The starved colon - Diminished mucosal nutrition, diminished absorption, and colitis
Department of Surgery, The Queen Elizabeth Hospital, Woodville, SA 5011 Australia
DIS. COLON RECTUM (USA), 1990, 33/10 (858-862)
Nutrition of colonic epithelial cells is mainly from short chain fatty acids (SCFAs) produced by bacterial fermentation in the colonic lumen. n-Butyrate contributes more carbon of oxidation to epithelial cells than glucose or glutamine from the vasculature. Incomplete starvation of colonic epithelial cells through lack of luminal SCFAs leads, in the short term, to mucosal hypoplasia with either diminished absorption or diarrhea. A chronic lack of SCFAs or complete organ starvation in conjunction with other factors leads to nutritional colitis, either ''diversion colitis'' or ''starvation colitis.'' Whether predominantly diarrhea or colitis develops in mucosal malnutrition appears to depend upon the severity and duration of starvation. Ulcerative colitis may be classified as a nutritional colitis in that colonic epithelial cells are unable to utilize SCFAs reflecting epithelial starvation despite abundant SCFAs.
Nutrition and ulcerative colitis
Burke A.; Lichtenstein G.R.; Rombeau J.L.
Prof. J.L. Rombeau, Department of Surgery, Hospital University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 USA
Bailliere's Clinical Gastroenterology (United Kingdom), 1997, 11/1 (153-174)
The role of diet in the aetiology and pathogenesis of ulcerative colitis (UC) remains uncertain. Impaired utilization by colonocytes of butyrate, a product of bacterial fermentation of dietary carbohydrates escaping digestion, may be important. Sulphur-fermenting bacteria may be involved in this impaired utilization. Oxidative stress probably mediates tissue injury but is probably not of causative importance. Patients with UC are prone to malnutrition and its detrimental effects. However, there is no role for total parenteral nutrition and bowel rest as primary therapy for UC. The maintenance of adequate nutrition is very important, particularly in the peri-operative patient. In the absence of massive bleeding, perforation, toxic megacolon or obstruction, enteral rather than parenteral nutrition should be the mode of choice. Nutrients may be beneficial as adjuvant therapy. Butyrate enemas have improved patients with otherwise recalcitrant distal colitis in small studies, Non-cellulose fibre supplements are of benefit in rats with experimental colitis. Eicosapentaenoic acid in fish oil has a steroid-sparing effect which, although modest, is important, particularly in terms of reducing the risk of osteoporosis, but it seems to have no role in the patient with inactive disease. gamma-Linolenic acid and anti-oxidants also are showing promise. Nutrients may also modify the increased risk of colorectal carcinoma. Oxidative stress can damage tissue DNA but there are no data published at present on possible protection from oral anti-oxidants. Butyrate protects against experimental carcinogenesis in rats with experimental colitis. Folate supplementation is weakly associated with decreased incidence of cancer in UC patients when assessed retrospectively. Vigilance should be maintained for increased micronutrient requirements and supplements given as appropriate. Calcium and low-dose vitamin D should be given to patients on long-term steroids and folate to those on sulphasalazine.
An enteral formula containing fish oil, indigestible oligosaccharides, gum arabic and antioxidants affects plasma and colonic phospholipid fatty acid and prostaglandin profiles in pigs
Campbell J.M.; Fahey G.C. Jr.; Lichtensteiger C.A.; Demichele S.J.; Garleb K.A.
