DOCOSAHEXAENOIC ACID (DHA) ABSTRACTS

(REFERENCE 1 OF 16)

Capone SL, Bagga D, Glaspy J

Dietary intervention increases omega-3/omega-6 polyunsaturated fatty acid (PUFA) ratios in breast and gluteal fat in women with breast cancer (Meeting abstract).

In: Proc Annu Meet Am Soc Clin Oncol (1997) 16:A213

Recent evidence suggests that the ratio of omega-3 (w-3) to omega-6 (w-6) PUFA in body fat correlates with breast cancer incidence; higher ratios being more protective. The balance of fatty acids in various diets may help explain the international differences in breast cancer risk. We are conducting a dietary intervention study in high risk breast cancer patients who have completed therapy with high dose chemotherapy and stem cell transplant or metastatic breast cancer who have failed conventional therapy. Patients receive a low fat (15% of total calories) diet, fish oil and soy supplements for 3 months. Breast and gluteal fat biopsies are done before and after dietary intervention. Data are available for the first 25 patients and are expressed as means with standard errors; p values refer to results of paired t-tests. In breast fat, increases were observed in eicosapentanoic acid (EPA, 20:5w3) (0 umol/g before, 3.4 +/- 0.67 after; p=0.0001), docosahexanoic acid (DHA, 22:6w3) (1.47 +/- 0.41 umol/gm before, 5.05 +/- 0.74 after; p=0.0001), and total w-3 PUFA (16.06 +/- 1.87 umol/g before, 23.15 +/- 2.78 after; p=0.04). The w- 3/w-6 PUFA ratio increased from 0.05 to 0.07 (p=0.0001). In gluteal fat, increases were also observed in EPA (0 umol/g before, 1.27 +/- 0.50 after; p=0.02), DHA (0.75 +/- 0.29 umol/g before, 2.56 +/- 0.89 after; p=0.01), and total w-3 PUFA (8.24 +/- 1.65 umol/g before, 14.27 +/- 3.43 after; p=0.05). In gluteal fat, the small increase in mean w-3/w-6 PUFA ratio (0.036 to 0.045) did not achieve significance. The composition of breast fat was significantly different from gluteal fat at baseline, as indicated by the mean w- 3/w-6 PUFA ratios (p=0.0006); this difference remained after dietary intervention (p=0.0002). Short term low fat dietary intervention with fish oil can lead to significant changes in the PUFA composition of the breast microenvironment. These changes may have important implications for the prevention of breast cancer. (C) American Society of Clinical Oncology 1997.

Institutional address: Division of Hematology/Oncology UCLA School of Medicine Los Angeles CA

(REFERENCE 2 OF 16)

Meterissian S, Thomas P, Steele GD Jr, Forse RA

EFFECTS OF CELL MEMBRANE FATTY ACID ALTERATIONS ON THE ADHESION OF A HUMAN COLORECTAL CARCINOMA CELL LINE (MEETING ABSTRACT)

In: Proc Annu Meet Am Assoc Cancer Res (201992) 33:A109

Diets rich in n-6 fatty acids promote metastases in murine tumor models while n-3 fatty acids are protective. Alterations of the membrane fatty acids of colorectal cancers may alter binding to matrix proteins. MIP-101, a poorly differentiated colorectal cancer cell line, was treated with docosahexanoic acid (n-3) or linoleic acid (n-6). Gas chromatography was used to document changes in membrane fatty acids. Cell attachment was measured by adding 51Cr- labeled tumor cells to wells coated with laminin (LN), collagen type IV (CIV) or fibronectin (FN). Cell surface expression of alpha-2 integrin was studied using fluorescent antibody-directed cell sorting. N-3-treated cells had significantly decreased binding to CIV (29 +/- 0.6 from 40 +/- 1.7, p less than 0.01) while n-6-treated cells had significantly decreased binding to both CIV (22 +/- 0.5, p less than 0.01) and FN (12 +/- 2.9 from 26 +/- 0.4, p less than 0.05). Binding to LN was decreased for both n-3 (28 +/- 6) and n-6 (19 +/- 6 from 40 +/- 0.7) treatments. There were decreases in cell surface alpha-2 integrin with both n-3 (54% decrease) and n-6 (24% decrease) treatments. These results demonstrate that membrane fatty acid changes alter the adhesiveness of colorectal carcinoma cells possibly through changes in cell surface integrins.

