fatty acid profiles of phosphatidyl ethanolamine (PE) and phosphatidyl choline (PC) of the red blood cells of 30 patients with mild inactive multiple sclerosis (MS) and 30 healthy controls were studied by gas chromatography. The groups were well matched for factors likely to influence tissue lipid levels, including diet. The MS patients showed a significant reduction in PE eicosapentaenoic acid (p = 0.009) especially in women, and an increase in both PE dihomo-gamma-linolenic acid (p = 0.004) and PC stearic acid (p = 0.04). No reduction in linoleic acid was observed in either the PC or PE fractions of the MS subjects. A similar study of the fatty acid profile in adipose tissue in 26 MS and 35 healthy controls found no detectable eicosapentaenoic acid in either group. However, whereas docosahexaenoic acid was not detectable in any MS patient, 40% of the controls had measurable levels varying from to 0.1 to 0.3% of total estimated fatty acid (p = 0.0003). No reduction in linoleic acid in MS subjects was observed. Supplementation with oral fish body oil demonstrated that n-3 fatty acids were incorporated into red blood cells over 5 weeks and this occurred equally in MS and controls. The effects of oral supplementation on adipose tissue were studied after 1 and 2 years. Whereas many fatty acids such as linoleic acid were raised at 1 year, but did not rise subsequently, eicosapentaenoic acid and docosahexaenoic acid continued to rise through the 2-year period.(ABSTRACT TRUNCATED AT 250 WORDS)
Vasorelaxant properties of n-3 polyunsaturated fatty acids in aortas from spontaneously hypertensive and normotensive rats.
J Cardiovasc Risk (ENGLAND) Jun 1994, 1 (1) p75-80
BACKGROUND: Dietary consumption of fish, rich in n-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been shown to reduce blood pressure in both animal studies and clinical trials. Although the antihypertensive mechanisms are not known, the blood-pressure-lowering effect of n-3 polyunsaturated fatty acids may be partially attributed to their vasorelaxant properties. METHODS: Aortic rings with and without endothelium, from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), 16-17 weeks old, were suspended in tissue baths and isometric tension was measured. Concentration-response curves were generated for DHA and EPA (1-100 mu mol/l) in norepinephrine-contracted rings. Blood pressure was measured using the tail-cuff method and aortic media thickness was determined. RESULTS: Blood pressure was significantly increased in SHR (n=10; 194 +/- 4.4 mmHg) compared with WKY (n=10; 124 +/- 1.2 mmHg, P < or = 0.0001). DHA (1-100 mu mol/l) relaxed aortic rings f rom WKY (-3.3 +/- 0.7 to -13 +/- 2.3%, P < or = 0.001) and from SHR (-6.5 +/- 1.8 to -22.9 +/- 4%, P < or = 0.01) in a concentration-dependent manner. EPA (1-100 mu mol/l) evoked greater relaxation in SHR (-10.1 +/- 2.0 to -33 +/- 3.9%, P < 0.01) than in WKY (-2.9 +/- 1.1 to -18.3 +/- 2.1%, P < 0.01) aortic rings. The relaxant effect of DHA in both WKY and SHR and of EPA in WKY were not dependent on an intact endothelium. However, EPA (1-10 mu mol/l) induced greater responses in intact SHR rings (-10.1 +/- 2.0 to -14.5 +/- 3.1%) than in de-endothelialized SHR rings (0 to -2.1 +/- 1.7%, P = 0.001). CONCLUSION: The direct relaxant effects of n-3 fatty acids as seen in WKY and SHR may contribute, in part, toward the blood-pressure-lowering effect of dietary fish and fish-oil supplementation.
Effects of fish oil, nifedipine and their combination on blood pressure and lipids in primary hypertension.
J Hum Hypertens (ENGLAND) Feb 1993, 7 (1) p25-32
In a double-blind, crossover, placebo-controlled study the effects of four weeks' treatment with 4.55 g/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on BP and serum lipids were assessed in 18 males with hypertension (WHO stage I-II). At the end of the double-blind phase, eight patients on placebo (olive oil) and ten patients on fish oil treatment were given nifedipine 20 mg twice daily added to their regimens for four weeks. Four weeks' fish oil treatment slightly reduced BP values; however, compared with placebo no changes were found. VLDL-cholesterol and triglycerides were significantly reduced by 24%, whereas total and LDL-cholesterol remained unchanged. Placebo did not change BP and lipid values. When nifedipine was added to fish oil/placebo, BP in the two groups was reduced to almost the same extent. When nifedipine was added to fish oil, total cholesterol was significantly reduced by 12% in comparison with baseline value and LDL-cholesterol was reduced by 15%, albeit insignificantly. Placebo plus nifedipine was lipid neutral. A significant correlation was found between the nifedipine-induced changes in supine mean arterial pressure and total, LDL- and VLDL-cholesterol, respectively, in those patients with and without fish oil treatment. In conclusion, the combined administration of fish oil and nifedipine possesses favourable antihypertensive and metabolic properties in hypertensive males with elevated lipid levels.
Eicosapentaenoic acid, but not docosahexaenoic acid, increases mitochondrial fatty acid oxidation and upregulates 2,4-dienoyl-CoA reductase gene expression in rats.
Lipids (UNITED STATES) Jun 1996, 31 (6) p579-92
The aim of the present study was to investigate whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was responsible for the triglyceride-lowering effect of fish oil. In rats fed a single dose of EPA as ethyl ester (EPA-EE), the plasma concentration of triglycerides was decreased at 8 h after acute administration. This was accompanied by an increased hepatic fatty acid oxidation and mitochondrial 2,4-dienoyl-CoA reductase activity. The steady-state level of 2,4-dienoyl-CoA reductase mRNA increased in parallel with the enzyme activity. An increased hepatic long-chain acyl-CoA content, but a reduced amount of hepatic malonyl-CoA, was obtained at 8 h after acute EPA-EE treatment. On EPA-EE supplementation, both EPA (20:5n-3) and docosapentaenoic acid (DPA, 22:5n-3) increased in the liver, whereas the hepatic DHA (22:6n-3) concentration was unchanged. On DHA-EE supplementation retroconversion to EPA occurred. No statistically significant differences were found, however, for mitochondrial enzyme activities, malonyl-CoA, long-chain acyl-CoA, plasma lipid levels, and the amount of cellular fatty acids between DHA-EE treated rats and their controls at any time point studied. In cultured rat hepatocytes, the oxidation of [1-14C]palmitic acid was reduced by DHA, whereas it was stimulated by EPA. In the in vivo studies, the activities of phosphatidate phosphohydrolase and acetyl-CoA carboxylase were unaffected after acute EPA-EE and DHA-EE administration, but the fatty acyl-CoA oxidase, the rate-limiting enzyme in peroxisomal fatty acid oxidation, was increased after feeding these n-3 fatty acids. The hypocholesterolemic properties of EPA-EE may be due to decreased 3-hydroxy-3-methylglutaryl-CoA reductase activity. Furthermore, replacement of the ordinary fatty acids, i.e., the monoenes (16:1n-7, 18:1n-7, and 18:1n-9) with EPA and some conversion to DPA concomitant with increased fatty acid oxidation is probably the mechanism leading to changed fatty acid composition. In contrast, DHA does not stimulate fatty acid oxidation and, consequently, no such displacement mechanism operates. In conclusion, we have obtained evidence that EPA, and not DHA, is the fatty acid primarily responsible for the triglyceride-lowering effect of fish oil in rats.
