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Fish Oil

Table of Contents

image Change of fatty acid composition, platelet aggregability and RBC function in elderly subjects with administration of low dose fish oil concentrate and comparison with those in younger subjects
image Inhibition of phagocyte-endothelium interactions by oxidized fatty acids: a natural anti-inflammatory mechanism?
image On the causes of multiple sclerosis
image Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence (a viewpoint). I.: Sunlight, dietary factors and epidemiology
image Biological effects of fish oils in relation to chronic diseases.
image Red blood cell and adipose tissue fatty acids in mild inactive multiple sclerosis.
image Magnesium taurate and fish oil for prevention of migraine.
image Nonpharmacologic treatment of hypertension.
image Fish oils modulate blood pressure and vascular contractility in the rat and vascular contractility in the primate
image Effects of fish oil, nifedipine and their combination on blood pressure and lipids in primary hypertension.
image Effects of a combination of evening primrose oil (gamma linolenic acid) and fish oil (eicosapentaenoic + docahexaenoic acid) versus magnesium, and versus placebo in preventing pre-eclampsia.
image Microbial infection or trauma at cardiovascular representation area of medulla oblongata as some of the possible causes of hypertension or hypotension.
image Fish oil and other nutritional adjuvants for treatment of congestive heart failure
image Dietary (n-3) fatty acids increase superoxide dismutase activity and decrease thromboxane production in the rat heart.
image Effects of n-3 fatty acids and fenofibrate on lipid and hemorrheological parameters in familial dysbetalipoproteinemia and familial hypertriglyceridemia.
image Repeated fasting and refeeding with 20:5, n-3 Eicosapentaenoic Acid (EPA): A novel approach for rapid fatty acid exchanges and its effect on blood pressure, plasma lipids and hemostasis.
image Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease.
image The protective effects of dietary fish oil on focal cerebral infarction
image Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders.
image The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer
image Modulation of antioxidant enzymes and programmed cell death by n-3 fatty acids
image Dietary marine lipids suppress continuous expression of interleukin-1beta gene transcription
image Tissue specific regulation of transforming growth factor beta by omega-3 lipid-rich krill oil in autoimmune murine lupus
image The effects of dietary lipid manipulation on the production of murine T cell-derived cytokines
image Dietary omega-3 lipids delay the onset and progression of autoimmune lupus nephritis by inhibiting transforming growth factor beta mRNA and protein expression
image Fish oil feeding modulates leukotriene production in murine lupus nephritis
image Effects of n-3 and n-6 fatty acids on the activities and expression of hepatic antioxidant enzymes in autoimmune-prone NZBxNZW F1 mice
image Increased TGF-beta and decreased oncogene expression by omega-3 fatty acids in the spleen delays onset of autoimmune disease in B/W mice
image Decreased pro-inflammatory cytokines and increased antioxidant enzyme gene expression by omega-3 lipids in murine lupus nephritis
image Suppression of autoimmune disease by dietary n-3 fatty acids
image Role of omega-3 fatty acids in health and disease
image Dietary marine lipids suppress murine autoimmune disease
image Depression of humoral responses and phagocytic functions in vivo and in vitro by fish oil and eicosapentanoic acid
image The type of dietary fat affects the severity of autoimmune disease in NZB/NZW mice
image Effects of dietary supplementation on autoimmunity in the MRL/lpr mouse: A preliminary investigation
image A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice
image The protective effect of dietary fish oil on murine lupus
image [Use of the fish oil "Polyen" in pediatric practice]
image The effect on human tumor necrosis factor alpha and interleukin 1beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil
image Validation of a meta-analysis: The effects of fish oil in rheumatoid arthritis
image n-3 Polyunsaturated fatty acids: Update 1995
image Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis-a double-blind placebo controlled study.
image Association of etretinate and fish oil in psoriasis therapy. Inhibition of hypertriglyceridemia resulting from retinoid therapy after fish oil supplementation.
image Effects of dietary fish oil lipids on allergic and inflammatory diseases.
image Omega-3 fatty acids in health and disease and in growth and development
image The effect of dietary fish oil supplement upon the content of dihomo-gammalinolenic acid in human plasma phospholipids.
image Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis.
image A double-blind placebo controlled trial of Efamol Marine on skin and joint symptoms of psoriatic arthritis.
image Fish-oil fatty acid supplementation in active rheumatoid arthritis. A double-blinded, controlled, crossover study.
image The cardiovascular protective role of docosahexaenoic acid
image Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action
image Omega3 fatty acids in the prevention-management of cardiovascular disease Simopoulos A.P.
image Dietary fish oil: Influence on lesion regression in the porcine model of atherosclerosis
image Enhanced capacity of n-3 fatty acid-enriched macrophages to oxidize low density lipoprotein mechanisms and effects of antioxidant vitamins
image Fish oil supplementation in patients with heterozygous familial hypercholesterolemia
image Increased serum level of total homocysteine in CAPD patients: Despite fish oil therapy
image Effects of interaction of RRR-alpha-tocopheryl acetate and fish oil on low-density-lipoprotein oxidation in postmenopausal women with and without hormone-replacement therapy
image Platelets, carotids, and coronaries. Critique on antithrombotic role of antiplatelet agents, exercise, and certain diets.
image [Changes in fatty acid composition, platelet aggregability and RBC function in elderly subjects with administration of low-dose fish oil concentrate and comparison with younger subjects]
image Do fish oils prevent restenosis after coronary angioplasty?
image n-3 fatty acid incorporation into LDL particles renders them more susceptible to oxidation in vitro but not necessarily more atherogenic in vivo.
image Nutrition in inflammatory bowel disease
image Nutrition and gastrointestinal disease
image Dietary fiber and gastrointestinal disease The role of short-chain fatty acid metabolism in colonic disorders
image Nutritional issues in pediatric inflammatory bowel disease
image The starved colon - Diminished mucosal nutrition, diminished absorption, and colitis
image Nutrition and ulcerative colitis
image An enteral formula containing fish oil, indigestible oligosaccharides, gum arabic and antioxidants affects plasma and colonic phospholipid fatty acid and prostaglandin profiles in pigs
image Influence of nutrition in ulcerative colitis - The significance of nutritional care in inflammatory bowel disease
image Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis
image The role of marine fish oils in the treatment of ulcerative colitis
image Fish oil fatty acid supplementation in active ulcerative colitis: A double-blind, placebo-controlled, crossover study
image Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: A randomised, placebo controlled trial
image Special issues in nutritional therapy of inflammatory bowel disease
image A randomized controlled study of evening primrose oil and fish oil in ulcerative colitis
image Treatment of ulcerative colitis with fish oil supplementation: A prospective 12 month randomised controlled trial
image Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease
image Fish oil may impede tumour angiogenesis and invasiveness by down-regulating protein kinase C and modulating eicosanoid production
image Fat, fish, fish oil and cancer
image Effect of dietary supplementation with omega-3 fatty acids on MED
image Arachidonic and docosahexanoic acid content of bovine brain myelin: Implications for the pathogenesis of multiple sclerosis
image Summary of the NATO advanced research workshop on dietary omega 3 and omega 6 fatty acids: biological effects and nutritional essentiality.
image Vasorelaxant properties of n-3 polyunsaturated fatty acids in aortas from spontaneously hypertensive and normotensive rats.
image Eicosapentaenoic acid, but not docosahexaenoic acid, increases mitochondrial fatty acid oxidation and upregulates 2,4-dienoyl-CoA reductase gene expression in rats.
image Improvement by eicosanoids in cancer cachexia induced by LLC-IL6 transplantation
image Docosahexaenoic and eicosapentaenoic acids inhibit human lymphoproliferative responses in vitro but not the expression of T cell surface activation markers
image Omega-3 polyunsaturated fatty acids: A potential new treatment of immune renal disease
image Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation
image Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network.
image Exposure to the n-3 polyunsaturated fatty acid docosahexaenoic acid impairs alpha1-adrenoceptor-mediated contractile responses and inositol phosphate formation in rat cardiomyocytes
image Omega-3 fatty acids and prevention of ventricular fibrillation.
image N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells.
image Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease.
image The fatty acid composition of human gliomas differs from that found in nonmalignant brain tissue
image The effect of unsaturated fatty acids on membrane composition and signal transduction in HT-29 human colon cancer cells
image 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
image Suppression of nitric oxide production in lipopolysaccharide-stimulated macrophage cells by omega3 polyunsaturated fatty acids
image 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
image Demonstration of organotropic effects of chemopreventive agents in multiorgan carcinogenesis models.
image Long-term effects of eicosapentaenoic acid on diabetic peripheral neuropathy and serum lipids in patients with type II diabetes mellitus
image Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia
image Comparison of the effectiveness of eicosapentaenoic acid administered as either the free acid or ethyl ester as an anticachectic and antitumour agent
image Kinetics of the inhibition of tumour growth in mice by eicosapentaenoic acid-reversal by linoleic acid
image Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover
image Altered fatty acid, cholesterol and Na+/K+ ATPase activity in erythrocyte membrane of rheumatoid arthritis patients.
image Health effects and metabolism of dietary eicosapentaenoic acid.
image [Potential value of eicosapentaenoic acid]
image 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?
image Effects of 11-week increases in dietary eicosapentaenoic acid on bleeding time, lipids, and platelet aggregation.
image Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vivo
image Dietary fats and coronary heart disease
image Eicosapentaenoic acid (C20:5) augments glucose-induced insulin secretion from beta-TC3 insulinoma cells