Institutional address: Dept. of Surgery New England Deaconess Hosp. Boston MA 02215

(REFERENCE 3 OF 16)

Morcos NC

Modulation of lipid profile by fish oil and garlic combination.

In: J Natl Med Assoc (1997 Oct) 89(10):673-8

Fish consumption has been shown to influence epidemiology of heart disease, and garlic has been shown to influence triglyceride levels. This study was undertaken to evaluate the effect of fish oil and garlic combinations as a dietary supplement on the lipid subfractions. Forty consecutive subjects with lipid profile abnormalities were enrolled in a single-blind, placebo-controlled crossover study. Each subject received placebo for 1 month and fish oil (1800 mg of eicosapentanoic acid [EPA] + 1200 mg of docosahexanoic acid) with garlic powder (1200 mg) capsules daily for 1 month. Lipid fractionation was performed prior to study initiation, after the placebo period, and after the intervention period. Subjects all had cholesterol levels > 200. Subjects were instructed to maintain their usual diets. Supplementation for 1 month resulted in an 11% decrease in cholesterol, a 34% decrease in triglyceride, and a 10% decrease in low-density lipoprotein (LDL) levels, as well as a 19% decrease in cholesterol/high-density lipoprotein (HDL) risk. Although not significant, there was a trend toward increase in HDL. There was no significant placebo effect. These results suggest that in addition to the known anticoagulant and antioxidant properties of both fish oil and garlic, the combination causes favorable shifts in the lipid subfractions within 1 month. Triglycerides are affected to the largest extent. The cholesterol lowering and improvement in lipid/HDL risk ratios suggests that these combinations may have antiatherosclerotic properties and may protect against the development of coronary artery disease.

Institutional address: Division of Cardiology University of California Irvine 92717 USA.

(REFERENCE 4 OF 16)

Marino O, Onofri E

[Preliminary evaluation of an association of polyunsaturated acids in primary hypertriglyceridemia]

In: Clin Ter (1993 Jul) 143(1):11-4

The above study was intended to evaluate changes in triglyceride blood level in subjects treated with a polyunsaturated fatty acid combination: docosahexanoic (DHA) and eicosapentaenoic (EPA) acid, compared to changes observed in patients treated with arachidonic acid. The results obtained show that a significant reduction of triglyceride blood level was achieved and was more marked in patients treated with the DHA-EPA combination compared to those treated with arachidonic acid only. An increase in the index of fatty acid unsaturation was observed in all patients without significant differences between treatments.

Institutional address: Cattedra di Medicina Interna Universita degli Studi di Roma La Sapienza.

(REFERENCE 5 OF 16)

Bordoni A, Biagi PL, Turchetto E, Rossi CA, Hrelia S

Diacylglycerol fatty acid composition is related to activation of protein kinase C in cultured cardiomyocytes.

In: Cardioscience (1992 Dec) 3(4):251-5

Using cultures of beating neonatal rat cardiomyocytes we have studied the fatty acid composition of the diacylglycerol produced after different stimulation times with an alpha 1-agonist (phenylephrine) and we have related it to the previously reported time course of the activation of particulate protein kinase C, in control cells and in cells grown in a medium supplemented with docosahexaenoic acid. Gas chromatography of the diacylglycerol produced after stimulation revealed significant differences between control cells and cells treated with docosahexanoic acid. In the cells treated with docosahexanoic acid, the more persistent activation of the membrane- bound protein kinase C might be sustained by an enrichment of diacylglycerol with docosahexanoic acid. The modification of the fatty acid composition of diacylglycerol can cause an alteration in the response of the cells to alpha 1-adrenoceptor stimulation.

Institutional address: Department of Biochemistry G Moruzzi University of Bologna Italy.

(REFERENCE 6 OF 16)

Nosari I, Cortinovis F, Lepore G, Maglio ML, Pagani G

[Use of omega-3 in diabetic patients]

In: Clin Ter (1994 Mar) 144(3):213-21

The use of omega-3 fatty acids for diabetic patients is based on well confirmed observations concerning the presence of cardiovascular risk factors in these patients. Changes of lipid metabolism, reduced erythrocyte deformability, increased platelet aggregation, and high blood pressure often found in subjects with diabetes mellitus are all favourably influenced by the administration of eicosapentanoic and docosahexanoic acid. In non insulin dependent subjects, these fatty acids may bring about a rapid reversible deterioration of blood glucose balance while in insulin dependent patients there is no relevant interference. Therefore, omega-3 administration would appear advisable in insulin dependent diabetics with increased cardiovascular risk factors.

