Supplementation with an algae source of docosahexaenoic acid increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects.

J Nutr, 16(12):3032-9 1996 Dec

The purpose of this double-blind study was to investigate the influence of dietary supplementation with an algae source of docosahexaenoic acid [DHA; 22:6(n-3)], devoid of any eicosapentaenoic acid [EPA; 20:5(n-3)], on serum/platelet DHA status, the estimated retroconversion of DHA to EPA, and risk factors for heart disease in vegetarian subjects. Healthy vegetarians (12 male, 12 female) consumed nine capsules daily of either DHA (1.62 g/d) or corn oil for 6 wk. Consumption of DHA capsules increased DHA levels in serum phospholipid by 246% (from 2.4 to 8.3 g/100 g fatty acids) and in platelet phospholipid by 225% (from 1.2 to 3.9 g/100 g fatty acids). EPA levels increased in serum phospholipid by 117% (from 0.57 to 1.3 g/100 g fatty acids) and in platelet phospholipid by 176% (0.21 to 0.58 g/100 g fatty acids) via metabolic retroconversion; the estimated extent of DHA retroconversion to EPA was 11.3 and 12.0%, based on the serum and platelet analyses, respectively. Arachidonic acid [AA; 20:4(n-6)] levels in serum and platelet phospholipids decreased moderately during the trial period (DHA group) as did both docosapentaenoic acids [22:5(n-6) and 22:5(n-3)]. Although no significant changes were found in the total and LDL-cholesterol levels with DHA supplementation, the total cholesterol:HDL-cholesterol ratio showed a moderate decrease over time as did the LDL-cholesterol:HDL-cholesterol ratio and serum triglyceride concentrations. DHA supplementation did not alter the various thrombogenic factors measured. In conclusion, DHA supplementation markedly enhanced the DHA status (of serum and platelets), provided for the formation of substantial EPA, and lowered the total and LDL-cholesterol:HDL-cholesterol ratios.




Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)?

Int J Vitam Nutr Res, 68(3):159-73 1998

A diet including 2-3 portions of fatty fish per week, which corresponds to the intake of 1.25 g EPA (20:5n-3) + DHA (22:6n-3) per day, has been officially recommended on the basis of epidemiological findings showing a beneficial role of these n-3 long-chain PUFA in the prevention of cardiovascular and inflammatory diseases. The parent fatty acid ALA (18:3n-3), found in vegetable oils such as flaxseed or rapeseed oil, is used by the human organism partly as a source of energy, partly as a precursor of the metabolites, but the degree of conversion appears to be unreliable and restricted. More specifically, most studies in humans have shown that whereas a certain, though restricted, conversion of high doses of ALA to EPA occurs, conversion to DHA is severely restricted. The use of ALA labelled with radioisotopes suggested that with a background diet high in saturated fat conversion to long-chain metabolites is approximately 6% for EPA and 3.8% for DHA. With a diet rich in n-6 PUFA, conversion is reduced by 40 to 50%. It is thus reasonable to observe an n-6/n-3 PUFA ratio not exceeding 4-6. Restricted conversion to DHA may be critical since evidence has been increasing that this long-chain metabolite has an autonomous function, e.g. in the brain, retina and spermatozoa where it is the most prominent fatty acid. In neonates deficiency is associated with visual impairment, abnormalities in the electroretinogram and delayed cognitive development. In adults the potential role of DHA in neurological function still needs to be investigated in depth. Regarding cardiovascular risk factors DHA has been shown to reduce triglyceride concentrations. These findings indicate that future attention will have to focus on the adequate provision of DHA which can reliably be achieved only with the supply of the preformed long-chain metabolite.




Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial.