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Change of fatty acid composition, platelet aggregability and RBC function in elderly subjects with administration of low dose fish oil concentrate and comparison with those in younger subjects

JPN. J. GERIATR. (Japan), 1994, 31/8 (596-603)

Anti-thrombotic and anti-atherogenic effects of eicosapentaenoic acid (EPA) through the modulation of various cell functions related to thrombogenesis have been reported recently. We previously reported that the administration of EPA at low doses could more effectively elevate the plasma EPA concentration in elderly subjects than in younger ones. Magnetic resonance imaging examination of the brain often reveals lacunar lesions in elderly subjects without any signs or symptoms of cerebrovascular diseases. In this study we clarified the effect of administration of low doses of fish oil concentrate on platelet and RBC function in elderly subjects, compared with younger subjects. Thirty-six elderly subjects (mean age 78) without any signs or symptoms of cerebrovascular diseases, all receiving the same diet in the same lodging house for the aged, were divided into 3 groups. Different amounts of fish oil concentrate (0.25-0.5 g/day of EPA) were administered to the 3 groups, daily for more than 1 month. Changes of plasma fatty acid composition, platelet aggregability, whole blood viscosity and RBC deformability was examined before and after EPA administration. One month after EPA treatment, the plasma EPA content had increased dose dependently, with suppression of platelet aggregation and improvement of RBC function. In younger subjects receiving the same amount of EPA, the elevation of plasma EPA was less than that observed in the elderly. In summary, low dose EPA administration can improve the function of platelet and RBC to an anti-thrombotic state and would be useful to prevent the occurrence of cerebrovascular diseases in elderly subjects without any side effects.



Inhibition of phagocyte-endothelium interactions by oxidized fatty acids: a natural anti-inflammatory mechanism?

Sethi S; Eastman AY; Eaton JW

Division of Experimental Pathology, Albany Medical College, NY, USA.

J Lab Clin Med (UNITED STATES) Jul 1996, 128 (1) p27-38

Diets rich in marine fish oil may protect against cardie not known, fish oils have been reported to exert anti-inflammatory actions. For example, dietary fish oil supplementation was observed to profoundly decrease the numbers of monocytic cells adherent to endothelium overlying atherosclerotic lesions in pigs. We have therefore investigated the possibility that fish oil components-particularly n-3 polyunsaturated fatty acids (PUFAs)-might inhibit phagocyte-endothelium interactions. We have found that binding of a monocytic cell line (U937) to cultured endothelium (with cell adhesion molecules up-regulated by exposure to lipopolysaccharide (LPS), interleukin-1 alpha, tumor necrosis factor-alpha, or phorbol myristate acetate (PMA) is greatly decreased by pre-exposure of endothelial cells to n-3 and other PUFAs that are incidentally or purposefully oxidized; unoxidized PUFAs are completely ineffective. Decreased monocyte adherence probably derives from diminished up-regulation of endothelial cell adherence molecules VCAM-1 and ELAM-1. Oxidized n-3 PUFAs prevent LPS- or PMA-induced activation of transcription factor NF-kappa B and the consequent induction of mRNA for both cell adhesion molecules. Hydroperoxy fatty acids are the active principle in oxidized PUFAs because the activity (1) is predominantly organic soluble, (2) is obliterated by pretreatment of oxidized material with chemical reducing agents, and (3) is diminished by enzymatic reduction of organic hydroperoxides with glutathione/glutathione peroxidase. We speculate that this suppression of phagocyte-endothelium interactions by oxidized PUFAs may help explain the anti-inflammatory and possible anti-atherogenic effects of diets rich in fish oil. Perhaps more importantly, this modulation of endothelial cell adhesion molecule expression by oxidized lipids may represent a natural mechanism whereby inflammation-mediated oxidation of endothelial PUFAs may retard ingress of phagocytes and thereby prevent unrestrained phlogistic responses.



On the causes of multiple sclerosis

MED. HYPOTHESES (United Kingdom), 1993, 41/2 (93-96)

Evidence on aetiology in multiple sclerosis suggests that the prevalence depends on the interaction of two factors, diet and exposure to visible sunlight. The dietary features which may be beneficial include supplementation with fish oils, avoidance of saturated fats, and the associated intake of antioxidants with unsaturated fatty acids. Inhibition, by antioxidants, of the enzyme lipoxygenase inhibits leukotriene synthesis, and the presence of fish oils leads to the production of leukotrienes with less inflammatory properties. This is of particular importance in the retina where leukotrienes might be the underlying cause of retrobulbar neuritis. The antioxidant properties of vitamin A may also lead to inhibition of leukotriene synthesis. Visible solar radiation could be of benefit therefore by releasing vitamin A from visual pigment rhodopsin. The interaction ot these two factors may explain the epidemiological observations on the prevalence of multiple sclerosis.



Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence (a viewpoint). I.: Sunlight, dietary factors and epidemiology

INT.J.ENVIRON.STUD. (ENGLAND), 1974, 6/1 (19-27)

A new theory for the etiology of multiple sclerosis (MS) has been developed which is compatible with epidemiologic, biochemical and genetic evidence. A predisposition for the disease is held to result from the development of abnormal myelin during puberty. Vitamin D and calcium are proposed as being essential for normal myelination. Curtailed supplies of these substances (from inadequate sunlight and phytate rich diets) correlate with geographic regions of high risk of MS. Conversely the prevalence of MS is lower where vitamin D is abundant, as in sunny climates, high altitudes, and littorals with dietaries rich in fish oils.



Biological effects of fish oils in relation to chronic diseases.