Institutional address: Divisione di Endocrinologia Ospedali Riuniti di Bergamo.

(REFERENCE 7 OF 16)

Shimura T, Miura T, Usami M, Ishihara E, Tanigawa K, Ishida H, Seino Y

Docosahexanoic acid (DHA) improved glucose and lipid metabolism in KK-Ay mice with genetic non-insulin-dependent diabetes mellitus (NIDDM).

In: Biol Pharm Bull 1997 May;20(5):507-10

The hypoglycemic and hypolipidemic effect of docosahexaenoic acid (DHA; C22: 6omega-3) ethyl ester was examined in KK-Ay mice and neonatal streptozotocin-induced diabetic (NSZ) which are respectively obese and lean animal models of non-insulin-dependent diabetes mellitus (NIDDM), and in ddY normal mice. Single administration of DHA (500 mg/kg body weight) to KK-Ay mice significantly reduced (p<0.05) the blood glucose levels (BG) (p<0.05) and plasma free fatty acid levels (FFA) (p<0.05) at 10 h after oral administration when compared with control group. DHA (500 mg/kg body weight)-treated NSZ and normal mice, however, showed no change in these parameters. In addition, repeated administration of DHA (100 mg/kg) to KK-Ay mice significantly suppressed the increment of BG (p<0.05) and plasma triglyceride levels (TG) (p<0.01), and significantly decreased FFA (p<0.05) at 30 d compared with control group. DHA also significantly decreased the blood glucose at 60 and 120 min on insulin tolerance test (ITT). From these findings, it seems likely that DHA exhibits its hypoglycemic effects by increasing insulin sensitivity. It is concluded that DHA would be useful for treatment of obese type NIDDM with insulin resistance.

Institutional address: Suzuka University of Medical Science and Technology, Mie, Japan.

(REFERENCE 8 OF 16)

Peet M, Murphy B, Shay J, Horrobin D

Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients.

In: Biol Psychiatry (1998 Mar 1) 43(5):315-9

BACKGROUND: It has been hypothesized that depletion of cell membrane n3 polyunsaturated fatty acids (PUFA), particularly docosahexanoic acid (DHA), may be of etiological importance in depression. METHODS: We measured the fatty acid composition of phospholipid in cell membranes from red blood cells (RBC) of 15 depressive patients and 15 healthy control subjects. RESULTS: Depressive patients showed significant depletions of total n3 PUFA and particularly DHA. Incubation of RBC from control subjects with hydrogen peroxide abolished all significant differences between patients and controls. CONCLUSIONS: These findings suggest that RBC membranes in depressive patients show evidence of oxidative damage. Possible interpretations, and implications for the etiology and treatment of depression, are discussed.

Institutional address: University Department of Psychiatry Sheffield United Kingdom.

(REFERENCE 9 OF 16)

Fitzgerald G, Harbige LS, Forti A, Crawford MA

The effect of nutritional counselling on diet and plasma EFA status in multiple sclerosis patients over 3 years.

In: Hum Nutr Appl Nutr (1987 Oct) 41(5):297-310

The dietary intake of 83 people with multiple sclerosis (MS) was assessed by the 7-day weighed intake method prior to dietary advice and at 6-monthly intervals thereafter up to 36 months. The P:S ratio of the diet increased from an initial value of 0.8 to 1.5 after 6 months and 1.34 at 36 months. Biochemical investigation of plasma essential fatty acid (EFA) status specifically linoleic, eicosapentanoic and docosahexanoic acids showed significant correlations with diet. Concurrent 6-monthly neurological and physiotherapy assessments were also carried out, the neurological results are discussed in relation to a nutrient scoring system.

Institutional address: ARMS Research Unit Central Middlesex Hospital Acton London UK.

(REFERENCE 10 OF 16)

Peet M, Laugharne JD, Mellor J, Ramchand CN

Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation.