Improvement by eicosanoids in cancer cachexia induced by LLC-IL6 transplantation
Journal of Cancer Research and Clinical Oncology (Germany)1996, 122/12 (711-715)
Cachexia frequently occurs in the late stages of cancer, and is difficult to manage. We previously reported that interleukin-6 (IL-6) cDNA transfection into Lewis lung carcinoma (LLC-IL6) induced cachexia-like symptoms in C57BL/6 mice. This was thought to be a useful experimental model of cancer cachexia. We have examined the effects of two eicosanoids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in order to evaluate whether they could relieve cachexia. LLC-IL6-bearing animals were divided into three treatment groups receiving DHA, EPA or water as the control; 80-microl samples of these compounds (purity > 95%) were administered orally by catheter daily starting 7 days after tumor transplantation. Tumor growth curves were similar in the three groups. There were no differences in water or food intake in the three groups. However, body weight, a marker of cachexia, was significantly higher in treated mice than in the control group. Sixteen days after tumor transplantation, the mean body weight was 17.45 g (P < 0.05), 17.2 g and 16.41 g in the groups receiving DHA, EPA and water respectively. The eicosanoids did not affect serum levels of IL-6. Ubiquitination of muscle protein, a marker of proteolysis coupled to cachexia, was compared in LLC-IL6- and LLC-transplanted mice. The eicosanoids prevented the ubiquitination of approximately 180 kDa protein. These results suggest that eicosanoids may prevent the cachexia mediated by IL-6.
Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia
Nutrition (USA)1996, 12/1 SUPPL. (S31-S33)
Depletion of muscle and adipose tissue in cancer cachexia appears to arise not only from decreased food intake but also from the production of catabolic factors by certain tumours. Experiments with the cachexia-inducing MAC16 tumour in mice showed that when part of the carbohydrate calories were replaced by fish oil, host body weight loss was inhibited. The effect occurred without an alteration of either the total calorie consumption or nitrogen intake. Instead, one of the polyunsaturated fatty acids (PUFA) in fish oil, eicosapentaenoic acid (EPA), was found directly to inhibit tumour- induced lipolysis. The effect was structurally specific, as two related PUFA, docosahexaenoic acid (DHA) and gamma-linolenic acid (GLA), were without effect. The antilipolytic effect of EPA arose from an inhibition of the elevation of cyclic AMP in adipocytes in response to the lipid mobilizing factor. The increased protein degradation in the skeletal muscle of cachectic animals was also inhibited by EPA. This effect was due to the inhibition of the rise in muscle prostaglandin E2 in response to a tumour-produced proteolytic factor by EPA. Thus, reversal of cachexia by EPA in this mouse model results from its capacity to interfere with tumour-produced catabolic factors. Similar factors have been detected in human cancer cachexia.
The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer
Nutrition (USA)1996, 12/1 SUPPL. (S27-S30)
Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2- 4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0.-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.
Comparison of the effectiveness of eicosapentaenoic acid administered as either the free acid or ethyl ester as an anticachectic and antitumour agent
PROSTAGLANDINS LEUKOTRIENES ESSENT. FATTY ACIDS (United Kingdom)1994, 51/2 (141-145)
A comparison has been made of the effectiveness of eicosapentaenoic (EPA) acid administered as either the free acid or the ethyl ester as an anticachectic and antitumour agent in mice bearing an experimental cachexia-inducing tumour (MAC16 colon adenocarcinoma). While the free acid of EPA was effective in reversing host body weight loss and inhibiting tumour growth the ethyl ester was ineffective in either respect at the same dose level, even when administered with a high fat diet. The lack of effectiveness of the ethyl ester correlated with the inability to reach effective plasma and tumour concentrations of EPA over the initial time period. Whereas effective plasma concentrations of EPA were achieved within 24 h after administration of the free acid, a time lapse of 96 h was required with the ethyl ester, even when combined with a high fat diet. Due to the acuteness of the MAC16 model this time is too long for a therapeutic benefit to be realized.
Kinetics of the inhibition of tumour growth in mice by eicosapentaenoic acid-reversal by linoleic acid
BIOCHEM. PHARMACOL. (United Kingdom)1993, 45/11 (2189-2194)
Oral administration of eicosapentaenoic acid (EPA) (2.0 g/kg) by gavage to female NMRI mice bearing the MAC16 colon adenocarcinoma and with weight loss, prevented further loss in body weight and produced a delay in the growth of the tumour. Cell production and loss were determined by the (125I)5-iodo-2'-deoxyuridine method during the stationary and growth phase of the tumour in animals treated with EPA. Tumour stasis appeared to arise from an increase in the rate of cell loss from 38 to 71% without a significant change in the potential doubling time. During the subsequent growth phase the cell loss factor was reduced to 52% and this was combined with a reduced potential doubling time from 32 to 26 hr. The antiproliferative, but not the anticachectic effect of EPA could be reversed by oral administration of pure linoleic acid (LA), (1.9 g/kg) which acted to increase tumour growth by reducing the cell loss factor to 45%. Despite this reversal, incorporation of EpA into tumour cell lipids was not significantly different in animals administered with either EpA alone or combined with LA. This suggests that the antiproliferative effect of EPA in this system may arise from an indirect effect through the blocking of the catabolic effect of the tumour on host adipose tissue, which normally supplies fatty acids essential for tumour growth. This suggests that LA may be required by some tumours to prevent cell loss and that the catabolism of adipose tissue, which accompanies cancer cachexia effectively supplies this fatty acid to the tumour.
Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover
CANCER RES. (USA)1991, 51/22 (6089-6093)
The effect of the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) on host body weight loss and tumor growth has been investigated in mice bearing a cachexia-inducing colon adenocarcinoma, the MAC16. EPA effectively inhibited both host weight loss and tumor growth rate in a dose-related manner with optimal effects being observed at a dose level of 1.25 to 2.5 g/kg. At these concentrations host body weight was effectively maintained, and there was a delay in the progression of growth of the tumor, such that overall survival was approximately doubled in EPA- treated animals, using the criteria dictated by the United Kingdom Coordinating Committee for the welfare of animals with neoplasms. Even when tumor growth resumed, weight loss did not occur. Animals bearing the MAC16 tumor showed a decreased protein synthesis and an increased degradation in skeletal muscle. Treatment with EPA significantly reduced protein degradation without an effect on protein synthesis. The effect of GLA on both host body weight loss and tumor growth was much less pronounced than that of EPA, with an effect only being seen at a dose of 5 g/kg, at which some toxicity was observed. In vitro studies showed that while EPA was effective in inhibiting tumor-induced lipolysis, GLA was ineffective in this respect. However, prostaglandin E1, which is formed from GLA in vivo, showed partial reversal of tumor-induced lipolysis and probably accounted for the anticachectic effect of GLA. These results suggest that EPA as the pure fatty acid should be considered for clinical investigation as both an anticachectic and antitumor agent, since prior work has shown that the other major component of fish oil docosahexaenoic acid is without pharmacological activity in this system.