Lipids (UNITED STATES) Dec 1986, 21 (12) p731-2

The low incidence of cardiovascular disease in Greenland Eskimos appears to be due to their high intake of seal, whale and fish. The lipids of these marine animals lower serum triglyceride and cholesterol levels and help to prevent blood clotting. The latter effect has been related to a change in the balance of prostacyclin and thromboxane as a result of replacing n-6 polyunsaturated fatty acids in the body by n-3 polyunsaturated fatty acids present in marine lipids. Dietary fish oils have also been shown to inhibit development of mammary, pancreatic, intestinal and prostatic tumors in experimental animals. This effect may likewise be due to changes in the production of prostaglandins or related compounds. The involvement of prostaglandins and leukotrienes in immune responses has led to studies on the effects of fish oil on various chronic diseases associated with abnormalities of the immune system. Some of these diseases, such as multiple sclerosis and psoriasis, are also relatively uncommon in Eskimos. Preliminary results of these studies are encouraging, but more work is required to assess the usefulness of dietary fish oils in treatment of these diseases. In addition to their apparent therapeutic value, n-3 fatty acids are considered essential dietary components since they cannot be synthesized in the body and appear necessary for normal vision and probably other body functions.



Red blood cell and adipose tissue fatty acids in mild inactive multiple sclerosis.

Acta Neurol Scand (DENMARK) Jul 1990, 82 (1) p43-50

The fatty acid profiles of phosphatidyl ethanolamine (PE) and phosphatidyl choline (PC) of the red blood cells of 30 patients with mild inactive multiple sclerosis (MS) and 30 healthy controls were studied by gas chromatography. The groups were well matched for factors likely to influence tissue lipid levels, including diet. The MS patients showed a significant reduction in PE eicosapentaenoic acid (p = 0.009) especially in women, and an increase in both PE dihomo-gamma-linolenic acid (p = 0.004) and PC stearic acid (p = 0.04). No reduction in linoleic acid was observed in either the PC or PE fractions of the MS subjects. A similar study of the fatty acid profile in adipose tissue in 26 MS and 35 healthy controls found no detectable eicosapentaenoic acid in either group. However, whereas docosahexaenoic acid was not detectable in any MS patient, 40% of the controls had measurable levels varying from to 0.1 to 0.3% of total estimated fatty acid (p = 0.0003). No reduction in linoleic acid in MS subjects was observed. Supplementation with oral fish body oil demonstrated that n-3 fatty acids were incorporated into red blood cells over 5 weeks and this occurred equally in MS and controls. The effects of oral supplementation on adipose tissue were studied after 1 and 2 years. Whereas many fatty acids such as linoleic acid were raised at 1 year, but did not rise subsequently, eicosapentaenoic acid and docosahexaenoic acid continued to rise through the 2-year period.(ABSTRACT TRUNCATED AT 250 WORDS)



Magnesium taurate and fish oil for prevention of migraine.

Med Hypotheses (ENGLAND) Dec 1996, 47 (6) p461-6

Although the pathogenesis of migraine is still poorly understood, various clinical investigations, as well as consideration of the characteristic activities of the wide range of drugs known to reduce migraine incidence, suggest that such phenomena as neuronal hyperexcitation, cortical spreading depression, vasospasm, platelet activation and sympathetic hyperactivity often play a part in this syndrome. Increased tissue levels of taurine, as well as increased extracellular magnesium, could be expected to dampen neuronal hyperexcitation, counteract vasospasm, increase tolerance to focal hypoxia and stabilize platelets; taurine may also lessen sympathetic outflow. Thus it is reasonable to speculate that supplemental magnesium taurate will have preventive value in the treatment of migraine. Fish oil, owing to its platelet-stabilizing and antivasospastic actions, may also be useful in this regard, as suggested by a few clinical reports. Although many drugs have value for migraine prophylaxis, the two nutritional measures suggested here may have particular merit owing to the versatility of their actions, their safety and lack of side-effects and their long-term favorable impact on vascular health. (94 Refs.)



Nonpharmacologic treatment of hypertension.

Curr Opin Nephrol Hypertens (UNITED STATES) Oct 1992, 1 (1) p85-90

A variety of lifestyle modifications will lower both the blood pressure and various other cardiovascular risk factors that are frequently present in patients with hypertension. Numerous recent studies document the overall efficacy of some (weight reduction, sodium restriction, physical activity, moderation of alcohol) and the relative lack of effect of others (stress management and calcium, magnesium, and fish oil supplements). In particular, the Trials of Hypertension Prevention, Phase I (a control trial funded by the National Heart, Lung, and Blood Institute) provides important new data on the ability of these various modalities to prevent the development of hypertension, an equally or even more important goal than the reduction of already-established disease. (32 Refs.)



Fish oils modulate blood pressure and vascular contractility in the rat and vascular contractility in the primate

Blood Press (NORWAY) May 1995, 4 (3) p177-86

The effect of dietary fish oils on development of hypertension and vascular response in vitro were studied in rats and a primate. Dietary fish oils (MaxEPA and an n-3 ethyl ester concentrate of higher EPA and DHA content) were administered to spontaneously hypertensive (SHR), stroke-prone spontaneously hypertensive (SHR-SP) and a backcross of SHR and Wistar Kyoto (SHR/WKY) rats from 4-16 weeks of age. Blood pressure was monitored during the feeding period and vascular responses measured in the aorta and mesenteric vascular bed in vitro. Depending on the strain of rat used and the composition of the fish oil the attenuation in blood pressure was 10-26 mmHg. Fish oils attenuated the response mediated by sympathetic nerve stimulation or intralumenal norepinephrine in the perfused mesenteric vascular bed preparation from the SHR. This attenuation was more pronounced for fish oils enriched with eicosapentaenoic acid and docosahexaenoic acid and was more prominent in the SHR and SHR/WKY backcross than it was in the SHR-SP. Prostanoid synthesis or nitric oxide modulation of alpha-adrenoceptor responses were shown not to be involved in the attenuation of vascular responses produced by fish oil. The maximum contraction of aortic ring preparations in response to norepinephrine (NE) was significantly smaller in SHR than WKY rats fed olive oil and for SHR rats maintained on fish oils the contraction was close to WKY olive oil values. Evidence was obtained also for a modulation of vasoconstrictor responses by dietary fish oils in the perfused mesenteric bed of the marmoset monkey.



Effects of fish oil, nifedipine and their combination on blood pressure and lipids in primary hypertension.

J Hum Hypertens (ENGLAND) Feb 1993, 7 (1) p25-32

In a double-blind, crossover, placebo-controlled study the effects of four weeks' treatment with 4.55 g/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on BP and serum lipids were assessed in 18 males with hypertension (WHO stage I-II). At the end of the double-blind phase, eight patients on placebo (olive oil) and ten patients on fish oil treatment were given nifedipine 20 mg twice daily added to their regimens for four weeks. Four weeks' fish oil treatment slightly reduced BP values; however, compared with placebo no changes were found. VLDL-cholesterol and triglycerides were significantly reduced by 24%, whereas total and LDL-cholesterol remained unchanged. Placebo did not change BP and lipid values. When nifedipine was added to fish oil/placebo, BP in the two groups was reduced to almost the same extent. When nifedipine was added to fish oil, total cholesterol was significantly reduced by 12% in comparison with baseline value and LDL-cholesterol was reduced by 15%, albeit insignificantly. Placebo plus nifedipine was lipid neutral. A significant correlation was found between the nifedipine-induced changes in supine mean arterial pressure and total, LDL- and VLDL-cholesterol, respectively, in those patients with and without fish oil treatment. In conclusion, the combined administration of fish oil and nifedipine possesses favourable antihypertensive and metabolic properties in hypertensive males with elevated lipid levels.