In: Prostaglandins Leukot Essent Fatty Acids (1996 Aug) 55(1-2):71-5

There is now convincing evidence that membrane phospholipid metabolism is abnormal in schizophrenic patients. Our own studies, consistent with those of other research groups, have shown marked depletion of essential fatty acids, particularly arachidonic acid and docosahexanoic acid, in red blood cell membranes from schizophrenic patients relative to healthy control subjects. We also present preliminary evidence that similar abnormalities are present in first degree relatives of schizophrenic patients. Furthermore, it appears that changes in diet, which modify membrane levels of fatty acids, can have significant effects upon symptoms of schizophrenia and tardive dyskinesia (TD). Thus, we have found that schizophrenic patients who eat more (n-3) fatty acids in their normal diet have less severe symptoms. In a pilot study of (n-3) fatty acid supplementation we observed significant improvement in both schizophrenic symptoms and tardive dyskinesia over a 6 week period.

Institutional address: Department of Psychiatry Northern General Hospital Herries Road Sheffield UK.

(REFERENCE 11 OF 16)

Peet M, Laugharne J, Rangarajan N, Horrobin D, Reynolds G

Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients.

In: J Psychiatr Res (1995 May-Jun May-Jun) 29(3):227-32

The fatty acid composition of red blood cell membranes from 23 drug- treated schizophrenic patients was measured and compared with a healthy control group. There were substantial depletions of fatty acids from the n6 and n3 series, particularly arachidonic and docosahexanoic acid. Significant negative correlations between depleted n6 fatty acids and plasma levels of thiobarbituric acid reactive substances suggests that depletion is caused by increased breakdown of these fatty acids rather than by impaired incorporation of fatty acids into membranes. Arachidonic and docosahexanoic acids appear to show a bimodal distribution. We propose that this may be a metabolic abnormality which is of aetiological importance in schizophrenia.

Institutional address: Department of Psychiatry Northern General Hospital Sheffield U.K.

(REFERENCE 12 OF 16)

Maurage C, Guesnet P, Pinault M, Rochette de Lempdes J, Durand G, Antoine J, Couet C

Effect of two types of fish oil supplementation on plasma and erythrocyte phospholipids in formula-fed term infants.

In: Biol Neonate 1998 Dec;74(6):416-29

We studied the effect of docosahexaenoic acid (DHA) supplementation of infant formulas on fatty acid composition of blood phospholipids in term infants. Two fish oil supplemented formulas containing 0.45 wt% DHA and high (0.35%) or low (0.10%) eicosapentaenoic acid (EPA) were fed for 42 days and compared with a standard formula and breast milk. Infants fed supplemented formulas and breast milk had similar time-dependent changes for DHA from birth to day 42, i.e., slight decreases in plasma phospholipids and erythrocyte phosphatidylcholine and no change in erythrocyte phosphatidylethanolamine. Low-EPA formula prevented EPA accumulation but did not limit the significant decrease in arachidonic acid (AA) noted in infants fed high-EPA formula. These results suggest that term infant formulas should be supplemented with DHA-rich EPA-low fish oil and AA to achieve a fatty acid status in formula-fed infants similar to that of breast-fed infants.

Institutional address: Equipe Associee, Universite de Tours EA2103-INRA, Laboratoire de Nutrition et Securite Alimentaire, Jouy-en-Josas, France.

(REFERENCE 13 OF 16)

Woltil HA, van Beusekom CM, Schaafsma A, Muskiet FA, Okken A

Long-chain polyunsaturated fatty acid status and early growth of low birth weight infants.

In: Eur J Pediatr 1998 Feb;157(2):146-52

We correlated arachidonic acid (AA) and docosahexaenoic acid (DHA) status with anthropometric measures and growth rates in a group of low birth weight infants (< or = 2500 g; gestational ages 30-41 weeks; n = 143). AA and DHA status were measured in erythrocytes (RBC) and plasma cholesterol esters (CE) during days 10 to 42. Infants received preterm formula without long-chain polyunsaturated fatty acids (LCP; n = 81), with LCP (n = 29) or maternal milk (n = 33). RBC AA contents on day 10 were correlated (P < 0.05) with birth weight in breast-fed infants and all formula-fed infants, with on day 10 a standard deviation score (SDS) for weight, length and occipito-frontal circumference in all formula-fed infants, and with on day 10 an SDS for length in breast-fed infants. Brain weight was related to RBC DHA and CE DHA contents on both day 10 and day 42 in formula-fed infants. Of the variances of brain growth parameters on day 42, 21-34% were explained by DHA status on day 42 and protein intake from days 10-42. CONCLUSION: We conclude that parameters of early neonatal AA status are related to intra-uterine rather than to post-natal growth. Parameters of post-natal brain growth are related to RBC DHA and CE DHA contents on day 42, and to dietary protein intake. These results point to the importance of dietary DHA for brain growth in the first 6 post-natal weeks.