J Am Coll Nutr, 16(3):236-43 1997 Jun

OBJECTIVE: The objective of this study was to evaluate the effects of daily dietary supplementation with 1.25 g or 2.5 g of docosahexaenoic (DHA), in the absence of eicosapentaenoic acid (EPA), on serum lipids and lipoproteins in persons with combined hyperlipidemia (CHL) [serum low-density lipoprotein cholesterol (LDL-C) 130 to 220 mg/dL and triglycerides 150 to 400 mg/dL]. METHODS: After a 6-week dietary stabilization period, subjects entered a 4-week single-blind placebo (vegetable oil) run-in phase. Those with adequate compliance during the the run-in were randomized into one of three parallel groups (placebo, 1.25, or 2.5 g/day DHA) for 6 weeks of treatment. Supplements were administered in a triglyceride form contained in gelatin capsules. Primary outcome measurements were plasma phospholipid DHA content, serum triglycerides, high-density lipoprotein cholesterol (HDL-C). LDL-C and non-HDL-C. RESULTS: The DHA content of plasma phospholipids increased dramatically (2 to 3 fold) in a dose-dependent manner. Significant (p < 0.05) changes were observed in serum triglycerides (17 to 21% reduction) and HDL-C (6% increase) which were of similar magnitude in both DHA groups. Non-HDL-C [+1.6 (NS) and +5.7% (p < 0.04)] and LDL-C [+9.3% (NS) and +13.6% (p < 0.001)] increased in the DHA treatment groups. All lipid effects reached an apparent steady state within the first 3 weeks of treatment. CONCLUSION: Dietary DHA, in the absence of EPA, can affect lipoprotein cholesterol and triglyceride levels in patients with combined hyperlipidemia. The desirable triglyceride and HDL-C changes were present at a dose which did not significantly increased non-HDL-C or LDL-C. These preliminary findings suggest that dietary supplementation with 1.25 g DHA/day, provided in a triglyceride form, may be an effective tool to aid in the management of hypertriglyceridemia.




Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial.

Cancer, 82(2):395-402 1998 Jan 15

BACKGROUND. The aim of the current prospective, randomized control study was to investigate the effect of dietary omega-3 polyunsaturated fatty acids plus vitamin E on the immune status and survival of well-nourished and malnourished patients with generalized malignancy. METHODS. Sixty patients with generalized solid tumors were randomized to receive dietary supplementation with either fish oil (18 g of omega-3 polyunsaturated fatty acids, PUFA) or placebo daily until death. Each group included 15 well-nourished and 15 malnourished patients. The authors measured total T cells, T-helper cells, T-suppressor cells, natural killer cells, and the synthesis of interleukin-1, interleukin-6, and tumor necrosis factor by peripheral blood mononuclear cells before and on Day 40 of fish oil supplementation. Karnofsky performance status, nutritional state, and survival were also estimated. RESULTS. The ratio of T-helper cells to T-suppressor cells was significantly lower in malnourished patients. Omega-3 PUFA had a considerable immunomodulating effect by increasing this ratio in the subgroup of malnourished patients. There were no significant differences in cytokine production among the various groups, except for a decrease in tumor necrosis factor production in malnourished cancer patients, which was restored by omega-3 fatty acids. The mean survival was significantly higher for the subgroup of well-nourished patients in both groups, whereas omega-3 fatty acids prolonged the survival of all the patients. CONCLUSIONS. Malnutrition appears to be an important predictor of survival for patients with end stage malignant disease. Omega-3 polyunsaturated fatty acids had a significant immunomodulating effect and seemed to prolong the survival of malnourished patients with generalized malignancy.




MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders [see comments]

Neurology, 51(1):26-32 1998 Jul

OBJECTIVE: We have found that docosahexaenoic acid (DHA; 22:6n-3), an important constituent of the CNS and retina, is dramatically decreased in patients with generalized peroxisomal disorders. Such a DHA deficiency could be pathogenic. Our aim was to test the possible beneficial effects of normalizing the DHA levels in these patients. The current report focuses on MRI changes during the treatment and reports follow-up evidence of myelin improvement in five peroxisomal disorder patients treated with DHA. METHODS: DHA ethyl ester (DHA-EE), about 90% pure, was used at daily oral doses of 100 to 600 mg. The treatment was monitored both clinically and biochemically, with periodic neurophysiologic and MRI examinations and repeated controls of liver tests and blood fatty acids by capillary column gas chromatography. RESULTS: DHA-EE normalized the blood levels of DHA in a few weeks. The levels of very-long-chain fatty acids decreased in plasma and those of plasmalogens increased in erythrocytes. Visual and liver function improved. On MRI, a virtual normalization of the brain myelin images was found in the three youngest patients. A clear improvement was noticed in the other two. CONCLUSIONS: The beneficial effects obtained indicate that DHA deficiency plays an important role in the pathogenesis of peroxisomal disease, probably in relation to myelinogenesis. Early initiation of DHA therapy is thus strongly recommended in patients with generalized peroxisomal disorders.




Eskimo plasma constituents, dihomo-gamma-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid inhibit the release of atherogenic mitogens.