Effects of a combination of evening primrose oil (gamma linolenic acid) and fish oil (eicosapentaenoic + docahexaenoic acid) versus magnesium, and versus placebo in preventing pre-eclampsia.

Women Health (UNITED STATES) 1992, 19 (2-3) p117-31

In a placebo controlled, partially double-blinded, clinical trial, a combination of evening primrose oil and fish oil was compared to Magnesium Oxide, and to a Placebo in preventing Pre-Eclampsia of Pregnancy. All were given as nutritional supplements for six months to a group of primiparous and multiparous pregnant women. Some of these women had personal or family histories of hypertension (21%). Only those patients who received prenatal care at the Central Maternity Hospital for Luanda were included in the study. Compared to the Placebo group (29%), the group receiving the mixture of evening primrose oil and fish oil containing Gamma-linolenic acid (GLA), Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA) had a significantly lower incidence of edema (13%, p = 0.004). The group receiving Magnesium Oxide had statistically significant fewer subjects who developed hypertension of pregnancy. There were 3 cases of eclampsia, all in the Placebo group.



Microbial infection or trauma at cardiovascular representation area of medulla oblongata as some of the possible causes of hypertension or hypotension.

Acupunct Electrother Res (UNITED STATES) 1988, 13 (2-3) p131-45

The author found that the onset of hypertension or hypotension is relatively often associated with infections or development of so-called "sneezing due to allergy to pollen or dust," with or without headache, or due to trauma to the occipital area of the head. Using the "Bi-Digital O-ring Test," it was possible to demonstrate that, among bacterial and viral infections, the most common cause of infection associated with the appearance of hypertension is chlamydia, herpes simplex virus, cytomegalovirus, or Epstein-Barr virus. Particularly chlamydia and/or herpes simplex virus, with or without coexistence of other microbes, is usually present at the heart representation area of the medulla oblongata, especially at the left ventricular representation area, often accompanied by upper respiratory infection, cephalic, cervical or facial pain, with or without coexisting genito-urinary infection. The left ventricular representation area of the medulla oblongata is usually located at the right side. In most hypertensive patients, the left ventricular representation area of the medulla oblongata is enlarged up to 3 or 4 times normal size. Sufficient antibiotic treatment of chlamydia with erythromycin sometimes eliminated severe hypertension which appeared after chlamydia infection. In the presence of viral infections, such as herpes simplex, which is also causing severe pain in the head or neck, oral administration of acyclovir, erythromycin, or EPA (Eicosa Pentaenoic acid)-DHA (docosa hexaenoic acid) Omega 3 fish oil often reduced associated intractable pain and hypertension toward the normal level. Thus, the author is proposing new possible mechanisms as among the causes of so-called essential hypertension as a result of microbial infection or trauma of the cardiovascular representation area, particularly that of the left ventricular representation area at the right side of the medulla oblongata.



Fish oil and other nutritional adjuvants for treatment of congestive heart failure

Medical Hypotheses (United Kingdom), 1996, 46/4 (400-406)

Published clinical research, as well as various theoretical considerations, suggest that supplemental intakes of the 'metavitamins' taurine, coenzyme Q10, and L-carnitine, as well as of the minerals magnesium, potassium, and chromium, may be of therapeutic benefit in congestive heart failure. High intakes of fish oil may likewise be beneficial in this syndrome. Fish oil may decrease cardiac afterload by an antivasopressor action and by reducing blood viscosity, may reduce arrhythmic risk despite supporting the heart's beta-adrenergic responsiveness, may decrease fibrotic cardiac remodeling by impeding the action of angiotensin II and, in patients with coronary disease, may reduce the risk of atherothrombotic ischemic complications. Since the measures recommended here are nutritional and carry little if any toxic risk, there is no reason why their joint application should not be studied as a comprehensive nutritional therapy for congestive heart failure.



Dietary (n-3) fatty acids increase superoxide dismutase activity and decrease thromboxane production in the rat heart.

Luostarinen R.; Wallin R.; Saldeen T.

Sweden

Nutrition Research (USA), 1997, 17/1 (163-175)

The aims of the present studies were to examine the effects of fish oil (containing (n-3) polyunsaturated fatty acids) on myocardial thromboxane and prostacyclin production, superoxide dismutase (SOD) activity and malondialdehyde (MDA) production in the rat. Male rats were fed standard pellet diets and the same diets enriched with 7% (w/w) stabilized fish oil or 7% butter (saturated fat) for 2-6 wk. Myocardial production of thromboxane was lower in rats given fish oil than in those fed standard pellets (P < 0.01) or saturated fat (P < 0.05) and the prostacyclin/thromboxane ratio was higher than in rats fed standard pellets (P < 0.05). Myocardial SOD activity was higher in rats fed stabilized fish oil than in those given saturated fat (P < 0.05). Supplementation of the stabilized fish oil with extra vitamin E did not have any major effect on thromboxane and prostacyclin production or SOD activity. The percentage of arachidonic acid in the myocardial phospholipids was lower (P < 0.001) during fish oil than during saturated fat feeding, with no modifying effect of vitamin E supplementation. Feeding with the stabilized fish oil did not alter the myocardial alpha-tocopherol concentration, but the myocardial MDA concentration in vitro was higher (P < 0.01) than after feeding with saturated fat. Supplementation of the stabilized fish oil with extra vitamin E resulted in a higher alpha-tocopherol (P < 0.05) and lower MDA concentration (P < 0.05) in the myocardium compared to the unsupplemented fish oil. Plasma MDA concentration was not changed by fish oil feeding. In conclusion, fish oil feeding resulted in higher myocardial SOD activity and lower thromboxane production. These changes may be contributory mechanisms underlying the antiarrhythmic effect of fish oil.



Effects of n-3 fatty acids and fenofibrate on lipid and hemorrheological parameters in familial dysbetalipoproteinemia and familial hypertriglyceridemia.

Otto C.; Ritter M.M.; Soennichsen A.C.; Schwandt P.; Richter W.O.

Medical Department II, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, D-81366 Munich Germany

Metabolism: Clinical and Experimental (USA), 1996, 45/10 (1305-1311)