G.C. Fahey Jr., Division of Nutritional Sciences, Department of Animal Sciences, University of Illinois, Urbana, IL 61801 USA
Journal of Nutrition (USA), 1997, 127/1 (137-145)
Evidence supports a pathogenic role of arachidonic acid-derived inflammatory mediators within the gastrointestinal tract of patients with inflammatory bowel disease. The purpose of this study was to assess the effects of an ulcerative colitis nutritional formula (UCNF) containing oligosaccharides, fish oil, gum arabic and antioxidants on plasma and colonic phospholipid fatty acid and prostaglandin profiles in pigs. Twenty-four growing barrows in two replications were equally randomized among four killing times (d 0, 7, 14 and 21), and one of two diets, a control and the UCNF. Diets contained comparable levels of protein, fat, and nonstructural carbohydrate and met 100% of the energy requirements of the pig. Intake and body weight were recorded daily while blood, urine and tissue samples were collected at time of kill. Within 1 wk of ingestion of the UCNF, the composition of plasma phospholipid fatty acids showed an increase in 20:5(n- 3) and 22:6(n-3) (P < 0.0001) and a decrease in 20:4(n-6) and 18:2(n-6) (P < 0.0001). Similar effects were observed for the phospholipids in the colonic and cecal mucosa. Plasma prostaglandin E was unaffected by treatment, whereas thromboxane B2 and 6-keto-prostaglandin F(1alpha) levels were significantly decreased after 7 d of UCNF ingestion. Ingestion of the UCNF resulted in a suppression in the synthesis of proinflammatory prostaglandins by cecal and colonic mucosal cells. Levels of colonic and cecal prostaglandin E, 6- ketoprostaglandin F(1alpha) and thromboxane B2 were significantly decreased after 7 d of UCNF ingestion. These changes may have been mediated by rapid increases of (n-3) fatty acids into cellular phospholipids. Dietary supplementation with the UCNF may prove beneficial for patients with ulcerative colitis by modulating colonic prostaglandin synthesis.
Influence of nutrition in ulcerative colitis - The significance of nutritional care in inflammatory bowel disease
Nagel E.; Bartels M.; Pichlmayr R.
Klinik fur Abdominal, Transplantationschirurgie, Konstanty-Gutschow-Stras se 8, D-30625 Hannover Germany
Langenbecks Archiv fur Chirurgie (Germany), 1995, 380/1 (4-11)
Nutritional therapy for ulcerative colitis (UC) is controversial. Studies are usually designed to investigate total parenteral (TPN) or total enteral nutrition (TEN), and before these can be compared it is necessary to differentiate between the different therapeutic aims. The aims of artificial nutritional support in patients with UC are the readjustment of the nutritional status, possible remission of disease activity, and decrease in the incidence of surgical intervention or postoperative complication. Owing to the heterogeneity of the results published so far, it is still difficult to compare studies. Nevertheless, they indicate that the extent and severity of the colitis and the patient selection are of paramount importance in the implementation of nutritional therapy. Positive effects of TPN reported from non-controlled studies were not confirmed by controlled trials. Moreover, TPN was no more effective than an oral diet. Regarding remission rates or operative interventions needed, TPN had more side effects than and no defined advantages over TEN. TEN seems to be useful for certain patients. In some patients with UC, it seems to be accompanied by fewer postoperative complications. However, a definitive conclusion on the effects of TEN or TPN is not yet possible. In this context, certain fatty acids may have an important role in the treatment of UC. In prospective, randomized and controlled studies omega-3 fatty acids were found to be therapeutically useful. A reduction of the steroid doses needed is particularly important. Another therapeutic approach in distal UC is seen in the rectal administration of short chain fatty acids.
Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis
Grimminger F.; Fuhrer D.; Papavassilis C.; Schlotzer E.; Mayer K.; Heuer K.-U.; Kiss L.; Walmrath D.; Piberhofer S.; Lubbecke F.; Kramer H.-J.; Stevens J.; Schutterle G.; Seeger W.