Docosahexaenoic and eicosapentaenoic acids inhibit human lymphoproliferative responses in vitro but not the expression of T cell surface activation markers
Scandinavian Journal of Immunology (United Kingdom)1996, 43/3
The effects of polyunsaturated fatty acids (PUFAs: docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids) on induced lymphocyte proliferation and expression of CD25alpha chain of interleukin-2 receptor, CD71 and HLA-DR were investigated. PUFAs had no effect on phytohaemagglutinin (PHA)-induced lymphocyte agglutination, but they strongly inhibited the lymphoproliferative response to PHA. This inhibitory effect is PUFA dose- dependent and seems to be more potent with DHA than EPA. Pre-incubation experiments showed that lymphocytes cultured with PUFAs for 6 h, then washed and exposed to PHA, still inhibited lymphocyte proliferation. The authors also showed that this inhibitory activity was time dependent but became non-significant when PUFAs were added after 48 h lymphocyte culture. The addition of excess exogenous human recombinant rIL-2 partly restored PHA-lymphocyte proliferation inhibited by EPA but not by DHA. On the other hand, the authors showed that PUFAs did not inhibit IL-2 stimulated lymphocyte proliferation. The addition of PUFAs to cell culture medium had no inhibitory action on the PHA-induced lymphocyte expression of CD25, CD71 and HLA-DR. Furthermore, this effect appeared independent of eicosanoid synthesis or peroxide formation. Indeed, the inclusion of aspirin and vitamin E in the culture medium did not prevent the inhibitory effects of PUFAs on lymphocyte proliferation. Regardless of the mechanism of action, the inhibitory effect of PUFAs on activated lymphocytes may explain why some clinical trials of fish oil supplemented diets containing high amounts of DHA and EPA have been successful in improving the health status of patients suffering from inflammatory and autoimmune disorders.
Increased TGF-beta and decreased oncogene expression by omega-3 fatty acids in the spleen delays onset of autoimmune disease in B/W mice
J. IMMUNOL. (USA)1994, 152/12 (5979-5987)
This study was designed to investigate the mechanisms by which marine lipids rich in long chain omega-3 fatty acids inhibit autoimmune disease and prolong the survival rate in female (NZB/NZW) F1 (B/W) mice, an animal model for human SLE. Nutritionally adequate semipurified diets containing at 10% either corn oil (CO) or fish oil (FO) were fed from 1 mo of age and were monitored for proteinuria and survival. Proteinuria was detected earlier and became progressively severe in CO-fed mice. The average life span was significantly shortened by the CO diet (266.7 days plus or minus 12.5), whereas FO extended the survival significantly (402.1 days plus or minus 26.1; p < 0.001). A cross- sectional study at 6.5 mo of age revealed an increased proliferative response to T cell mitogens including bacterial superantigens and decreased serum anti-dsDNA Ab titers in the FO group compared with the CO group. Furthermore, splenocytes from the FO group when stimulated with Con A had higher IL-2 and lower IL-4 production similar to that of young (3.5 mo) mice. Flow cytometric analyses of splenocytes revealed lower Ig+, higher lymphocyte endothelial cell adhesion molecule-1, and lower Pgp-1+ cells within CD4+ and CD8+ subsets in FO-fed mice. Also, elevated IL-2 and IL-4 and significantly higher TGF-beta1 and lower c-myc and c-ras mRNA expression and higher TGF-beta1 and significantly lower c-Myc and c-Ha-Ras proteins were detected in spleens of FO-fed mice. Fatty acid analysis revealed significantly higher linoleic (18:2omega-6) and arachidonic (20:4omega-6) acid levels in splenocytes of the CO- fed group and higher eicosapentanoic (20:5omega-3) and docosahexanoic (22:6omega- 3) acid levels in the FO-fed group, indicating that changes in membrane fatty acid composition may contribute to the altered immune function and gene expression during the development of murine SLE.
Suppression of autoimmune disease by dietary n-3 fatty acids
J. LIPID RES. (USA)1993, 34/8 (1435-1444)
Previous studies have demonstrated that dietary fish oil preparations have anti-inflammatory effects in humans and in experimental animals, but the individual components of fish oils that are responsible for their anti- inflammatory effects have not been documented. We therefore investigated in (NZB x NZW)F1 mice, a model for human systemic lupus erythematosus, the effects of diets containing ethyl esters of two purified n-3 fatty acids, eicosapentaenoic acid (EPA-E) and docosahexaenoic acid (DHA-E), a refined fish oil triglyceride (FO) which contained 55% n-3 fatty acids, and beef tallow (BT) which contains no n-3 fatty acids. The diets were initiated prior to the development of overt renal disease at age 22 weeks, and continued for 14 weeks. The extent of the renal disease was quantified by light microscopy and by proteinuria. Diets containing either 10 wt% FO, 10% EPA-E, or 6% or 10% DHA-E alleviated the severity of the renal disease, compared to the BT diet, whereas diets containing either 3% or 6% EPA-E or 3% DHA-E were less effective. Two diets containing approximately 3:1 mixtures of EPA-E and DHA- E alleviated the renal disease to a greater extent than expected for either of these fatty acids given singly. We believe that these experiments provide the first demonstration of anti- inflammatory effects of individual dietary n- 3 fatty acids. The results also indicate that the anti-inflammatory effects of fish oils depend on synergistic effects of at least two n-3 fatty acids.
Omega-3 polyunsaturated fatty acids: A potential new treatment of immune renal disease
MAYO CLIN. PROC. (USA)1991, 66/10 (1018-1028)
Omega-3 polyunsaturated fatty acids are among new treatments being tested for efficacy in immune renal disease. The principal omega-3 polyunsaturated fatty acids are eicosapentaenoic acid and docosahexaenoic acid. They are derived from alpha-linolenic acid, which is found mainly in marine lipids. Eicosapentaenoic acid and docosahexaenoic acid undergo biologic transformation into trienoic eicosanoids that alter inflammatory mediators and vascular reactivity, both of which are important in the pathogenesis of certain glomerular immune diseases. Investigators have shown that proteinuria was prevented and survival was prolonged in autoimmune models of nephritis after dietary supplementation with fish oil. Furthermore, vascular damage may be modified by the influence of eicosapentaenoic acid and docosahexaenoic acid on blood rheology, aggregation of platelets, and plasma lipids. In short-term clinical studies, omega-3 polyunsaturated fatty acids seem to diminish cyclosporine-induced nephrotoxicity and the attendant complication of hypertension, to inhibit inflammatory and atherogenic mechanisms in lupus nephritis, and to preserve renal function and reduce proteinuria in IgA nephropathy. Long-term clinical trials for testing fish oil in these three clinical conditions are under way to confirm or refute these apparent beneficial therapeutic results.