Lipids, 24(1):70-5 1989 Jan

Studies in man and laboratory animals suggest that omega 3 polyunsaturated fatty acid constituents of fish oils have antiatherosclerotic properties. We have studied the effects of several such polyunsaturated fatty acids for ability to modify the in vitro release of mitogens from human platelets. Such mitogens may produce the fibro-proliferative component of atherosclerotic plaques. Both 5,8,11,14,17-eicosapentaenoic acid (20:5 omega 3) and 4,7,10,13,16,19-docosahexaenoic acid (22:6 omega 3), major constituents of fish oils, inhibited adenosine diphosphate-induced aggregation of platelets and the accompanying release of mitogens. These effects are dose dependent. Linolenic acid (18:3 omega 3), the biosynthetic precursor of eicosapentaenoic acid, also inhibited platelet aggregation and mitogen release. Eicosapentaenoic acid also inhibited mitogen release from human monocyte-derived macrophages, which, in vivo, are an additional source of mitogens during atherogenesis. Potent inhibition of human platelet aggregation and mitogen release was also seen with dihomo-gamma-linolenic acid (8,11,14-eicosatrienoic acid 20:3 omega 6), whose levels are reportedly elevated in Eskimos subsisting on marine diets. We conclude that diets that elevate plasma and/or tissue levels of eicosapentaenoic acid, docosahexaenoic acid and dihomo-gamma-linolenic acid precursor gamma-linolenic acid (18:3 omega 6) may exert antiatherosclerotic effects by inhibiting the release of mitogens from platelets and other cells.




Effect of docosahexaenoic acid on rate of differentiation of HL-60 human leukemia.

Cancer Res, 24(1):3252-8 1989 Jun 15

We have utilized an experimental model of cell lipid modification that allows study of the effect of a polyunsaturated fatty acid on the linked processes of cellular differentiation and growth arrest. HL-60 human leukemia cells were grown in media supplemented with 10 microM concentrations of the fatty acid docosahexaenoic acid (22:6) or oleic acid (18:1) or in unsupplemented media. Gas chromatographic analysis of phospholipid extracts from HL-60 cells grown in unmodified or 18:1-supplemented media revealed 39% and 36% 18:1, 13 and 12% polyenoics, and 2 and 3% 22:6, respectively. In contrast, cells from 22:6-supplemented cultures had 22% 18:1, 18% total polyunsaturated fatty acids, and 10% 22:6. Retinoic acid was added to cells grown in the various media, and phorbol ester-induced superoxide generation, nitroblue tetrazolium reduction, and growth arrest were determined as measures of differentiation. Unmodified and 18:1-enriched cells showed inducible oxidative burst activity beginning at 48 h after the addition of retinoic acid and continuing to increase for 5 days. In marked contrast, the 22:6-enriched leukemia cells exhibited an increased oxidative activity as early as 24 h which is equivalent to about one division cycle time. G1/0-specific growth arrest was associated with the oxidative phenotypic differentiation in all three cell types. However, cells enriched with 22:6 demonstrated early growth arrest and differentiation considerably in advance of 18:1-modified or unmodified cells. An effect on the cellular differentiation process could be detected after even a brief 1-h exposure of the cells to 22:6. Therefore, a highly polyunsaturated fatty acid which is actively incorporated into membrane structures appreciably accelerates the differentiation process of this human neoplastic cell.




Effects of eicosapentaenoic and docosahexaenoic acids on apoprotein B mRNA and secretion of very low density lipoprotein in HepG2 cells.

Arteriosclerosis, 9(6):836-41 1989 Nov-Dec

Oleic acid (18:1n-9, OA), docosahexaenoic acid (22:6n-3, DHA), or eicosapentaenoic acid (20:5n-3, EPA) was added to HepG2 cells at a concentration of 1 mM in a 5:1 or 2:1 molar complex with bovine serum albumin (BSA), and this was incubated for 3 hours. The incorporation of 3H-glycerol into cellular and medium triglyceride (TG), and the mass of TG were measured. The effects of these fatty acids on the secretion of very low density lipoprotein (VLDL) apolipoprotein B (apo B) were estimated from the incorporation of 3H-leucine into the medium apo B in comparison to cells incubated with fatty acid-poor albumin. The secretion of human albumin by the cells was also estimated by immunochemical precipitation of the labeled albumin. In addition, the intracellular levels of apo B messenger ribonucleic acid (mRNA) were measured by the dot-blot hybridization technique. Relative to control cells incubated with BSA, OA (complexed to BSA at a 5:1 molar ratio) stimulated TG synthesis and secretion sevenfold. Compared to OA, EPA was 24% less effective for both processes, whereas DHA inhibited only the secretion of TG (-43%). The secretion of VLDL apo B was not affected by OA, but was decreased 31% by EPA and 54% by DHA. When the molar ratio of fatty acid complexed to albumin was changed to 2:1, similar results were obtained with respect to TG production. The levels of apo B mRNA relative to actin mRNA were not significantly altered by any of the fatty acids.