Department of Internal Medicine, Justus-Liebig-University, Klinikstrasse 36, D-6300 Giessen Germany
EUR. J. CLIN. INVEST. (United Kingdom), 1993, 23/11 (706-715)
N-3 fatty acids were supplied to a 36-year-old female patient suffering from ulcerative colitis and severe steroid side-effects, in a sequence of parenteral and enteral administration. During a moderately active period of disease, 200 ml d-1 fish oil-derived lipid emulsion (eicosapentaenoic acid (EPA), 4.2 g; docosahexaenoic acid (DHA), 4.2 g) was infused for 9 days, in parallel with rapid tapering of the steroid dose. Disease activity declined rapidly, and the patient was subsequently provided with 16 fish oil capsules per day (EPA, 2.9 g; DHA, 1.9 g) for 2 months. At the end of this period of therapy, severe colitis recurred with intestinal and extraintestinal manifestations. The n-3 lipid emulsion was then used for intravenous alimentation (29 days, maximum dose 300 ml per day); during this time, marked improvement of the inflammatory bowel disease was noted. During both periods of parenteral n-3 lipid administration, total plasma EPA and DHA contents increased several-fold, surpassing that of arachidonic acid; this plasma n-3 fatty acid enrichment was only maintained to a minor extent during the intermediate period of dietary fish oil supplementation. The intravenously administered EPA-containing triglycerides were rapidly hydrolyzed, as evidenced by the appearance of substantial quantities of EPA in the plasma free fatty acid fraction. Platelet and neutrophil total membrane content of EPA and DHA as well as n-3 fatty acid/AA membrane ratios similarly increased during the periods of intravenous n-3 lipid administration and declined during oral fish oil uptake. In contrast, erythrocyte membrane enrichment in EPA and DHA occurred only after the prolonged (2 month) period of dietary n-3 lipid supplementation. Ex vivo stimulation of neutrophils with A23187 showed progressive increase in 5-series leukotriene- and 5-HEPE-generation during both periods of n-3 lipid infusion, in parallel with the rise of plasma EPA contents. Maximum 5-series/4-series leukotriene ratios surpassed 0.25. Similarly, ratios of thromboxane B3/B2 liberated from ex vivo stimulated platelets surpassed 0.4 during ongoing n-3 lipid infusion. The profound changes in fatty acid profiles and lipid mediator generation may be related to the reduction in colitis activity observed during the periods of intravenous n-3 lipid supplementation.
The role of marine fish oils in the treatment of ulcerative colitis
Department of Internal Medicine, Tufts University School of Medicine, Boston, MA 02111 USA
NUTR. REV. (USA), 1993, 51/2 (47-49)
Recent studies suggest that marine fish-oil supplements, which are rich in n-3 fatty acids, may reduce the inflammation associated with ulcerative colitis. Fish oils may exert their beneficial effects by shifting eicosanoid synthesis to less inflammatory species or by modulating tissue levels of certain cytokines.
Fish oil fatty acid supplementation in active ulcerative colitis: A double-blind, placebo-controlled, crossover study
Aslan A.; Triadafilopoulos G.
Gastroenterology Section, Martinez VA Medical Center, 150 Muir Road, Martinez, CA 94553 USA
AM. J. GASTROENTEROL. (USA), 1992, 87/4 (432-437)
Arachidonic acid metabolites formed by both the cyclooxygenase and lipoxygenase pathways may contribute to the clinical diarrhea and colitis of inflammatory bowel disease. Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa, and these levels tend to correlate with severity of the disease. In this study, we evaluated the efficacy of ingestion of fish oil n-3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. Eleven patients with ulcerative colitis of mild to moderate severity were studied in a 8-month, double-blind, placebo-controlled, crossover trial of dietary supplementation with fish oil, which provided about 4.2 g of omega-3- fatty acids per day. A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mucosal leukotriene B4 production was measured by radioimmunoassay. Mean disease activity index declined 56% for patients receiving fish oil and 4% for patients on placebo (p < 0.05). There were no statistically significant differences in histopathologic scores or colonic mucosal leukotriene B4 levels. All patients tolerated fish oil ingestion and showed no alteration in routine blood studies. No patient worsened; anti-inflammatory drugs could be reduced or eliminated in eight patients (72%) while receiving fish oil. We conclude that fish oil dietary supplementation results in clinical improvement of active mild to moderate ulcerative colitis but is not associated with significant reduction in mucosal leukotriene B4 production, compared with placebo therapy. Further studies are needed to elucidate the mechanism of action and optimal dose and duration of fish oil supplementation in ulcerative colitis.
Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: A randomised, placebo controlled trial
Breuer R.I.; Soergel K.H.; Lashner B.A.; Christ M.L.; Hanauer S.B.; Vanagunas A.; Harig J.M.; Keshavarzian A.; Robinson M.; Sellin J.H.; Weinberg D.; Vidican D.E.; Flemal K.L.; Rademaker A.W.
Dr. R.I. Breuer, Evanston Hospital, Special GH Laboratory, 2650 Ridge Avenue, Evanston, IL 60201 USA
Gut (United Kingdom), 1997, 40/4 (485-491)
Background - Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. Aims - To assess the efficacy of topical SCFA treatment in ulcerative colitis. Patients and Methods - 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. Results - Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (<6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores. Conclusions - Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit.