There is increasing evidence that hemorrheological abnormalities are associated with an enhanced risk of atherosclerosis. The n-3 fatty acids (n- 3-FA) have been shown to have beneficial effects on atherosclerosis in patients with dyslipoproteinemias. We studied 23 patients with elevated plasma triglycerides to evaluate the influence of fish oil and fenofibrate therapy on hemorrheological parameters (15 patients with familial hypertriglyceridemia (FHTG) and eight with familial dysbatalipoproteinemia (FDL)). The patients (one woman and 22 men aged 45.7 plus or minus 2.0 years) were treated with increasing doses of n-3-FA (1.8 to 3.6 g/d: 0.9 to 1.8 g eicosapentaenoic acid and 0.6 to 1.2 g docosahexaenoic acid) for 8 weeks. Lipid parameters, whole-blood viscosity at different shear rates, plasma viscosity, fibrinogen concentration, and red blood cell aggregation (RCA) were measured at baseline and at weeks 2, 4, g (end of n-3-FA therapy), and 12. Compliance was ensured by measuring plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid. After 12 weeks, patients began treatment with fenofibrate (250 mg daily); investigations were performed again at week 20. Total triglycerides (from 6.90 plus or minus 1.70 to 3.61 plus or minus 0.78 mmol/L in FDL and 7.44 plus or minus 1.50 to 4.15 plus or minus 0.55 in FHTG), very-low- density lipoprotein (VLDL) triglycerides, and VLDL cholesterol were significantly decreased with n-3-FA therapy in both groups (P < .05). In FHTG, low-density lipoprotein (LDL) cholesterol increased significantly (from 2.75 plus or minus 0.28 to 3.97 plus or minus 0.35 mmol/L, P < .01); in FDL, total cholesterol decreased (from 9.76 plus or minus 1.32 to 7.34 plus or minus 1.07 mmol/L, P < .05). No significant changes were observed in hemorrheological parameters, except for reduced RCA with 3.6 g n-3-FA in FHTG. However, with fenofibrate therapy, in addition to comparable lipoprotein changes seen with fish oil, fibrinogen levels and plasma and blood viscosity decreased in patients with FDL. We conclude that n-3-FA and fenofibrate have comparable effects on lipid parameters in patients with FDL and FHTG. Because of additional beneficial effects on hemorrheological parameters, fenofibrate may be preferred for the treatment of FDL.



Repeated fasting and refeeding with 20:5, n-3 Eicosapentaenoic Acid (EPA): A novel approach for rapid fatty acid exchanges and its effect on blood pressure, plasma lipids and hemostasis.

Yosefy C.; Viskoper J.R.; Varon D.; Ilan Z.; Pilpel D.; Lugassy G.; Schneider R.; Adan Y.; Raz A.

Department of Medicine B, Barzilai Medical Center, Ashkelon Israel

Journal of Human Hypertension (United Kingdom), 1996, 10/SUPPL. 3 (S135-S139)

Twenty hypertensive subjects participated in three clinical trials of 13 days each, to examine the effects of Alsepa fish oil (20:5, n-3 eicosapentaenoic acid (EPA) 180 mg, and 22:6 n-3 docosahexaenoic acid (DHA) 120 mg) on n-3 for n-6 polyunsaturated fatty acids (PUFA) exchange on serum phospholipids, blood pressure (BP), triglycerides (TG) and primary hemostasis. After 13 days, plasma phospholipids showed an increase in Sigman-3 (EPA and DHA) from 2.0 to 5.9% (P < 0.01), and a decrease in Sigman-6 (arachidonic acid and linoleic acid) from 29.8 to 22.6% (P < 0.01). A concomitantly significant reduction in systolic BP (SBP) (158.7 plus or minus 23.8 mmHg to 146.5 plus or minus 17.0 mmHg, P = 0.04), and diastolic BP (DBP) (80.8 plus or minus 8.4 mmHg to 72.9 plus or minus 14.9 mmHg, P = 0.04) as well as a significant decrease in platelet adhesion and aggregation on extra cellular matrix measured as a percentage of surface coverage (11.9 plus or minus 4.8% to 4.2 plus or minus 3.2%, P = 0.0001) was observed. In addition, a significant reduction in baseline dependent To was observed; the higher the baseline level TG, the more pronounced the reduction (average 159.2 plus or minus 74.6 mg% to 108.0 plus or minus 46.1 mg%, P = 0.001). No change was observed in total cholesterol, high and low density lipoprotein (HDL, LDL), platelet and fibrinogen. Repeated fasting and refeeding with fish oil facilitated plasma exchange of n-3 for n-6 PUFA, improved BP, clinical metabolic parameters and lowered platelet reactivity in the vessel wall (primary hemostasis). In severe and life-threatening situations, the beneficial effects of fish oil should be considered for rapid exchange of n-3 for n-6 PUFA. In this study we describe a novel approach for rapid fatty acid exchange by fasting/refeeding with fish oil supplementation, as well as improved BP, plasma lipids and primary hemostasis. Further research is required on the therapeutic use of fish oils and the physiological mechanisms involved in fatty acid exchange.



Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease.

Mori T.A.; Beilin L.J.; Burke V.; Morris J.; Ritchie J.

Dr. T.A. Mori, University Department of Medicine, Medical Research Foundation Building, Box X2213 GPO, Perth, WA 6001 Australia

Arteriosclerosis, Thrombosis, and Vascular Biology (USA), 1997, 17/2 (279-286)

Recent studies have suggested that omega3-fats of marine origin may have a protective role in heart disease. This study aimed to compare the effects of fish or fish oil, in the setting of a high- or low fat diet, on platelet aggregation and platelet thromboxane in men with increased risk of cardiovascular disease. One hundred twenty men who were nonsmokers, 30 to 60 years old, with mildly elevated blood pressure and cholesterol were randomly allocated to one of five high-fat (40% of daily energy) or two low-fat (30%) groups for 12 weeks. The five high fat groups took either 6 or 12 fish oil capsules daily; fish a combination of fish and fish oil; or placebo capsules. The two low-fat groups took either fish or placebo capsules. Fish meals provided 1.3 g of eicosapentaenoic acid daily, equivalent to 6 fish oil capsules, and contained an average of 3.65 g/d of omega3-fatty acids. Multiple regression analysis of the combined groups showed that all groups taking omega3- fatty acids reduced platelet aggregation to both collagen (P<.0001) and platelet activating factor (PAF) (P<.05) and platelet thromboxane B2 responses (P<.05) to collagen-induced aggregation. The low-fat diet alone had no effect on PAF-induced platelet aggregation and only a small effect on platelet responses to collagen (P<.05). Platelet aggregation responses to PAF were reduced more by fish oil than fish in a high-fat diet, whereas fish had a greater effect when part of a low-fat rather than a high-fat diet. There was no significant difference in collagen-induced aggregation or platelet thromboxane between fish and fish oils on a high or low fat intake. In conjunction with our previous findings of improvements in lipoproteins, blood pressure, and heart rate in this population, these results on platelet function suggest that dietary omega3-fatty acids incorporated into a low rather than a high-fat diet have a wider spectrum of more favorable effects on cardiovascular risk factors.



The protective effects of dietary fish oil on focal cerebral infarction

PROSTAGLANDINS MED. (USA), 1979, 3/5 (257-268)

The protective effect of the (n-3) fatty acids in menhaden fish oil on acute cerebral ischemia was investigated in cats. Cerebral ischemia was produced by ligation of the left middle cerebral artery of cats fed either a basal diet of feline cat chow or the basal diet supplemented with 8% of the calories as menhaden oil for 18-24 days. Fatty acid esters of 20:5 (n-3) were increased and the 18:2 (n-6) decreased in the heart and liver of cats fed supplemental fish oil, but the brain lipid showed no effect of the diet. We found that the neurological deficit and the volume of brain infarction in the group treated with fish oil was less than that of the control group. The present findings suggest that moderate dietary supplements of fish oil may be beneficial in the prophylactic treatment of ischemic cerebral vascular disease.



Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders.