Depression of humoral responses and phagocytic functions in vivo and in vitro by fish oil and eicosapentanoic acid
CLIN. IMMUNOL. IMMUNOPATHOL. (USA)1989, 52/2 (257-270)
Previous studies have demonstrated that eicosapentanoic acid (EPA) has anti-inflammatory properties in both humans and experimental animals and may also depress humoral immunity in experimental animals. Our investigations showed that the addition of eicosapentanoic acid to human peripheral blood mononuclear cell cultures inhibited B cell responses to mitogenic stimulation and depressed the expression of interleukin 2 receptors in pokeweed mitogen-stimulated lymphocytes. Neutrophils were also affected in their ability to release the contents of primary and secondary granules, particularly when stimulated with antigen-antibody complexes. Similar depressions of B cell responses and neutrophil functions were observed in a normal volunteer who ingested 6 g/day of a commercially available fish oil extract (equivalent to 2.1 g of EPA/day) during a 6-week period. Phagocytosis, enzymatic release, circulating immunoglobulin levels, and the response to tetanus toxoid both in vivo and in vitro were depressed during ingestion of fish oil. Most parameters showed a trend toward normalization 6 weeks after the suspension of fish-oil supplementation. These effects of fish oil extracts and EPA on phagocytosis and humoral responses may be advantageously used in the therapy of chronic inflammatory diseases and autoimmune diseases but could be a cause for concern when these compounds are used for longer periods of time and with minimal medical supervision for the prophylaxis of atherosclerosis.
A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice
J. IMMUNOL. (USA)1985, 134/3 (1914-1919)
Dietary supplementation of fish oil as the exclusive source of lipid suppresses autoimmune lupus in MRL-lpr mice. This marine oil diet decreases the lymphoid hyperplasia regulated by the lpr gene, prevents an increase in macrophage surface Ia expression, reduces the formation of circulating retroviral gp70 immune complexes, delays the onset of renal disease, and prolongs survival. We show that a fatty acid component uniquely present in fish oil but not in vegetable oil decreases the quantity of dienoic prostaglandin E, thromboxane B, and prostacyclin normally synthesized by multiple tissues, including kidney, lung, and macrophages, and promotes the synthesis of small amounts of trienoic prostaglandin in autoimmune mice. We suggest that this change in endogenous cyclooxygenase metabolite synthesis directly suppresses immunologic and/or inflammatory mediators of murine lupus.
Docosahexaenoic and eicosapentaenoic acids inhibit human lymphoproliferative responses in vitro but not the expression of T cell surface activation markers
Scandinavian Journal of Immunology (United Kingdom)1996, 43/3 (248-256)
The effects of polyunsaturated fatty acids (PUFAs: docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids) on induced lymphocyte proliferation and expression of CD25alpha chain of interleukin-2 receptor, CD71 and HLA-DR were investigated. PUFAs had no effect on phytohaemagglutinin (PHA)-induced lymphocyte agglutination, but they strongly inhibited the lymphoproliferative response to PHA. This inhibitory effect is PUFA dose-dependent and seems to be more potent with DHA than EPA. Pre-incubation experiments showed that lymphocytes cultured with PUFAs for 6 h, then washed and exposed to PHA, still inhibited lymphocyte proliferation. The authors also showed that this inhibitory activity was time dependent but became non-significant when PUFAs were added after 48 h lymphocyte culture. The addition of excess exogenous human recombinant rIL-2 partly restored PHA-lymphocyte proliferation inhibited by EPA but not by DHA. On the other hand, the authors showed that PUFAs did not inhibit IL-2 stimulated lymphocyte proliferation. The addition of PUFAs to cell culture medium had no inhibitory action on the PHA-induced lymphocyte expression of CD25, CD71 and HLA-DR. Furthermore, this effect appeared independent of eicosanoid synthesis or peroxide formation. Indeed, the inclusion of aspirin and vitamin E in the culture medium did not prevent the inhibitory effects of PUFAs on lymphocyte proliferation. Regardless of the mechanism of action, the inhibitory effect of PUFAs on activated lymphocytes may explain why some clinical trials of fish oil supplemented diets containing high amounts of DHA and EPA have been successful in improving the health status of patients suffering from inflammatory and autoimmune disorders.
Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation
International Archives of Allergy and Immunology (Switzerland)1996, 111/3 (284-290)
Laboratory animal models and clinical studies suggest that dietary n-3 fatty acids are beneficial in diseases with an inflammatory component such as rheumatoid arthritis or psoriasis. In the present study we investigated the effect of purified docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on phorbol ester (TPA)-induced acute inflammation. Mice were fed for 6 weeks a diet containing 5% corn oil enriched with either 1% DHA or 1% EPA and compared with a group receiving 6% corn oil only. The dietary treatment with DHA or EPA elevated the n-3 polyunsaturated fatty acids as expected in the spleen and ear phospholipids, associated with a reduction in arachidonic acid levels. The degree of ear inflammation was quantified by measuring the four parameters including (1) edema as the increase in ear biopsy weight, (2) polymorphonuclear cell infiltration as myeloperoxidase activity (MPO) at the site of inflammation, (3) prostaglandin E2 (PGE2) and (4) leukotriene B4 (LTB4) concentrations in ear edema. The addition of DHA to the diet reduced significantly the edema formation and the MPO activity 24 h after a TPA challenge. Both DHA and EPA significantly reduced the PGE2 and LTB4 levels compared with animals fed corn oil. This result suggests that DHA rather than EPA may be useful in the adjuvant treatment of diseases where acute inflammatory processes play a role.
Altered fatty acid, cholesterol and Na+/K+ ATPase activity in erythrocyte membrane of rheumatoid arthritis patients.
Z Naturforsch [C] (GERMANY) May-Jun 1996, 51 (5-6) p401-3
Rheumatoid arthritis (RA) is a chronic inflammatory disease whose cause remains obscure. Blood from 15 RA patients and controls was taken and their ghosts separated. The ghosts were analysed for cholesterol content, Na+/K+ ATPase activity and eicosapentaenoic acid. The cholesterol content in the ghosts of RA patients was significantly lower as compared with the set of controls. There was a major difference in the activity of Na+/K+ ATPase between the two groups with RA patients showing significantly elevated activity. The ghosts of the RA patients exhibited major abnormality in the polyunsaturated fatty acids of phospholipids with the level of eicosapentaenoic acid (omega-3, 20:5) being significantly reduced.