Institutional address: Department of Paediatrics, Martini Hospital, Groningen, The Netherlands.

(REFERENCE 14 OF 16)

Boehm G, Borte M, Bohles HJ, Muller H, Kohn G, Moro G

Docosahexaenoic and arachidonic acid content of serum and red blood cell membrane phospholipids of preterm infants fed breast milk, standard formula or formula supplemented with n-3 and n-6 long-chain polyunsaturated fatty acids.

In: Eur J Pediatr 1996 May;155(5):410-6

The contents of docosahexaenoic (DHA) and arachidonic acid (AA) of plasma and red blood cell membrane phospholipids were studied in 41 very low birth weight infants fed either breast milk (n = 18), a standard formula without long-chain polyunsaturated fatty acids with 20 or 22 carbon atoms (LCP) but with alpha-linolenic acid and linoleic acid (n = 11) or a formula additionally supplemented with n-3 and n-6 LCP in relations typical for human milk (n = 12) after 2, 6, and 10 weeks of feeding. The content of DHA and AA in plasma phospholipids declined in the infants fed the LCP-free formula but remained more or less constant during the whole feeding period in those infants fed breast milk as well as in those fed the LCP-supplemented formula. The differences between the group fed the LCP-free standard formula and the two groups fed LCP-containing diets became significant during the first 2 weeks of feeding. In contrast, there were no differences between the group fed breast milk and the group fed the supplemented formula during the study period. Similar effects could be observed regarding the composition of red blood cell membrane phospholipids, but the differences between the infants fed the LCP-free standard formula and the two other groups with LCP-containing diets were significant only for AA. The data indicate that very low birth weight infants are unable to synthesize LCP from alpha-linolenic acid and linoleic acid in sufficient amounts to prevent a decline of LCP in plasma and red blood cell phospholipids. Additionally, the data show, that supplementation of formulas with n-3 and n-6 LCP in amounts typical for human milk fat results in similar fatty acid profiles of plasma and red blood cell membrane phospholipids as found during breast milk feeding. CONCLUSION: Supplementation of formula with long-chain polyunsaturated fatty acids improves the LCP status of very low birth weight infants.

Institutional address: Centre for Infant Nutrition, Milano, Italy.

(REFERENCE 15 OF 16)

Uauy-Dagach R, Mena P

Nutritional role of omega-3 fatty acids during the perinatal period.

In: Clin Perinatol (1995 Mar) 22(1):157-75

There is now clear evidence that dietary supplementation of omega-3 fatty acid is essential for normal eye and brain development. Corn oil-based diets induce omega-3 deficiency in preterm infants, affecting retinal responses to light, cortical visual evoked potentials, and behavioral measures of visual acuity. Preterm infants require docosahexanoic acid (DHA) because they are unable to form sufficient quantities from precursors provided by soy oil-based formula products. Human milk provides an ideal source of essential fatty acids for premature infants. There is increasing evidence that premature infant formulas containing vegetable oils should be supplemented with long-chain EFAs to promote optimal retinal and cortical visual development.

Institutional address: Clinical Nutrition Unit University of Chile Santiago.

(REFERENCE 16 OF 16)

Fernandes G, Bysani C, Venkatraman JT, Tomar V, Zhao W

Increased TGF-beta and decreased oncogene expression by omega-3 fatty acids in the spleen delays onset of autoimmune disease in B/W mice.

In: J Immunol (1994 Jun 15) 152(12):5979-87

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 +/- 12.5), whereas FO extended the survival significantly (402.1 days +/- 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-beta 1 and lower c-myc and c-ras mRNA expression and higher TGF-beta 1 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 (18:2 omega-6) and arachidonic (20:4 omega-6) acid levels in splenocytes of the CO-fed group and higher eicosapentaenoic (20:5 omega-3) and docosahexanoic (22:6 omega-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.

Institutional address: Department of Medicine University of Texas Health Science Center San Antonio 78284.

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