The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study.

J Clin Invest, 97(4):1129-33 1996 Feb 15

41 students took either docosahexaenoic acid (DHA)-rich oil capsules containing 1.5-1.8 grams DHA/day (17 females and 5 males) or control oil capsules containing 97% soybean oil plus 3% fish oil (12 females and 7 males) for 3 mo in a double-blind fashion. They took a psychological test (P-F Study) and Stroop and dementia-detecting tests at the start and end of the study. The present study started at the end of summer vacation and ended in the middle of mental stress such as final exams. In the control group extraggression (aggression against others) in P-F Study was significantly increased at the end of the study as compared with that measured at the start (delta = +8.9%, P = 0.0022), whereas it was not significantly changed in the DHA group (delta = -1.0%). The 95% CI of differences between the DHA and control groups were -16.8 to -3.0%. DHA supplementation did not affect the Stroop and dementia-detecting tests. Thus, DHA intake prevented extraggression from increasing at times of mental stress. This finding might help understand how fish oils prevent disease like coronary heart disease.




Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cells in nude mice.

J Natl Cancer Inst, 87(8):587-92 1995 Apr 19

BACKGROUND: Diets rich in omega-6 polyunsaturated fatty acids (e.g., corn oil and other fats containing linoleic acid) stimulate the growth and metastasis of human breast cancer cells in athymic nude mice. On the other hand, diets containing fish oil, which is rich in omega-3 fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids), exert suppressive effects. PURPOSE: Our objective was twofold: 1) to compare the effects of diets containing linoleic acid with those of diets containing eicosapentaenoic acid and docosahexaenoic acid on the growth and metastasis of MDA-MB-435 human breast cancer cells in the nude mouse model and 2) to determine how such effects relate to observed changes in the chemical content of tumor fatty acids and eicosanoid production. METHODS: Groups of 30 female athymic nude mice were fed 20% (wt/wt) fat diets containing either linoleic acid (8%) alone, linoleic acid (8%) plus eicosapentaenoic acid (4%) or docosahexaenoic acid (4%), or linoleic acid (4%) plus eicosapentaenoic acid (8%) or docosahexaenoic acid (8%) for 7 days before one million MDA-MB-435 cells were injected into a thoracic mammary fat pad. Diets were continued for 12 more weeks. Primary tumors were measured weekly. The mice were then killed and necropsied, and tumor tissues preserved. Cell membrane phospholipid fatty acid analyses and eicosanoid assays were performed. All P values represent two-tailed tests of statistical significance. RESULTS: The growth of the primary tumors was retarded in mice fed the diets supplemented with eicosapentaenoic or docosahexaenoic acid compared with the growth of primary tumors in mice fed the 8% linoleic acid diet. Growth inhibition was statistically significant (P < .05) and most effective in association with the diets containing 8% of either omega-3 fatty acid, where tumors were smaller than those in the group fed the diet containing 8% linoleic acid alone at all time points after the 2nd week. The occurrence and severity of lung metastases were reduced in the groups fed omega-3 fatty acid (P < .05). In groups of mice fed eicosapentaenoic or docosahexaenoic acid, the representation of these acids in tumor phospholipids increased, with a statistically significant reduction in the concentrations of arachidonic acid (all groups), tumor 12- and 15-hydroxyeicosatetraenoic acid, and prostaglandin E. Levels of 5-hydroxyeicosatetraenoic acid and leukotriene B4 were unaffected by the omega-3 fatty acids. CONCLUSION: The inhibitory effects of dietary fish oil on human breast cancer cell growth and metastasis in this model system are ascribable to its high eicosapentaenoic acid and docosahexaenoic acid content; the mechanism very likely involves suppression of tumor eicosanoid biosynthesis. IMPLICATION: Future dietary intervention trials designed to reduce the risk of recurrence in the postsurgical breast cancer patient should include the evaluation of eicosapentaenoic acid and docosahexaenoic acid supplementation.