Omega-3 fatty acids in health and disease and in growth and development
Am J Clin Nutr (UNITED STATES) Sep 1991, 54 (3) p438-63
Several sources of information suggest that man evolved on a diet with a ratio of omega 6 to omega 3 fatty acids of approximately 1 whereas today this ratio is approximately 10:1 to 20-25:1, indicating that Western diets are deficient in omega 3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. Omega-3 fatty acids increase bleeding time; decrease platelet aggregation, blood viscosity, and fibrinogen; and increase erythrocyte deformability, thus decreasing the tendency to thrombus formation. In no clinical trial, including coronary artery graft surgery, has there been any evidence of increased blood loss due to ingestion of omega 3 fatty acids. Many studies show that the effects of omega 3 fatty acids on serum lipids depend on the type of patient and whether the amount of saturated fatty acids in the diet is held constant. In patients with hyperlipidemia, omega 3 fatty acids decrease low-density-lipoprotein (LDL) cholesterol if the saturated fatty acid content is decreased, otherwise there is a slight increase, but at high doses (32 g) they lower LDL cholesterol; furthermore, they consistently lower serum triglycerides in normal subjects and in patients with hypertriglyceridemia whereas the effect on high-density lipoprotein (HDL) varies from no effect to slight increases. The discrepancies between animal and human studies most likely are due to differences between animal and human metabolism. In clinical trials eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oils along with antirheumatic drugs improve joint pain in patients with rheumatoid arthritis; have a beneficial effect in patients with ulcerative colitis; and in combination with drugs, improve the skin lesions, lower the hyperlipidemia from etretinates, and decrease the toxicity of cyclosporin in patients with psoriasis. In various animal models omega 3 fatty acids decrease the number and size of tumors and increase the time elapsed before appearance of tumors. Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants. Because omega 3 fatty acids are essential in growth and development throughout the life cycle, they should be included in the diets of all humans. Omega-3 and omega 6 fatty acids are not interconvertible in the human body and are important components of practically all cell membranes. Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake.
Summary of the NATO advanced research workshop on dietary omega 3 and omega 6 fatty acids: biological effects and nutritional essentiality.
J Nutr (UNITED STATES) Apr 1989, 119 (4) p521-8
A number of human studies presented at the workshop indicate that the premature infant at birth is biochemically deficient in docosahexaenoic acid (DHA) in both the brain and liver phospholipids, and that DHA is essential for normal visual acuity. The amount of DHA necessary to maintain normal amounts of the liver and brain phospholipids postnatally is 11 mg/kg daily. Elderly patients on long-term gastric tube feedings and others on long-term intravenous fluids and on total parenteral nutrition are particularly prone to deficiencies of alpha-linolenic acid, eicosapentaenoic acid (EPA) and DHA. The amounts estimated to prevent deficiencies in the elderly are 800-1100 mg/d of alpha-linolenic acid and 300-400 mg/d of EPA and DHA combined. Preliminary data indicate that children with malnutrition and mucoviscidosis, women with toxemia, and elderly people have decreased amounts of DHA in plasma phospholipids. The omega 3 fatty acids lower triglycerides and, at high levels, lower cholesterol. The anti-aggregatory, anti-thrombotic and anti-inflammatory properties of omega 3 fatty acids have been confirmed, and a dose-response curve is emerging. Despite the increase in bleeding time, no clinical evidence of bleeding has been noted by the investigators in any of the studies. Clinical trials are necessary in order to precisely define the dose and mechanisms involved in defining the essentiality of omega 3 fatty acids in growth and development and their beneficial effects in coronary heart disease, hypertension, inflammation, arthritis, psoriasis, other autoimmune disorders, and cancer. (56 Refs.)
Health effects and metabolism of dietary eicosapentaenoic acid.
Prog Food Nutr Sci (ENGLAND) 1988, 12 (2) p111-50
Eicosapentaenoic acid (EPA), a long chain fatty acid of the n-3 series, is found in marine foods. Beneficial effects of these foods containing EPA on factors associated with cardiovascular disease risk and arterial thrombosis have been demonstrated. More recently, studies have suggested that EPA may also have a favourable effect on other human diseases such as arthritis, renal disorders, psoriasis and possibly also cancer. EPA is metabolized in a manner generally similar to that of arachidonic acid (AA) although some significant differences between the two are apparent. The metabolic fate of dietary EPA in human subjects is reviewed herein with inclusion of information from animal studies where human data is not available. The metabolism of EPA in the phospholipids of human platelets is emphasized to some extent. Effects of EPA on AA metabolism are also described. (244 Refs.)
[Potential value of eicosapentaenoic acid]
Allerg Immunol (Paris) (FRANCE) Oct 1987, 19 (8 Suppl) p12-3
The arachidonic acid substitution by an alternative fatty acid, substrate for the 5-lipoxygenase and the cyclo-oxygenase pathway constitutes a novel therapeutic approach or a complement for other therapeutics in the inflammation area. Eicosapentaenoic acid (EPA), one of the fish oil components, is a substrate for both enzymes and an inhibitor for several enzymes of arachidonic acid cascade, in vitro and in vivo. The EPA-generated metabolites have less pro-inflammatory effects than those produced by arachidonic acid metabolism. (14 Refs.)
Low prevalences of coronary heart disease (CHD), psoriasis, asthma and rheumatoid arthritis in Eskimos: are they caused by high dietary intake of eicosapentaenoic acid (EPA), a genetic variation of essential fatty acid (EFA) metabolism or a combination of both?
Med Hypotheses (ENGLAND) Apr 1987, 22 (4) p421-8
The low prevalences of CHD, psoriasis, asthma and rheumatoid arthritis in Eskimos have been attribute to the high dietary intake of EPA from fish and marine mammals. However, even on a Western diet, Eskimos have plasma arachidonic acid (AA) levels far below those seen in Europeans while dihomogammalinolenic acid (DGLA) levels are higher in Eskimos. These low AA and high DGLA levels seem to be due to a genetic abnormality in EFA desaturation since they are found even when EPA intakes are low. Since AA is known to be important in the pathogenesis of CHD, asthma, psoriasis and arthritis, while DGLA has properties which make it of likely therapeutic value in these conditions, the genetically high DGLA and low AA are likely to be as important as dietary EPA in determining Eskimo disease patterns.
Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network.
Prostaglandins Leukot Essent Fatty Acids (SCOT) Sep 1994,51 (3) p207-13
Systemic lupus erythematosus (SLE) is a chronic inflammatory condition characterised by arthritis, cutaneous rash, vasculitis, and involvement of central nervous system, renal and cardiopulmonary manifestations. Abnormalities in the cytokine network is believed to be involved in the pathobiology of this condition. The n-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can suppress T-cell proliferation and the production of interleukin-1, interleukin-2, and tumor necrosis factor by these cells both in vitro and in vivo. Oral supplementation of EPA and DHA induced prolonged remission of SLE in 10 consecutive patients without any side-effects. These results suggest that n-3 fatty acids, EPA and DHA, are useful in the management of SLE and possibly, other similar collagen vascular diseases.