Special issues in nutritional therapy of inflammatory bowel disease
CRC, Dalhousie University, 5849 University Avenue, Halifax, NS B3H 4H7 Canada
CAN. J. GASTROENTEROL. (Canada), 1993, 7/2 (196-199)
There are many issues and controversies concerning nutrition in inflammatory bowel disease (IBD). Most authorities now accept that total parenteral nutrition (TPN) is useful, both as primary and adjunct therapy in the management of patients with Crohn's disease, but only useful as adjunct therapy in patients with acute flare-ups of ulcerative colitis. In both, there is a role for TPN in preparing patients for imminent surgery. In comparison with TPN, defined formula (elemental diet) therapy has less complications, is easier to monitor, is less costly, and gives equivalent results. Several controlled trials have shown that elemental diet therapy is as useful as prednisone in inducing remission in patients with active Crohn's disease. Elemental diets have been compared with polymeric diets in patients with Crohn's disease, and have been shown to be effective; recently a semi-elemental diet has also been shown to be as effective as elemental diet, but with a conferred benefit of maintaining essential fatty acid levels. Elemental diets do not appear to be effective in closing fistulas. If the problems of palatability and, in some patients, nausea, vomiting, abdominal cramps and diarrhea persist, these can be overcome to some extent by flavour changes, chilling, gradual introduction and counselling or nasogastric tube feeding. Recently, fish oils have been used in patients with IBD. There is suggestive evidence that they are of benefit in patients with ulcerative colitis but not in Crohn's disease. There is a suggestion that fish oils have a steroid-sparing effect which, if confirmed, will be of great potential benefit to patients with ulcerative colitis.
A randomized controlled study of evening primrose oil and fish oil in ulcerative colitis
Greenfield S.M.; Green A.T.; Teare J.P.; Jenkins A.P.; Punchard N.A.; Ainley C.C.; Thompson R.P.H.
Gastrointestinal Laboratory, The Rayne Institute, St Thomas' Hospital, London SE1 7EH United Kingdom
ALIMENT. PHARMACOL. THER. (United Kingdom), 1993, 7/2 (159-166)
In a placebo-controlled study, 43 patients with stable ulcerative colitis were randomized to receive either MaxEPA (n = 16), super evening primrose oil (n = 19), or olive oil as placebo (n = 8) for 6 months, in addition to their usual treatment. Treatment with MaxEPA increased red-cell membrane concentrations of eicospentaenoic acid (EPA) at 3 months by three-fold and at 6 months by four-fold (both P < 0.01), and doubled docosahexaenoic acid (DHA) levels at 6 months (P < 0.05). Treatment with super evening primrose oil increased red-cell membrane concentrations of dihomogamma-linolenic acid (DGLA) by 40% at 6 months (P < 0.05), whilst treatment with placebo reduced levels of DGLA and DHA at 6 months (both P < 0.05). Clinical outcome was assessed by patient diary cards, sigmoidoscopy and histology of rectal biopsy specimens. Super evening primrose oil significantly improved stool consistency compared to MaxEPA and placebo at 6 months, and this difference was maintained 3 months after treatment was discontinued (P <0.05). There was however, no difference in stool frequency, rectal bleeding, disease relapse, sigmoidoscopic appearance or rectal histology in the three treatment groups. Despite manipulation of cell-membrane fatty acids, fish oils do not exert a therapeutic effect in ulcerative colitis, while evening primrose oil may be of some benefit.
Treatment of ulcerative colitis with fish oil supplementation: A prospective 12 month randomised controlled trial
Hawthorne A.B.; Daneshmend T.K.; Hawkey C.J.a; Belluzzi A.; Everitt S.J.; Holmes G.K.T.; Malkinson C.; Shaheen M.Z.; Willars J.E.
Department of Therapeutics, University Hospital, Nottingham NG7 2UH United Kingdom
GUT (United Kingdom), 1992, 33/7 (922-928)
The effect of fish oil on the course of ulcerative colitis was investigated in a randomised blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentanoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore-stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.
Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease
Hillier K.; Jewell R.; Dorrell L.; Smith C.L.