Supplementation with an algae source of docosahexaenoic acid increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects.

J Nutr, 16(12):3032-9 1996 Dec

The purpose of this double-blind study was to investigate the influence of dietary supplementation with an algae source of docosahexaenoic acid [DHA; 22:6(n-3)], devoid of any eicosapentaenoic acid [EPA; 20:5(n-3)], on serum/platelet DHA status, the estimated retroconversion of DHA to EPA, and risk factors for heart disease in vegetarian subjects. Healthy vegetarians (12 male, 12 female) consumed nine capsules daily of either DHA (1.62 g/d) or corn oil for 6 wk. Consumption of DHA capsules increased DHA levels in serum phospholipid by 246% (from 2.4 to 8.3 g/100 g fatty acids) and in platelet phospholipid by 225% (from 1.2 to 3.9 g/100 g fatty acids). EPA levels increased in serum phospholipid by 117% (from 0.57 to 1.3 g/100 g fatty acids) and in platelet phospholipid by 176% (0.21 to 0.58 g/100 g fatty acids) via metabolic retroconversion; the estimated extent of DHA retroconversion to EPA was 11.3 and 12.0%, based on the serum and platelet analyses, respectively. Arachidonic acid [AA; 20:4(n-6)] levels in serum and platelet phospholipids decreased moderately during the trial period (DHA group) as did both docosapentaenoic acids [22:5(n-6) and 22:5(n-3)]. Although no significant changes were found in the total and LDL-cholesterol levels with DHA supplementation, the total cholesterol:HDL-cholesterol ratio showed a moderate decrease over time as did the LDL-cholesterol:HDL-cholesterol ratio and serum triglyceride concentrations. DHA supplementation did not alter the various thrombogenic factors measured. In conclusion, DHA supplementation markedly enhanced the DHA status (of serum and platelets), provided for the formation of substantial EPA, and lowered the total and LDL-cholesterol:HDL-cholesterol ratios.




Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)?

Int J Vitam Nutr Res, 68(3):159-73 1998

A diet including 2-3 portions of fatty fish per week, which corresponds to the intake of 1.25 g EPA (20:5n-3) + DHA (22:6n-3) per day, has been officially recommended on the basis of epidemiological findings showing a beneficial role of these n-3 long-chain PUFA in the prevention of cardiovascular and inflammatory diseases. The parent fatty acid ALA (18:3n-3), found in vegetable oils such as flaxseed or rapeseed oil, is used by the human organism partly as a source of energy, partly as a precursor of the metabolites, but the degree of conversion appears to be unreliable and restricted. More specifically, most studies in humans have shown that whereas a certain, though restricted, conversion of high doses of ALA to EPA occurs, conversion to DHA is severely restricted. The use of ALA labelled with radioisotopes suggested that with a background diet high in saturated fat conversion to long-chain metabolites is approximately 6% for EPA and 3.8% for DHA. With a diet rich in n-6 PUFA, conversion is reduced by 40 to 50%. It is thus reasonable to observe an n-6/n-3 PUFA ratio not exceeding 4-6. Restricted conversion to DHA may be critical since evidence has been increasing that this long-chain metabolite has an autonomous function, e.g. in the brain, retina and spermatozoa where it is the most prominent fatty acid. In neonates deficiency is associated with visual impairment, abnormalities in the electroretinogram and delayed cognitive development. In adults the potential role of DHA in neurological function still needs to be investigated in depth. Regarding cardiovascular risk factors DHA has been shown to reduce triglyceride concentrations. These findings indicate that future attention will have to focus on the adequate provision of DHA which can reliably be achieved only with the supply of the preformed long-chain metabolite.




Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial.