The cardiovascular protective role of docosahexaenoic acid
European Journal of Pharmacology (Netherlands)1996, 300/1-2 (83-89)
Dietary fish oils rich in n-3 polyunsaturated fatty acids can modulate a diverse range of factors contributing to cardiovascular disease. This study examined the relative roles of eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3; DHA) which are the principal n-3 polyunsaturated fatty acids regarded as candidates for cardioprotective actions. At low dietary intakes (0.4-1.1% of energy (%en)), docosahexaenoic acid but not eicosapentaenoic acid inhibited ischaemia-induced cardiac arrhythmias. At intakes of 3.9-10.0%en, docosahexaenoic acid was more effective than eicosapentaenoic acid at retarding hypertension development in spontaneously hypertensive rats (SHR) and inhibiting thromboxane-like vasoconstrictor responses in aortas from SHR. In stroke-prone SHR with established hypertension, docosahexaenoic acid (3.9-10.0%en) retarded the development of salt-loading induced proteinuria but eicosapentaenoic acid alone was ineffective. The results demonstrate that purified n-3 polyunsaturated fatty acids mimic the cardiovascular actions of fish oils and imply that docosahexaenoic acid may be the principal active component conferring cardiovascular protection.
Omega-3 fatty acids and prevention of ventricular fibrillation.
Prostaglandins Leukot Essent Fatty Acids (SCOTLAND) Feb-Mar 1995, 52
Interest in the potential cardiovascular benefits of omega-3 long chain polyunsaturated fatty acids has been largely focused on possible antiatherothrombotic effects. In addition, however, definitive antiarrhythmic effects of these dietary omega-3 fatty acids have been reported by Charnock & McLennan. Our studies commenced with the observation that two of these fatty acids, eicosapentaenoic (C20:5n-3, EPA) and docosahexaenoic acid (C22:6n-3, DHA) prevented contracture and fibrillation of isolated neonatal cardiac myocytes when exposed to toxic levels of ouabain (0.1 mM). This protection was associated with prevention of excessively high intracellular calcium concentrations in the myocyte. Further, it was shown that these fatty acids modulate calcium currents through L-type calcium channels and that the effect occurs within a few minutes of adding EPA or DHA to the medium perfusing the cultured cardiac myocytes. Infusing an emulsion of the omega-3 fatty acids intravenously just prior to compression of a coronary artery in a conscious, prepared dog will prevent the expected subsequent ischemia-induced ventricular fibrillation. (9 Refs.)
Enhanced capacity of n-3 fatty acid-enriched macrophages to oxidize low density lipoprotein mechanisms and effects of antioxidant vitamins
Atherosclerosis (Ireland)1996, 124/2 (157-169)
We have investigated possible mechanisms by which n-3 fatty acid-enriched macrophages enhance the oxidation of low density lipoprotein (LDL), and the ability of antioxidant vitamins to prevent this. Macrophages were enriched with n-3 fatty acids (eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid) following incubation with fish oil. These macrophages produced large amount of TEARS in medium containing metals, and showed enhanced capacity to oxidize LDL (3-4 fold increase compared to control cells) and to accumulate the modified LDL. 5,8,11,14-eicosatetraynoic acid (ETYA, 15-lipoxygenase inhibitor) and superoxide dismutase (SOD) did not inhibit the enhanced capacity of n-3 fatty acid-enriched cells to oxidize LDL. However antioxidants, (vitamin E-enriched macrophages or vitamin C in the medium), inhibited this enhanced capacity. Medium conditioned by n-3 fatty acid-enriched cells had pro-oxidant effects on metal-initiated LDL oxidation. We conclude that n-3 fatty acid-enriched macrophages display increased oxidant capacity which is not inhibited by ETYA or SOD, and that antioxidant vitamins inhibit the enhanced capacity to oxidize LDL.
Effects of 11-week increases in dietary eicosapentaenoic acid on bleeding time, lipids, and platelet aggregation.
Lancet (ENGLAND) Nov 28 1981, 2 (8257) p1190-3
The effect of a diet rich in eicosapentaenoic acid (EPA) on platelet phospholipid fatty acid composition, platelet aggregation, and bleeding time was studied in 10 healthy men, whose usual diet was partly replaced by fish for 11 weeks. This diet provided 2-3 g EPA per day. Two doses (3.5 and 10 mg/kg body-weight) of acetylsalicylic acid (ASA) were given before and during the diet. The fish diet prolonged bleeding time (by 42%) and decreased platelet aggregability. The changes in platelet phospholipid fatty acid composition consisted of increases in the omega-3 series (C20: 5 and C22:6) and decreases in the omega-6 series (C18:2 and C20:3). The reduction in platelet aggregation induced by collagen and ADP did not parallel the changes in platelet membrane phospholipids and bleeding times. Diminished platelet aggregation induced by collagen lasted only 3 weeks (while subject was still on the diet), whereas the decreased sensitivity to ADP persisted for at least 11 weeks after the volunteers had resumed their normal diet. ASA taken before the diet prolonged bleeding time by as much as did the diet itself. ASA taken during the diet prolonged bleeding time by more than the sum of the increases in bleeding time caused by ASA and by the EPA diet separately, but the synergism was not significantly more than additive. The findings suggest that a diet rich in omega-3 polyunsaturated fatty acids reduces tha interaction between platelets and the vessel wall by mechanisms which are more complex than just a reduction in susceptibility of platelets to the naturally occurring agents collagen and ADP, or an imbalance between proaggregatory and anti- aggregatory prostaglandin derivatives.
N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells.
Cell Biochem Funct (ENGLAND) Sep 1995, 13 (3) p211-6
CD36, a multifunctional adhesion receptor e.g. for thrombospondin and collagen, as well as a scavenger receptor for oxidized low density lipoprotein, is expressed e.g. on platelets and monocytes. By this dual role it might be involved in early steps of atherosclerosis like the recruitment of monocytes and formation of foam cells. We therefore studied the effects of n-3 fatty acids on CD36 expression in human monocytic cells. Incorporation of eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) into cellular phospholipids resulted in a significant reduction of CD36 expression at the mRNA and protein level, whereas arachidonic acid (AA, C20: 4n-6) and linoleic acid (LA, C18:2n-6) tended to increase CD36 expression compared to the control. This specific down-regulation of CD36 by n-3 fatty acids in cells involved in the initiation and progression of atherogenesis and inflammation, represents a further mechanism that may contribute to the beneficial effects of n- 3 polyunsaturated fatty acids (PUFA) in these disorders.
Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease.