Clinical Pharmacology Group, Faculty of Medicine, University of Southampton, Southampton SO9 3TU United Kingdom
GUT (United Kingdom), 1991, 32/10 (1151-1155)
The incorporation of the fatty acids in fish and olive oil into the colonic mucosa of patients with inflammatory bowel disease was examined during 12 weeks' dietary supplementation with the oils, and the influence on colonic mucosal prostaglandin and thromboxane generation was measured. With a dietary supplement of 18 g fish oil daily, concentrations of the major polyunsaturated fatty acids in fish oil, eicosapentaenoic acid and docosahexaenoic acid, were significantly raised in mucosal lipids. The first time these were measured, after three weeks' supplementation, the mean increases in eicosapentaenoic and docosahexaenoic acid were seven fold and 1.5 fold respectively, and these increases were maintained during the 12 week study. Arachidonic acid values fell throughout the study and this reduction was significant at 12 weeks. Mucosal prostaglandin E2 (PGE2), thromboxane B2, and 6-keto prostaglandin F(1alpha) synthesis were suppressed, and this reached significance (p < 0.05) at three and 12 weeks for PGE2 and at 12 weeks for thromboxane B2. The predominant fatty acid in olive oil is oleic acid. Supplementation with 18 g/day resulted in a significant increase in oleic acid in colonic mucosa at 12 weeks (p < 0.05) and a fall in stearic acid and docosahexaenoic acid; there was no significant change in eicosanoid synthesis. It is concluded that colonic lipids and prostaglandin and thromboxane synthesis can be readily altered by dietary supplementation with fish oil. The extent of incorporation of the fatty acids present in oils is dependent upon the individual fatty acid.
Fish oil may impede tumour angiogenesis and invasiveness by down-regulating protein kinase C and modulating eicosanoid production
Medical Hypotheses (United Kingdom), 1996, 46/2 (107-115)
Inhibition of angiogenesis shows considerable promise as a strategy for treating solid malignancies. Induction of collagenase by protein kinase C plays an important role in the angiogenic process as well as in metastasis. Lipoxygenase products are required for endothelial cell mitosis, and also promote collagenase production. By down-regulating hormonal activation of protein kinase C and modulating eicosanoid metabolism, ingestion of omega-3-rich fish oils may impede angiogenesis and reduce tumor invasiveness - thus rationalizing the growth-retardant and anti-metastatic effects of fish oil feeding almost invariably seen in animal tumour models. Certain other anti-inflammatory agents - including cromolyn (an inhibitor of protein kinase C activation) and gamma-linolenic acid (which indirectly inhibits lipoxygenase) may have analogous tumour-retardant activity. Clinical application of supplemental fish oil in cancer therapy is long overdue.
Fat, fish, fish oil and cancer
British Journal of Cancer (United Kingdom), 1996, 74/1 (159-164)
There is an ecological association between total and animal fat consumption and colorectal and breast cancer risk. Mortality data for breast and colorectal cancer for 24 European countries correlated, as expected, with the consumption of animal, but not vegetable, fat. There was an inverse correlation with fish and fish oil consumption, when expressed as a proportion of total or animal fat, and this correlation was significant for both male and female colorectal cancer and for female breast cancer, whether the intakes were in the current time period, or 10 years or 23 years before cancer mortality. These effects were only seen in countries with a high ( > 85 g caput-1 day-1) animal fat intake. This evidence suggests that fish oil consumption is associated with protection against the promotional effects of animal fat in colorectal and breast carcinogenesis.
Effect of dietary supplementation with omega-3 fatty acids on MED
Nouvelles Dermatologiques (France), 1996, 15/5 (369-371)
Objectives: Exposure of skin to ultraviolet radiation produces short and long term responses: erythema, pigmentation, carcinogenesis, photoaging. Studies indicate that a dietary lipid rich in omega-3 fatty acids results in a reduction of UVB-erythemal sensitivity and protects against photocarcinogenesis. The aim of this study was to determine influence of a dietary lipid rich in omega-3 fatty acids on MED and free radicals production. Methods: In an open study, 20 Caucasian volunteers took 100 mg eicosapentaenoic acid and 720 mg docosahexaenoic acid each day during 3 weeks M.E.D., plasmatic lipids, malondialdehyde (MDA), beta carotene and reduced glutathion were measured before and after fish oil therapy. Results: Omega-3/omega-6 increased except for arachidonic acid. The increase of M.E.D. was not significant. MDA increased significantly, while beta carotene and reduced glutathion decreased. Conclusion: In this study, dietary fish oil supplementation did not protect significantly skin from ultraviolet radiation. But free radicals production was increased, a better antioxidative protection should be associated.