J Am Coll Nutr, 16(3):236-43 1997 Jun

OBJECTIVE: The objective of this study was to evaluate the effects of daily dietary supplementation with 1.25 g or 2.5 g of docosahexaenoic (DHA), in the absence of eicosapentaenoic acid (EPA), on serum lipids and lipoproteins in persons with combined hyperlipidemia (CHL) [serum low-density lipoprotein cholesterol (LDL-C) 130 to 220 mg/dL and triglycerides 150 to 400 mg/dL]. METHODS: After a 6-week dietary stabilization period, subjects entered a 4-week single-blind placebo (vegetable oil) run-in phase. Those with adequate compliance during the the run-in were randomized into one of three parallel groups (placebo, 1.25, or 2.5 g/day DHA) for 6 weeks of treatment. Supplements were administered in a triglyceride form contained in gelatin capsules. Primary outcome measurements were plasma phospholipid DHA content, serum triglycerides, high-density lipoprotein cholesterol (HDL-C). LDL-C and non-HDL-C. RESULTS: The DHA content of plasma phospholipids increased dramatically (2 to 3 fold) in a dose-dependent manner. Significant (p < 0.05) changes were observed in serum triglycerides (17 to 21% reduction) and HDL-C (6% increase) which were of similar magnitude in both DHA groups. Non-HDL-C [+1.6 (NS) and +5.7% (p < 0.04)] and LDL-C [+9.3% (NS) and +13.6% (p < 0.001)] increased in the DHA treatment groups. All lipid effects reached an apparent steady state within the first 3 weeks of treatment. CONCLUSION: Dietary DHA, in the absence of EPA, can affect lipoprotein cholesterol and triglyceride levels in patients with combined hyperlipidemia. The desirable triglyceride and HDL-C changes were present at a dose which did not significantly increased non-HDL-C or LDL-C. These preliminary findings suggest that dietary supplementation with 1.25 g DHA/day, provided in a triglyceride form, may be an effective tool to aid in the management of hypertriglyceridemia.




Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial.

Cancer, 82(2):395-402 1998 Jan 15

BACKGROUND. The aim of the current prospective, randomized control study was to investigate the effect of dietary omega-3 polyunsaturated fatty acids plus vitamin E on the immune status and survival of well-nourished and malnourished patients with generalized malignancy. METHODS. Sixty patients with generalized solid tumors were randomized to receive dietary supplementation with either fish oil (18 g of omega-3 polyunsaturated fatty acids, PUFA) or placebo daily until death. Each group included 15 well-nourished and 15 malnourished patients. The authors measured total T cells, T-helper cells, T-suppressor cells, natural killer cells, and the synthesis of interleukin-1, interleukin-6, and tumor necrosis factor by peripheral blood mononuclear cells before and on Day 40 of fish oil supplementation. Karnofsky performance status, nutritional state, and survival were also estimated. RESULTS. The ratio of T-helper cells to T-suppressor cells was significantly lower in malnourished patients. Omega-3 PUFA had a considerable immunomodulating effect by increasing this ratio in the subgroup of malnourished patients. There were no significant differences in cytokine production among the various groups, except for a decrease in tumor necrosis factor production in malnourished cancer patients, which was restored by omega-3 fatty acids. The mean survival was significantly higher for the subgroup of well-nourished patients in both groups, whereas omega-3 fatty acids prolonged the survival of all the patients. CONCLUSIONS. Malnutrition appears to be an important predictor of survival for patients with end stage malignant disease. Omega-3 polyunsaturated fatty acids had a significant immunomodulating effect and seemed to prolong the survival of malnourished patients with generalized malignancy.




MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders [see comments]

Neurology, 51(1):26-32 1998 Jul

OBJECTIVE: We have found that docosahexaenoic acid (DHA; 22:6n-3), an important constituent of the CNS and retina, is dramatically decreased in patients with generalized peroxisomal disorders. Such a DHA deficiency could be pathogenic. Our aim was to test the possible beneficial effects of normalizing the DHA levels in these patients. The current report focuses on MRI changes during the treatment and reports follow-up evidence of myelin improvement in five peroxisomal disorder patients treated with DHA. METHODS: DHA ethyl ester (DHA-EE), about 90% pure, was used at daily oral doses of 100 to 600 mg. The treatment was monitored both clinically and biochemically, with periodic neurophysiologic and MRI examinations and repeated controls of liver tests and blood fatty acids by capillary column gas chromatography. RESULTS: DHA-EE normalized the blood levels of DHA in a few weeks. The levels of very-long-chain fatty acids decreased in plasma and those of plasmalogens increased in erythrocytes. Visual and liver function improved. On MRI, a virtual normalization of the brain myelin images was found in the three youngest patients. A clear improvement was noticed in the other two. CONCLUSIONS: The beneficial effects obtained indicate that DHA deficiency plays an important role in the pathogenesis of peroxisomal disease, probably in relation to myelinogenesis. Early initiation of DHA therapy is thus strongly recommended in patients with generalized peroxisomal disorders.




Eskimo plasma constituents, dihomo-gamma-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid inhibit the release of atherogenic mitogens.