Prostaglandins Leukot Essent Fatty Acids (SCOTLAND) Jun 1995, 52 (6) p387-91
Mortality and morbidity from coronary heart disease (CHD), diabetes mellitus (DM) and essential hypertension (HTN) are higher in people of South Asian descent than in other groups. There is evidence to believe that essential fatty acids (EFAs) and their metabolites may have a role in the pathobiology of CHD, DM and HTN. Fatty acid analysis of the plasma phospholipid fraction revealed that in CHD the levels of gamma- linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are low, in patients with HTN linoleic acid (LA) and AA are low, and in patients with non-insulin dependent diabetes mellitus (NIDDM) and diabetic nephropathy the levels of dihomo-gamma-linolenic acid (DGLA), AA, alpha-linolenic acid (ALA) and DHA are low, all compared to normal controls. These results are interesting since DGLA, AA and EPA form precursors to prostaglandin E1, (PGE1), prostacyclin (PGI2), and PGI3, which are potent platelet anti- aggregators and vasodilators and can prevent thrombosis and atherosclerosis. Further, the levels of lipid peroxides were found to be high in patients with CHD, HTN, NIDDM and diabetic nephropathy. These results suggest that increased formation of lipid peroxides and an alteration in the metabolism of EFAs are closely associated with CHD, HTN and NIDDM in Indians.( ABSTRACT TRUNCATED AT 250 WORDS)
Improvement by eicosanoids in cancer cachexia induced by LLC-IL6 transplantation
Journal of Cancer Research and Clinical Oncology (Germany)1996, 122/12 (711-715)
Cachexia frequently occurs in the late stages of cancer, and is difficult to manage. We previously reported that interleukin-6 (IL-6) cDNA transfection into Lewis lung carcinoma (LLC-IL6) induced cachexia-like symptoms in C57BL/6 mice. This was thought to be a useful experimental model of cancer cachexia. We have examined the effects of two eicosanoids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in order to evaluate whether they could relieve cachexia. LLC-IL6-bearing animals were divided into three treatment groups receiving DHA, EPA or water as the control; 80-microl samples of these compounds (purity > 95%) were administered orally by catheter daily starting 7 days after tumor transplantation. Tumor growth curves were similar in the three groups. There were no differences in water or food intake in the three groups. However, body weight, a marker of cachexia, was significantly higher in treated mice than in the control group. Sixteen days after tumor transplantation, the mean body weight was 17.45 g (P < 0.05), 17.2 g and 16.41 g in the groups receiving DHA, EPA and water respectively. The eicosanoids did not affect serum levels of IL-6. Ubiquitination of muscle protein, a marker of proteolysis coupled to cachexia, was compared in LLC-IL6- and LLC-transplanted mice. The eicosanoids prevented the ubiquitination of approximately 180 kDa protein. These results suggest that eicosanoids may prevent the cachexia mediated by IL-6.
The effect of unsaturated fatty acids on membrane composition and signal transduction in HT-29 human colon cancer cells
Cancer Letters (Ireland)1996, 108/1 (25-33)
The objective of the present study was to investigate the effect of membrane fatty acid (FA) composition on the activity of phospholipase C (PLC) in HT-29 human colon cancer cells. The membrane FA composition was altered by supplementing cultured cells with FAs of different composition. The FAs were stearic acid (18:0;SA), gammalinolenic acid (18:3omega6;gammaLnA); a linolenic acid (18:3omega3; alphaLnA;); eicosapentaenoic acid (20:5omega3;EPA) and docosahexaenoic acid (22:6omega3;DHA). The fatty acids were supplemented as a FA/BSA complex. Cells supplemented with SA served as the control. Tumor growth was followed by counting the number of cells in culture. The results indicate that polyunsaturated fatty acid (PUFA) supplementation had no consistent effect on tumor growth from 1 day to another throughout the 15 days of growth. The fatty acid composition of membranes indicates that cells incorporated and modified the supplemented fatty acids by desaturation, elongation and retroconversion. The unsaturation index (UI) of membranes of cells supplemented with EPA and DHA was higher than other groups. PLC activity; measured in the absence of GTPgamma(S) in the assay mixture; was not influenced by membrane FA modification. However, in the presence of GTPgamma(S) PLC of cells supplemented with 18:3(omega6) was the lowest among the groups. It has been shown that 18:3(omega6) accumulated the most in the phosphatidylethanolamine (PE) fraction. There was a negative correlation between the activity of PLC in the presence of G protein activation and PE 18:3(omega6) content without affecting UI. It was concluded that G protein may be sensitive to the level of 18:3(omega6) content and not to the general fluidity of the membranes.
Effect of omega-3 fatty acids on the progression of metastases after the surgical excision of human breast cancer cell solid tumors growing in nude mice
Clinical Cancer Research (USA)1996, 2/10 (1751-1756)
We showed previously that a diet rich in linoleic acid (LA), an omega-6 fatty acid, stimulates the growth and metastasis of human breast cancer cells in athymic nude mice. In contrast, diets supplemented with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), omega-3 fatty acids, exert suppressive effects. We have now assessed EPA and DHA as adjuvant nutritional therapy in the nude mouse model and compared the responses when the intervention was commenced 1 week before ('neoadjuvant') or immediately after ('postoperative adjuvant') surgical excision of the primary tumor. Female nude mice received a high-fat, 8% LA diet beginning 7 days before 106 MDA-MB-435 human breast cancer cells were injected into a thoracic mammary fat pad. As the tumor surface areas approached 0.7 cm2,the mice were assigned to either continue on the LA-rich diet or to commence one containing 8, 4, or 2% EPA or DHA. Seven days later, the mammary fat pad tumors were excised; the mice still consuming the 8% LA diet were then allocated sequentially to either continue this diet or commence one of the six postexcision omega-3 fatty acid dietary interventions. Eight weeks later, the mice were necropsied and evaluated for local recurrence and lung metastases. Although there were no differences in the incidence of local recurrence between groups, EPA and DHA both inhibited the development of lung metastases. When the dietary interventions were commenced 7 days before surgery, the severity of lung metastasis was reduced by the two omega-3 fatty acids in a dose-dependent manner; at all three levels, the suppressive effects were statistically significant (P < 0.05). Postexcision EPA treatment produced small, statistically insignificant effects, but lung involvement was reduced significantly by feeding DHA at the 2 and 4% levels (< 0.05). Overall, these results suggest that omega-3 fatty acids may have a place as adjuvant nutritional therapy in breast cancer and particularly as part of a neoadjuvant regimen.
Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vivo
British Journal of Cancer (United Kingdom)1996, 74/9 (1375-1383)
Eicosapentaenoic acid (EPA) has been shown to have an inhibitory effect on the growth of several pancreatic cancer cell lines in vitro. This study investigates the mechanism of growth inhibition and cytotoxicity of EPA on the pancreatic cancer cell line MIA PaCa-2. Cells were analysed for cell count, viability, cell cycle distribution and ultrastructural changes. There was a time- and dose-dependent decrease in cell count and viability in cultures of pancreatic cancer cells supplemented with EPA. Flow cytometric DNA anlaysis of MIA PaCa-2 cells incubated with EPA demonstrated the presence of sub G1 populations corresponding to the presence of apoptotic cells and the blockade of cell cycle progression in S-phase and G2/M-phase. The presence of apoptosis in EPA-supplemented cultures was further confirmed by DNA fragmentation and ultrastructural changes associated with apoptosis. Therefore, we conclude that EPA mediates its effect on the pancreatic cancer cell line MIA PaCa-2, at least in part, via cell cycle arrest and the induction of apoptosis.