Arachidonic and docosahexanoic acid content of bovine brain myelin: Implications for the pathogenesis of multiple sclerosis
NEUROCHEM. RES. (USA), 1990, 15/1 (7-11)
Lipids were extracted from bovine brain myelin using a mixture of hexane and isopropanolol (3:2). Myelin lipids were resolved, using Sep Pak chromatography, into four fractions: Fraction 1 contained neutral lipids, fraction 2, free fatty acids, fraction 3, ethanolamine phospholipids and fraction 4, choline phospholipids. Docosahexanoic (DHA) and arachidonic (AA) acids in these fractions were measured by RPHPLC. Fraction 2 was analyzed directly, the other three fractions were subjected to alkaline hydrolysis before analysis for DHA and AA. DHA and AA were not found in fraction 1. Both DHA and AA were found in fractions 2 and 3. Only AA was consistently found in fraction 4. These results were confirmed by GC.
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.)
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.
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.
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.
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.
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.
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.
Exposure to the n-3 polyunsaturated fatty acid docosahexaenoic acid impairs alpha1-adrenoceptor-mediated contractile responses and inositol phosphate formation in rat cardiomyocytes
Naunyn-Schmiedeberg's Archives of Pharmacology (Germany), 1996, 354/2 (109-119)
The beneficial effects of n-3 polyunsaturated fatty acids of fish oil in the prevention of fatal arrhythmias in myocardial ischemia were suggested to be at least in part mediated by a modulation of dihydropyridine-sensitive L-type calcium channels. As cardiac alpha1-adrenoceptor stimulation has been suggested to have no significant effect on L-type calcium channels, the aim of this study using cultured neonatal rat cardiomyocytes was to investigate whether chronic n-3 polyunsaturated fatty acid exposure may have an influence on alpha1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias. Pretreatment of the rat cardiomyocytes for 3 days in the presence of the n-3 polyunsaturated fish oil-derived fatty acid docosahexaenoic acid (60 micromol/l) markedly decreased alpha1-adrenoceptor-stimulated increase in contraction velocity and induction of arrhythmias. The increase in contraction velocity of the cardiomyocytes induced by the beta-adrenoceptor agonist isoprenaline was also markedly reduced by the n-3 fatty acid pretreatment. Basal contractile amplitude and spontaneous beating frequency of the cardiomyocytes were not significantly altered by the docosahexaenoic acid exposure. The pretreatment of the rat cardiomyocytes for 3 days in the presence of docosahexaenoic acid (60 micromol/l) decreased alpha1-adrenoceptor-stimulat ed formation of the calcium-mobilizing second messenger IP3 and its metabolites IP2 and IP1 by 55%. The depression of IP3 formation by docosahexaenoic acid treatment was not mediated by a decreased uptake of myo-inositol into the cardiomyocytes nor by a decreased synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of phospholipase C. The level of glycerol-3-phosphate, an important substrate of the phosphoinositide cycle, was unaltered by the docosahexaenoic acid pretreatment. Receptor binding studies revealed that the dissociation constant and maximal binding capacity of the alpha1-adrenoceptor antagonist (3H)prazosin was unchanged by the n-3 polyunsaturated fatty acid exposure. beta-Adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were not diminished by the docosahexaenoic acid pretreatment. Chronic exposure of the cardiomyocytes to the n-6 polyunsaturated fatty acid arachidonic acid (60 micromol/l) did neither significantly alter alpha1-adrenoceptor-induced inositol phosphate formation nor alpha1-adrenoceptor-stimulated increase in contraction velocity. The results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat cardiomyocytes leads to a marked impairment of alpha1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation. This derangement of the phosphoinositide pathway by chronic n-3 fatty acid exposure may, thus, contribute to the beneficial effects of fish oil-derived fatty acids in the prevention of fatal arrhythmias in myocardial ischemia.
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.)