Metabolism (UNITED STATES) Jan 1996, 45 (1) p12-23

Patients with chronic intestinal disorders causing malabsorption, nutritional losses through diarrhea, or catabolic illness would be expected to have essential fatty acid (EFA) deficiency (EFAD), but such deficiency has not been demonstrated in patients treated in accordance with the prevailing standard of care. We studied plasma fatty acid patterns of 56 reference or control subjects and 47 patients with chronic intestinal disorders (mostly Crohn's disease) using high-resolution capillary column gas-liquid chromatography. Patients exhibited a shift in fatty acid metabolism similar to that previously shown to be associated with EFAD. Compared with control subjects, patients had (1) decreased polyunsaturated fatty acid (PUFA) levels (43.7% v 50.4%, P < .0001), (2) increased monounsaturated fatty acid (MUFA) levels (25.8% v 22.0%, P < .0001), (3) higher ratios of mead (20:3 omega 9) to arachidonic (20:4 omega 6) acid (0.020 v 0.013, P < .04), and (4) lower concentrations of total (214 v 284 mg/dL, P < .01), saturated ([SFA] 63 v 75 mg/dL, P < .001), MUFA (56 v 63 mg/dL, P < .001), and PUFA (93 v 143 mg/dL, P < .001). Patients had metabolic shifts toward increased production of MUFA and an increased ratio of derivatives to precursors of omega 6 fatty acids, shifts that occur when cells are EFA-deficient. More than 25% of the patients had biochemical evidence of EFAD according to at least one criterion. Optimal diagnosis requires a concurrent evaluation of concentrations of fatty acids in plasma and in lipoproteins (percent fatty acids). On indices of EFA status that depend on percents, ratios, or concentrations of fatty acids or on the production of abnormal fatty acids, the patients were between patients with severe whole-body EFAD and healthy subjects, a state referred to as absolute EFA insufficiency. Patients with chronic intestinal disease should be evaluated for likely EFA deficiencies and imbalances, and treated with substantial amounts of supplements rich in EFAs, such as oral vegetable and fish oils, or intravenous lipids if necessary.



The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer

Nutrition (USA), 1996, 12/1 SUPPL. (S27-S30)

Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2- 4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0.-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.



Modulation of antioxidant enzymes and programmed cell death by n-3 fatty acids

Lipids (USA), 1996, 31/3 SUPPL. (S91-S96)

Studies from our laboratory indicate that n-3 (fish oil, FO) lipids at 10% (w/w) in a nutritionally adequate, semi-purified diet, and supplemented with equal levels of antioxidants, extended the life span of lupus-prone (NZB/NZW)F1 (B/W) female mice as compared to n-6 (corn oil, CO) lipids. The early rise of autoimmune disease in CO-fed mice was closely linked to the loss of T-cell function. Both IL-2 production and IL-2 receptor expression were reduced due to the loss of naive T-cells and a rise in memory T-cells. Proliferative response to both mitogens and superantigens (staphylococcal enterotoxins A and B) was higher in FO-fed 6.5-mon-old mice. These changes paralleled decreased PGE2 production by splenic cells from FO-fed mice. Analysis of mRNA expression in different organs revealed differential effects of dietary lipids. In FO-fed mice, transforming growth factor beta1 (TGF beta1) expression was decreased in kidneys, but splenic tissues had higher expression of TGF beta mRNA. As TGF beta promotes programmed cell death (PCD), we studied the effects of CO and FO on PCD rates in lymphocytes. Both propidium iodide staining and DNA fragmentation were elevated in lymphocytes of FO-fed mice when compared to CO-fed mice of similar age. Also, increased PCD correlated closely with increased Fas gene expression. Thus, in addition to various other antiinflammatory effects, dietary FO appears to increase PCD and prevent accumulation of self reactive immune cells in lymphoid organs. Further studies are required to dissect the pro- and antiinflammatory mechanisms associated with dietary n-3 and n 6 lipids in modulating autoimmune disorders or malignancy during aging.



Dietary marine lipids suppress continuous expression of interleukin-1beta gene transcription

Lipids (USA), 1996, 31/3 SUPPL. (S23-S31)

n-3 Polyunsaturated fatty acids abundant in marine lipids suppress certain inflammatory and immune reactions, and dietary marine lipid supplements have antiinflammatory effects in experimental and human autoimmune disease. Previous work by other investigators demonstrated that dietary marine lipid supplements suppressed production of cytokines from stimulated human peripheral blood mononuclear cells ex vivo. The present study further documents the ability of n 3 fatty acids to inhibit cytokine formation, and in part defines the mechanism of the inhibition of production of interleukin- 1beta (IL-1beta) by dietary n-3 fatty acid. Female BALB/c mice were each fed a fat-free balanced diet to which was added either a refined fish oil (FO) preparation as a source of n-3 fatty acid, or beef tallow (BT), which consisted primarily of saturated and monoenoic fatty acids. After ingesting the experimental diets for periods ranging from 3 to 12 wk, spleen cell preparations were stimulated ex vivo with either lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA), and proIL-1beta mRNA (IL-1beta mRNA) was measured by northern analysis. Levels of IL-1beta mRNA in both LPS- and PMA- stimulated cells from BT-fed mice were elevated to a greater extent than in cells from FO-fed mice, at most concentrations of LPS and PMA. Stability of LPS-stimulated mRNA levels after actinomycin D was similar for BT and FO groups, indicating that lower levels of IL-1 mRNA with FO groups was related to suppressed IL-1 gene transcription and not due to accelerated transcript degradation. Nuclear run-on transcription assays revealed a more transient expression of the IL-1beta gene in LPS-stimulated spleen cells from FO-fed mice compared to cells from BT-fed mice. We conclude that dietary marine lipids reduce transient expression of the IL-1beta gene in stimulated splenic monocytic cells. Preliminary results from nuclear run-on transcription assays indicate that n-3 fatty acids may not change the initial rate of gene transcription but may promote more rapid shutting down of transcription of this gene after induction than do alternative lipids.



Tissue specific regulation of transforming growth factor beta by omega-3 lipid-rich krill oil in autoimmune murine lupus

Nutrition Research (USA), 1996, 16/3 (489-503)

We have previously reported that hybrid New Zealand female mice I(NZBxNZW) F1 or B/W) fed a diet enriched in omega-3 lipid-rich fish oil vs. omega-6 lipid- rich corn oil show delayed development of autoimmune lupus nephritis and longer life span. The present study was carried out to explore the possible beneficial effects of oil from Antarctic krill (Euphausia superba) as an alternative source of omega-3 lipids. Weanling B/W mice were fed a nutritionally adequate semipurified diet supplemented with either 10% (wt/wt) krill oil (KO) or corn oil (CO). Cross-sectional studies were carried out on kidneys and spleens at 3.5 and 6.5 months of age. Our results indicate that KO prolonged life span (CO, 266.7 days plus or minus 12.5; KO, 330.2 days plus or minus 19.2; P<0.001) and delayed the onset of proteinuria. Splenocytes from KO mice displayed greater proliferative responses to mitogen (concavalin A), and significantly lower Pgp-1+ cells in both CD4+ and CD8+ T cell subsets. Lipid extracts of splenocytes from KO fed mice revealed higher levels of eicosapentaenoic (20:5omega-3; EPA) and docosahexaenoic (22:6omega-3; DHA) acids; EPA suppresses prostaglandin synthesis. Further, Northern blot analysis showed decreased expression of the oncogene c-ras (1.5-fold, P<0.05) in the spleens of KO fed mice. The expression of transforming growth factor beta1 (TGFbeta1) was higher in spleen cell extracts (3.5-fold; P<0.025), but lower in kidney extracts (5.97- fold; P<0.025) of KO fed mice. The data indicate that dietary supplementation with KO modulates expression of TGFbeta in an organ specific manner. In the spleen, TGFbeta could be immunosuppressive, whereas its expression in the kidney may be pathological and proinflammatory. In summary, dietary KO, like fish oil, can suppress the development of autoimmune murine lupus, and its effects on inflammatory mediators are organ specific.