Suppression of nitric oxide production in lipopolysaccharide-stimulated macrophage cells by omega3 polyunsaturated fatty acids
Japanese Journal of Cancer Research (Japan)1997, 88/3 (234-237)
Although nitric oxide (NO) is an important biological mediator, its excessive production in inflammation is thought to be a causative factor for cellular injury and, over the long term, cancer. In the present study, the effects of several fatty acids on NO production in murine macrophage cell line RAW264 cells stimulated with lipopolysaccharide were examined. Suppression of NO production was observed with the omega3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid, eicosapentaenoic acid and alpha-linolenic acid, in a dose-dependent fashion. In contrast, no inhibition was observed with omega6 PUFA (linoleic acid), omega9 PUFA (oleic acid) or a saturated fatty acid (stearic acid). Western and northern blot analyses suggested that suppression of the induction of inducible NO synthase gene expression is responsible for the inhibition of NO production by omega3 PUFAs. The inhibitory effect of omega3 PUFA on NO production in activated macrophages could contribute to their cancer chemopreventive influence.
Demonstration of organotropic effects of chemopreventive agents in multiorgan carcinogenesis models.
Tsuda H; Iwahori Y; Asamoto M; Baba-Toriyama H; Hori T; Kim DJ; Uehara N; Iigo M; Takasuka N; Murakoshi M; Nishino H; Kakizoe T; Araki E; Yazawa K National Cancer Center Research Institute, National Cancer Center Hospital, Tokyo, Japan. IARC Sci Publ (FRANCE) 1996, (139) p143-50
Organotropic chemopreventive effects of three (pro)vitamins and three unsaturated fatty acids were examined using mouse and rat multiorgan carcinogenesis models. For the study of (pro)vitamins, male and female B6C3F1 mice were treated with N,N-diethylnitrosamine (DEN) and N-methyl-N-nitrosourea (MNU) during the first 11 weeks, then from weeks 12 to 32 they received alpha-carotene (0.4 mg/mouse), beta-carotene (0.4 mg/mouse) or alpha-tocopherol (40 mg/mouse) three times a week by gavage; control mice received vehicle alone. In male mice, alpha-carotene significantly reduced liver weights, representing a reduced tumour mass (P < 0.001), and alpha-carotene, beta-carotene and alpha-tocopherol significantly reduced the numbers of liver tumours (adenomas a0.01) as compared with control mice, the effects being greatest with alpha-carotene. In female mice, alpha-carotene significantly decreased the number of liver tumours (P < 0.001). In the lung, alpha-carotene and alpha-tocopherol reduced the area of lesions (hyperplasias and adenomas combined) only in males (P < 0.05). For the study of unsaturated fatty acids, F344 male rats were treated with DEN, MNU, N-butyl-N-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and N,N-bis(2-hydroxy)propylnitrosamine during the first 5 weeks, then from weeks 6 to 36 they were given docosahexaenoic acid (C22:6), eicosapentaenoic acid (C20:5) or linoleic acid (C18:2) at 1.0 g/rat, three times a week by gavage; control rats were treated with oleic acid (C18:1) using the same protocol. All animals were fed a low linoleic acid and calorie-adjusted basal diet during fatty acid administration. Docosahexaenoic acid and linoleic acid reduced tumours in the large and small intestines, respectively. However, they did not influence the yield of preneoplastic liver, lung, kidney, forestomach and urinary bladder lesions. The data thus provide evidence for organotropic effects of carotenoids and unsaturated fatty acids on carcinogenesis.
Effects of dietary supplementation on autoimmunity in the MRL/lpr mouse: A preliminary investigation
ANN. RHEUM. DIS. (UK)1986, 45/12 (1019-1024)
The effects of dietary fatty acid supplementation on various disease parameters in the spontaneously autoimmune MRL-mp-lpr/lpr mouse model of systemic lupus erythematosus before onset of disease were investigated. A fat deficient diet was supplemented with the following oils: olive oil, sunflower oil, evening primrose oil (EPO), fish oil, and a fish oil/EPO mixture. The mice receiving a diet enriched with EPO showed an increase in survival, as did those receiving a fish oil/EPO mixture. These results, taken together with those of the other parameters monitored, suggest that EPO may be of benefit in alleviating the murine form of the disease.
Dietary fats and coronary heart disease
Biomedicine and Pharmacotherapy (France)1996, 50/6-7 (261-268)
The prevention and treatment of coronary heart disease (CHD) necessitates vigorous dietary intervention so as to lower the serum cholesterol level by at least 6%. Greater decreases in serum cholesterol can bring about reversal of atherosclerosis. The critical dietary change is the reduction in intake of saturated fat and cholesterol. Some of this fat may be replaced by unsaturated fats, especially monounsaturated fat (olive or canola oil). Fish and the omega-3 fats they contain may also be useful for the prevention of CHD. The benefits of omega-3 fats occur within a few months and probably involve an anti-thrombotic effect. There is evidence that the intake of trans-fatty acids formed by the hydrogenation of oils should be reduced as they are associated with CBD. Hypolipidaemic drugs may be useful for persons at very high risk of CHD but should generally be avoided for primary prevention.
Eicosapentaenoic acid (C20:5) augments glucose-induced insulin secretion from beta-TC3 insulinoma cells
Pancreas (USA)1996, 13/3 (253-258)
There has been a large amount of recent literature suggesting that omega-3 unsaturated fatty acids found in fish oils should be incorporated into the diet for the purpose of decreasing serum cholesterol levels. Inclusion of these fatty acids in the diet has been shown to decrease total serum cholesterol as well as low-density lipoprotein cholesterol. Some of these trials have been complicated by the fact that many of the subjects are afflicted with non-insulin-dependent diabetes mellitus. Unfortunately, the effects of omega-3 unsaturated fatty acids on insulin secretion have not been well characterized. In this study, we have examined the effect of a common omega-3 unsaturated fatty acid, eicosapentaenoic acid (C20:5), on insulin secretion. Using the beta-TC3 insulinoma cell line as a model system for studying insulin exocytosis, C20:5 selectively potentiated glucose-induced insulin secretion. At the same concentration at which it significantly increased glucose-induced insulin secretion, C20:5 did not affect glucose metabolism or intracellular free calcium concentrations. C20:5 also augmented potassium-induced insulin secretion. These data suggest that C20:5, an abundant omega-3 unsaturated fatty acid, acts to augment insulin secretion in a glucose-dependent manner.
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