Lipids, 24(1):70-5 1989 Jan

Studies in man and laboratory animals suggest that omega 3 polyunsaturated fatty acid constituents of fish oils have antiatherosclerotic properties. We have studied the effects of several such polyunsaturated fatty acids for ability to modify the in vitro release of mitogens from human platelets. Such mitogens may produce the fibro-proliferative component of atherosclerotic plaques. Both 5,8,11,14,17-eicosapentaenoic acid (20:5 omega 3) and 4,7,10,13,16,19-docosahexaenoic acid (22:6 omega 3), major constituents of fish oils, inhibited adenosine diphosphate-induced aggregation of platelets and the accompanying release of mitogens. These effects are dose dependent. Linolenic acid (18:3 omega 3), the biosynthetic precursor of eicosapentaenoic acid, also inhibited platelet aggregation and mitogen release. Eicosapentaenoic acid also inhibited mitogen release from human monocyte-derived macrophages, which, in vivo, are an additional source of mitogens during atherogenesis. Potent inhibition of human platelet aggregation and mitogen release was also seen with dihomo-gamma-linolenic acid (8,11,14-eicosatrienoic acid 20:3 omega 6), whose levels are reportedly elevated in Eskimos subsisting on marine diets. We conclude that diets that elevate plasma and/or tissue levels of eicosapentaenoic acid, docosahexaenoic acid and dihomo-gamma-linolenic acid precursor gamma-linolenic acid (18:3 omega 6) may exert antiatherosclerotic effects by inhibiting the release of mitogens from platelets and other cells.




Effect of docosahexaenoic acid on rate of differentiation of HL-60 human leukemia.

Cancer Res, 24(1):3252-8 1989 Jun 15

We have utilized an experimental model of cell lipid modification that allows study of the effect of a polyunsaturated fatty acid on the linked processes of cellular differentiation and growth arrest. HL-60 human leukemia cells were grown in media supplemented with 10 microM concentrations of the fatty acid docosahexaenoic acid (22:6) or oleic acid (18:1) or in unsupplemented media. Gas chromatographic analysis of phospholipid extracts from HL-60 cells grown in unmodified or 18:1-supplemented media revealed 39% and 36% 18:1, 13 and 12% polyenoics, and 2 and 3% 22:6, respectively. In contrast, cells from 22:6-supplemented cultures had 22% 18:1, 18% total polyunsaturated fatty acids, and 10% 22:6. Retinoic acid was added to cells grown in the various media, and phorbol ester-induced superoxide generation, nitroblue tetrazolium reduction, and growth arrest were determined as measures of differentiation. Unmodified and 18:1-enriched cells showed inducible oxidative burst activity beginning at 48 h after the addition of retinoic acid and continuing to increase for 5 days. In marked contrast, the 22:6-enriched leukemia cells exhibited an increased oxidative activity as early as 24 h which is equivalent to about one division cycle time. G1/0-specific growth arrest was associated with the oxidative phenotypic differentiation in all three cell types. However, cells enriched with 22:6 demonstrated early growth arrest and differentiation considerably in advance of 18:1-modified or unmodified cells. An effect on the cellular differentiation process could be detected after even a brief 1-h exposure of the cells to 22:6. Therefore, a highly polyunsaturated fatty acid which is actively incorporated into membrane structures appreciably accelerates the differentiation process of this human neoplastic cell.




Effects of eicosapentaenoic and docosahexaenoic acids on apoprotein B mRNA and secretion of very low density lipoprotein in HepG2 cells.

Arteriosclerosis, 9(6):836-41 1989 Nov-Dec

Oleic acid (18:1n-9, OA), docosahexaenoic acid (22:6n-3, DHA), or eicosapentaenoic acid (20:5n-3, EPA) was added to HepG2 cells at a concentration of 1 mM in a 5:1 or 2:1 molar complex with bovine serum albumin (BSA), and this was incubated for 3 hours. The incorporation of 3H-glycerol into cellular and medium triglyceride (TG), and the mass of TG were measured. The effects of these fatty acids on the secretion of very low density lipoprotein (VLDL) apolipoprotein B (apo B) were estimated from the incorporation of 3H-leucine into the medium apo B in comparison to cells incubated with fatty acid-poor albumin. The secretion of human albumin by the cells was also estimated by immunochemical precipitation of the labeled albumin. In addition, the intracellular levels of apo B messenger ribonucleic acid (mRNA) were measured by the dot-blot hybridization technique. Relative to control cells incubated with BSA, OA (complexed to BSA at a 5:1 molar ratio) stimulated TG synthesis and secretion sevenfold. Compared to OA, EPA was 24% less effective for both processes, whereas DHA inhibited only the secretion of TG (-43%). The secretion of VLDL apo B was not affected by OA, but was decreased 31% by EPA and 54% by DHA. When the molar ratio of fatty acid complexed to albumin was changed to 2:1, similar results were obtained with respect to TG production. The levels of apo B mRNA relative to actin mRNA were not significantly altered by any of the fatty acids.