The effects of dietary lipid manipulation on the production of murine T cell-derived cytokines

Cytokine (United Kingdom), 1995, 7/6 (548-553)

Lymphocytes play an important part in the development and progression of a number of autoimmune and inflammatory disorders, which are characterized by the presence of activated T cells and cytokines at the site of tissue injury and in the circulation. There has been considerable interest in using dietary polyunsaturated fatty acids (PUFA), particularly the n-3 PUFA found in fish oils, in the therapy of these conditions; such therapies aim, primarily, to suppress T-lymphocyte activity. While several studies have investigated the effects of fatty acids on the production of monocyte- and macrophage-derived cytokines, few have investigated their effects on the production of T cell-derived cytokines. Each of these studies have been restricted to IL-2 and have produced results which are not entirely clear. Moreover, there have been no studies to investigate the effects of dietary lipids other than fish oils on IL-2 production or the effects of dietary lipids on lymphokines other than IL-2. To investigate the effects of dietary lipid manipulation on the production of IL-2, IL-4, IL-10 and IFN-gamma by lymphocytes, mice were fed for 8 weeks on a low fat (LF) diet or one of 4 high fat diets, which contained 20% (by weight) hydrogenated coconut oil (HCO), olive oil (OO), safflower oil (SO) or menhaden oil (MO), Culture medium of lymphocytes from mice fed the OO or SO diets contained significantly more IL-2 than that of lymphocytes from mice fed the LF or HCO diets. Although this was the only statistically significant difference, there was a trend towards a lower concentration of IL-10 in the culture medium of lymphocytes from mice fed the unsaturated diets (OO, SO and MO) compared with those fed the LF or HCO diets. Whether this represents increased production of IL-2 and decreased production of IL-10 or decreased utilization of IL-2 and increased utilization of IL-10 by lymphocytes from mice fed the unsaturated diets is uncertain and requires further characterization.



Dietary omega-3 lipids delay the onset and progression of autoimmune lupus nephritis by inhibiting transforming growth factor beta mRNA and protein expression

Journal of Autoimmunity (United Kingdom), 1995, 8/3 (381-393)

The present study was carried out to test whether transforming growth factor beta (TGFbeta) plays a pathological role in the induction or progression of glomerulonephritis in a murine model of systemic lupus erythematosus (SLE), and whether dietary supplementation with fish oil (FO) can modulate the expression of TGFbeta. Weanling female (NZB x NZW) F1 (B/W) mice were divided into three groups. One group was fed an unmanipulated diet (lab. chow; LC) and the other two groups were fed a nutritionally adequate semipurified diet supplemented with 10% CO or FO. Both water and food were provided ad libitum. Proteinuria and serum anti-dsDNA antibody levels were measured to assess disease progression. Mice were killed at 3.5 and 6.5 months of age and renal mRNA levels for TGFbeta isoforms, fibronectin-1 (FN-1) and intercellular adhesion molecule-1 (ICAM-1) were studied by Northern blot analysis. TGFbeta protein levels were also examined in kidneys by Western blot analysis. Our results indicate that at 3.5 months of age, when urinary protein levels were undetectable and very low levels of anti-dsDNA were detected, no mRNA signal could be detected for TGFbeta isoforms, ICAM-1 and FN-1 in either dietary group. However, at 6.5 months, the FO-fed mice, compared to LC and CO, had (1) greatly reduced proteinuria (LC: 2-3+, CO: 2-3+; FO: trace -1+) and serum anti-dsDNA antibodies; (2) improved survival (CO: 100% death (15/15) occurred by 8 months; FO: 50% were alive at 12 months (8115) and (3) reduced renal TGFbeta1 mRNA and protein levels. TGFbeta2 and beta3 were not significantly affected by FO diet. Similarly, lower levels of renal FN-1 and ICAM-1 mRNA were observed in FO fed mice. These data indicate that in B/W mice on a FO diet, prolonged survival and amelioration of renal disease may be attributed at least in part to lower levels of TGFbeta1 mRNA and protein in the kidneys.



Fish oil feeding modulates leukotriene production in murine lupus nephritis

PROSTAGLANDINS (USA), 1994, 48/5 (331-348)

Diets enriched with fisk oil (FO) ameliorate kidney disease in the MRL-lpr/lpr murine model of lupus nephritis. Although the mechanisms of this effect are not known, FO is rich in the polyunsaturated fatty acid eicosapentaenoic acid (EPA) which may have profound effects on eicosanoid metabolism. In MRL-lpr/lpr mice) FO feeding reduces renal production of cyclooxygenase metabolites. However, EPA may also affect the metabolism of arachidonate by the 5-lipoxygenase (5-LO) pathway and enhanced production of 5-LO metabolites has been implicated in the pathogenesis of kidney disease in MRL-lpr/lpr mice. We therefore investigated the effects of FO feeding on production of 5-LO metabolites in 20 week old MRL-lpr/ lpr mice. After 8 weeks of dietary supplementation with FO, both renal hemodynamic function and glomerular histology were improved compared to safflower oil (SO) controls. Amelioration of kidney disease was associated with alterations in the pattern of leukotriene production by macrophages and kidneys from FO fed mice. There was a significant decrease in the production of leukotriene B4 (LTB4) and tetraene peptidoleukotrienes by peritoneal macrophages isolated from mice given FO compared to control animals. Similarly, dietary supplementation with FO decreased renal production of LTB4. Reduced production of tetraene leukotrienes was accompanied by a modest increase in the production of pentaene leukotrienes by macrophages from FO fed mice. We speculate that this modulation of leukotriene production by FO feeding may have beneficial effects on renal disease in autoimmune nephritis.



Effects of n-3 and n-6 fatty acids on the activities and expression of hepatic antioxidant enzymes in autoimmune-prone NZBxNZW F1 mice

LIPIDS (USA), 1994, 29/8 (561-568)

Menhaden fish oil (FO) containing n-3 fatty acids dramatically extends the life span and delays the onset and progression of autoimmune disease in (NZBxNZW)F1 (B/W) female mice as compared to those fed corn oil (CO) rich in n-6 lipids. As an inefficient antioxidant defense system has been linked to autoimmune diseases, the present study was undertaken to determine whether the protective action of n-3 lipids is mediated through their antioxidant defense system. Weanling B/W mice were fed a nutritionally adequate, semipurified diet containing CO or krill oil (KO) or FO at 10% level (w/w) ad libitum until the mice were 6.5 months old. All diets contained the same level of vitamin E (21.5 mg/100 g diet). We compared the effects of feeding D-6 and n-3 lipids on survival, kidney disease, hepatic microsomal lipid composition, peroxidation, and on the activity and mRNA expression of the antioxidant enzymes catalase, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in 6.5-month-old B/W mice. The results showed that when compared to livers from CO-fed mice, livers from KO- and FO-fed mice showed: (i) significantly higher (P < 0.001) activities and expression of CAT, GSH- Px and SOD; (ii) significantly lower (P < 0.001) arachidonic acid (20:4n-6) and linoleic acid (18:2n-6) and higher (P < 0.001) eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) levels in hepatic microsomes; and (iii) significantly lower (P < 0.001) estimated peroxidation indices and thiobarbituric acid reactive substances generation. The data indicate that one of the mechanisms through which the n-3 lipids delay the onset of autoimmune diseases in B/W mice may be through maintenance of higher activities and expression of hepatic antioxidant enzymes.