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)
The fatty acid composition of human gliomas differs from that found in nonmalignant brain tissue
Lipids (USA), 1996, 31/12 (1283-1288)
To compare the fatty acid composition of tumor tissue from glioma patients with that of normal brain tissue, tissue samples were obtained from 13 glioma patients and from 3 nonmalignant patients. Following lipid extraction, total fatty acid composition was measured using gas liquid chromatography. Samples were further separated into phospholipids and neutral lipids. Representative samples were then separated into phospholipid classes by thin-layer chromatography and the fatty acid composition assayed. Levels of the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA), were significantly reduced (P= 0.029) in the glioma samples compared with normal brain samples; mean values were 4.8 plus or minus 2.9% and 9.2 plus or minus 1.0%, respectively. This reduction in glioma DHA content was also observed in terms of phospholipids (4.6 plus or minus 2.1% vs. 9.6 plus or minus 0.8%, P = 0.002). The phosphatidylserine and phosphatidylethanolamine phospholipid classes were reduced in the glioma samples. Differences were also noted in the n-6 PUFA content between glioma and normal brain samples. The glioma content of the n-6 PUFA linoleic acid was significantly greater (P < 0.05) than that observed in the control samples in terms of total lipids. Thus, the fatty acid composition of human gliomas differs from that found in nonmalignant brain tissue.
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.
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.
Incorporation of long-chain n-3 fatty acids in tissues and enhanced bone marrow cellularity with docosahexaenoic acid feeding in post-weanling Fischer 344 rats
Lipids (USA), 1997, 32/3 (293-302)
We wanted to examine the effects of an oil rich in docosahexaenoic acid (DHA), without eicosapentaenoic acid, on the composition of membrane phospholipid in a variety of tissues. Our in vitro studies had previously shown that DHA could modify glucose and nucleoside transport in cells in culture and also increase selectivity of the nucleoside drug, arabinosylcytosine (araC) toward tumor cells. Here we wanted to examine what effect DHA supplementation would have in the whole animal in terms of the chemosensitivity of normal bone marrow, the dose-limiting tissue during chemotherapy, to araC. The purpose was to determine whether fatty acid supplementation might be useful as an adjuvant to chemotherapy. We fed diets containing 5% (w/w) low fat-corn oil (LF-CO group), 10% moderate fat-safflower oil (MF-SO group), or 10% DHASCO(TM) (MF-DHA group) to weanling Fischer 344 rats for 8-9 wk. Feed intake and growth were not different between the different diets. Similarly, treatment of animals with the chemotherapeutic drug araC did not differentially affect growth, feed intake, or tissue fatty acid composition for the different diet groups. Fatty acid compositions of bone marrow, liver, red blood cells, and cardiac muscle, were substantially different between the dietary groups. The DHASCO(TM) oil contained 46%DHA (22:6n-3) and resulted in profound incorporation of DHA in all tissues examined. The most dramatic response was seen in skeletal muscle of MF-DHA fed animals where DHA represented 46% of membrane phospholipid fatty acids. This is likely to have consequences to muscle function. Although DHASCO(TM) contains a similar level of saturated fatty acids (42%), few differences in saturates were noted between the various dietary groups for most of the tissues examined. Both LF-CO and MF-SO diets were hypercholesterolemic, and the LF-CO was also hypertriglyceridemic compared to the chow-fed animals. Animals fed the MF-DHA diet had the lowest triglyceride levels of any of the treatment groups and cholesterol levels comparable to chow-fed animals. MF- DHA had substantially higher numbers of colony-forming units-granulocyte macrophage (CFU-GM) as reflected in a twofold higher bone marrow cellularity than either chow or LF-CO animals, suggesting expansion of the bone marrow compartment with DHA feeding. Although higher than LF-SO, the number of CFU- GM in MF-SO animals was not significantly higher than animals fed chow. Bone marrow from LF-CO animals appeared to be more resistant to araC treatment than either MF group. Thus, DHA, fed as DHASCO(TM), has advantages over low or moderate n-6 diets and chow as it is has both hypolipidemic- and bone marrow enhancing properties in weanling Fischer 344 rats. This suggests that DHA supplementation may be useful in adjuvant chemotherapy.
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.
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.
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.
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.
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.
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.
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.
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.
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.