The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study.

J Clin Invest, 97(4):1129-33 1996 Feb 15

41 students took either docosahexaenoic acid (DHA)-rich oil capsules containing 1.5-1.8 grams DHA/day (17 females and 5 males) or control oil capsules containing 97% soybean oil plus 3% fish oil (12 females and 7 males) for 3 mo in a double-blind fashion. They took a psychological test (P-F Study) and Stroop and dementia-detecting tests at the start and end of the study. The present study started at the end of summer vacation and ended in the middle of mental stress such as final exams. In the control group extraggression (aggression against others) in P-F Study was significantly increased at the end of the study as compared with that measured at the start (delta = +8.9%, P = 0.0022), whereas it was not significantly changed in the DHA group (delta = -1.0%). The 95% CI of differences between the DHA and control groups were -16.8 to -3.0%. DHA supplementation did not affect the Stroop and dementia-detecting tests. Thus, DHA intake prevented extraggression from increasing at times of mental stress. This finding might help understand how fish oils prevent disease like coronary heart disease.




Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cells in nude mice.

J Natl Cancer Inst, 87(8):587-92 1995 Apr 19

BACKGROUND: Diets rich in omega-6 polyunsaturated fatty acids (e.g., corn oil and other fats containing linoleic acid) stimulate the growth and metastasis of human breast cancer cells in athymic nude mice. On the other hand, diets containing fish oil, which is rich in omega-3 fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids), exert suppressive effects. PURPOSE: Our objective was twofold: 1) to compare the effects of diets containing linoleic acid with those of diets containing eicosapentaenoic acid and docosahexaenoic acid on the growth and metastasis of MDA-MB-435 human breast cancer cells in the nude mouse model and 2) to determine how such effects relate to observed changes in the chemical content of tumor fatty acids and eicosanoid production. METHODS: Groups of 30 female athymic nude mice were fed 20% (wt/wt) fat diets containing either linoleic acid (8%) alone, linoleic acid (8%) plus eicosapentaenoic acid (4%) or docosahexaenoic acid (4%), or linoleic acid (4%) plus eicosapentaenoic acid (8%) or docosahexaenoic acid (8%) for 7 days before one million MDA-MB-435 cells were injected into a thoracic mammary fat pad. Diets were continued for 12 more weeks. Primary tumors were measured weekly. The mice were then killed and necropsied, and tumor tissues preserved. Cell membrane phospholipid fatty acid analyses and eicosanoid assays were performed. All P values represent two-tailed tests of statistical significance. RESULTS: The growth of the primary tumors was retarded in mice fed the diets supplemented with eicosapentaenoic or docosahexaenoic acid compared with the growth of primary tumors in mice fed the 8% linoleic acid diet. Growth inhibition was statistically significant (P < .05) and most effective in association with the diets containing 8% of either omega-3 fatty acid, where tumors were smaller than those in the group fed the diet containing 8% linoleic acid alone at all time points after the 2nd week. The occurrence and severity of lung metastases were reduced in the groups fed omega-3 fatty acid (P < .05). In groups of mice fed eicosapentaenoic or docosahexaenoic acid, the representation of these acids in tumor phospholipids increased, with a statistically significant reduction in the concentrations of arachidonic acid (all groups), tumor 12- and 15-hydroxyeicosatetraenoic acid, and prostaglandin E. Levels of 5-hydroxyeicosatetraenoic acid and leukotriene B4 were unaffected by the omega-3 fatty acids. CONCLUSION: The inhibitory effects of dietary fish oil on human breast cancer cell growth and metastasis in this model system are ascribable to its high eicosapentaenoic acid and docosahexaenoic acid content; the mechanism very likely involves suppression of tumor eicosanoid biosynthesis. IMPLICATION: Future dietary intervention trials designed to reduce the risk of recurrence in the postsurgical breast cancer patient should include the evaluation of eicosapentaenoic acid and docosahexaenoic acid supplementation.