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

J. IMMUNOL. (USA), 1994, 152/12 (5979-5987)

This study was designed to investigate the mechanisms by which marine lipids rich in long chain omega-3 fatty acids inhibit autoimmune disease and prolong the survival rate in female (NZB/NZW) F1 (B/W) mice, an animal model for human SLE. Nutritionally adequate semipurified diets containing at 10% either corn oil (CO) or fish oil (FO) were fed from 1 mo of age and were monitored for proteinuria and survival. Proteinuria was detected earlier and became progressively severe in CO-fed mice. The average life span was significantly shortened by the CO diet (266.7 days plus or minus 12.5), whereas FO extended the survival significantly (402.1 days plus or minus 26.1; p < 0.001). A cross- sectional study at 6.5 mo of age revealed an increased proliferative response to T cell mitogens including bacterial superantigens and decreased serum anti-dsDNA Ab titers in the FO group compared with the CO group. Furthermore, splenocytes from the FO group when stimulated with Con A had higher IL-2 and lower IL-4 production similar to that of young (3.5 mo) mice. Flow cytometric analyses of splenocytes revealed lower Ig+, higher lymphocyte endothelial cell adhesion molecule-1, and lower Pgp-1+ cells within CD4+ and CD8+ subsets in FO-fed mice. Also, elevated IL-2 and IL-4 and significantly higher TGF-beta1 and lower c-myc and c-ras mRNA expression and higher TGF-beta1 and significantly lower c-Myc and c-Ha-Ras proteins were detected in spleens of FO-fed mice. Fatty acid analysis revealed significantly higher linoleic (18:2omega-6) and arachidonic (20:4omega-6) acid levels in splenocytes of the CO- fed group and higher eicosapentanoic (20:5omega-3) and docosahexanoic (22:6omega- 3) acid levels in the FO-fed group, indicating that changes in membrane fatty acid composition may contribute to the altered immune function and gene expression during the development of murine SLE.



Decreased pro-inflammatory cytokines and increased antioxidant enzyme gene expression by omega-3 lipids in murine lupus nephritis

BIOCHEM. BIOPHYS. RES. COMMUN. (USA), 1994, 200/2 (893-898)

Enrichment of diet with omega-3 lipid rich-menhaden fish oil (FO) when fed ad libitum to autoimmune lupus-prone NZB/NZW F1 (B/W) female mice delayed the onset and slowed progression of renal disease while significantly extending life-span compared to omega-6 lipid rich-corn oil (CO)-fed mice. Northern blot analysis of kidneys from FO-fed mice revealed no detectable levels of IL-1beta, IL-6 and TNFalpha mRNA contrasted to levels that were easily detected in CO-fed mice. In contrast to the cytokines, FO-fed mice showed higher renal levels of the antioxidant enzymes-catalase, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD)-mRNAs compared to CO-fed mice. The results suggest that dietary supplementation with FO, as compared to CO, inhibits the production of pro-inflammatory cytokines and ameliorates immune-complex-mediated kidney injury possibly by enhancing the ability of cells to dispose of harmful reactive oxygen intermediates.



Suppression of autoimmune disease by dietary n-3 fatty acids

J. LIPID RES. (USA), 1993, 34/8 (1435-1444)

Previous studies have demonstrated that dietary fish oil preparations have anti-inflammatory effects in humans and in experimental animals, but the individual components of fish oils that are responsible for their anti- inflammatory effects have not been documented. We therefore investigated in (NZB x NZW)F1 mice, a model for human systemic lupus erythematosus, the effects of diets containing ethyl esters of two purified n-3 fatty acids, eicosapentaenoic acid (EPA-E) and docosahexaenoic acid (DHA-E), a refined fish oil triglyceride (FO) which contained 55% n-3 fatty acids, and beef tallow (BT) which contains no n-3 fatty acids. The diets were initiated prior to the development of overt renal disease at age 22 weeks, and continued for 14 weeks. The extent of the renal disease was quantified by light microscopy and by proteinuria. Diets containing either 10 wt% FO, 10% EPA-E, or 6% or 10% DHA-E alleviated the severity of the renal disease, compared to the BT diet, whereas diets containing either 3% or 6% EPA-E or 3% DHA-E were less effective. Two diets containing approximately 3:1 mixtures of EPA-E and DHA- E alleviated the renal disease to a greater extent than expected for either of these fatty acids given singly. We believe that these experiments provide the first demonstration of anti- inflammatory effects of individual dietary n- 3 fatty acids. The results also indicate that the anti-inflammatory effects of fish oils depend on synergistic effects of at least two n-3 fatty acids.



Role of omega-3 fatty acids in health and disease

NUTR. RES. (USA), 1993, 13/SUPPL. 1 (S19-S45)

Dietary lipid interventions have an important role in modulating the onset of autoimmunity, cardiovascular diseases and cancer. Many studies carried out in the past have established the adverse effects of saturated fats in humans and in animal models. Based on these adverse effects, the consumption of vegetable oils containing both monounsaturated omega (omega)-9 and polyunsaturated fatty acids (rich in 18:2 omega-6) is rising significantly in the United States. The increased consumption of many vegetable oils particularly of omega-6 series is however to be viewed as pro-inflammatory and its suspected as one of the possible causes for the gradual rise in certain malignant tumors, rheumatoid arthritis and autoimmune diseases primarily due to the increased production of pro-inflammatory cytokines although its increased usage has reduced cardiovascular disease nearly 30% in the United States. Diets based on omega-6 enriched oils can increase the level of linoleic acid in tissue phosphoglycerides and are able to reduce cholesterol levels, yet these lipids usually tend to elevate excessive arachidonic acid (20:4 omega- 6) levels. In contrast, omega-3 fatty acid-enriched fish oil (FO) and/or omega-3 precursors from certain vegetable oils (linolenic acid, 18:3 omega-3) are found to provide protection against cardiovascular disease, rheumatoid arthritis, cancer and possibly against the severity of viral infections. Nutritional modification of cellular functions by dietary lipids with a balanced ratio of omega-6 and omega-3 fatty acids offers an attractive avenue to correct, modify and/or prevent many patho-physiological processes in health and disease state and to reduce toxicity of drugs in many patients. The mediation of such effects is thought to be primarily achieved through alterations of cellular membranes composition and other endogenous lipid stores which may modify the functional activity of various receptors on plasma membranes. In summary, the protective effects of omega-3 lipids have been explained based on changes in eicosanoid synthesis and the reduced risk of sudden death from cardiac arrhythmia, increased protection from ischemic myocardium, improved myocardial function and reduction of other cardiovascular and autoimmune disease risks. However, well-designed studies are still required to further define the key role of both combination of omega-6 and omega-3 fatty acids, from marine and vegetable sources, both as a supplement to infant nutrition specifically for optimizing the development of cognitive function, and also as preventive measure for reducing the incidence of diseases of aging in rapidly growing elderly populations.



Dietary marine lipids suppress murine autoimmune disease

J. INTERN. MED. SUPPL. (United Kingdom), 1989, 225/731

Dietary marine lipids reduce both mortality and the severity of glomerulonephritis in inbred murine strains which develop spontaneous autoimmune disease. The protective effects of marine lipids appear to be accounted for by the major n-3 fatty acids in these preparations, 20:5 and 22:6. The n-3 fatty acids in dietary fish oil are extensively incorporated into several lipid classes in the spleen of autoimmune mice, including phosphatidylinositol, phosphatidylethanolamine, plasmalogens and saturated ether-linked phospholipids as well as diacylphosphoglycerides. The effects of dietary marine lipids on autoimmune disease in experimental models are highly specific. Careful controlled trials will be required to establish the role of dietary marine lipids in the therapy of human autoimmune disease.

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