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Omega-3 fatty acid supplementation increases anti-inflammatory cytokines and attenuates systemic disease sequelae in experimental pancreatitis.
BACKGROUND: The cytokines involved in the systemic inflammatory response in acute pancreatitis (AP) comprise lipid mediators (eg, prostanoids, thromboxanes, leukotrienes) generated from arachidonic acid (AA) and eicosapentaenoic acid (EPA). The AA-derived mediators are generated from omega-6 fatty acid (FA) and have strong proinflammatory effects and the EPA-derived mediators generated from omega-3-fatty acid are less active or even exhibit anti-inflammatory effects. Basic parenteral nutrition delivers omega-6-FA and omega-3 FA at a ratio of approximately 7:1. AIM: To investigate whether altering the FA composition by fish oil supplementation (omega-3-FA) affects cytokine production and the parameters reflecting systemic disease severity in experimental AP. METHODS: Severe AP was induced in 30 rats by standardized intraductal infusion of bile salt and IV cerulein. Six hours after AP induction, rats were randomized to TPN using commercial solutions with identical amounts of glucose, amino acids, and fat but different FA compositions: group 1 received a soybean-based fat solution without additional fish oil and group 2 was supplemented with 0.2 g/kg per day fish oil. TPN was continued for two days. Serum concentrations of IL-6 and IL-10 were measured before and after AP induction and at 24 and 48 hours after starting TPN. Routine cardiorespiratory and renal parameters were monitored to assess the systemic response at the organ level. RESULTS: Animals treated with fish oil had significantly higher IL-10 values (at 24 hours, 63 +/- 7 versus 46 +/- 3 pg/mL), produced more urine (28 +/- 0.9 versus 21 +/- 1.6 mL), and had significantly fewer episodes of respiratory dysfunction (defined as a pO2 < 80 mm Hg or pCO2 > 50 mm Hg for >15 minutes; 29% versus 67%) during the observation period. CONCLUSIONS: Altering eicosanoid mediator precursor availability by infusion of (omega-3 fatty acid increases anti-inflammatory cytokines in this model of AP. This together with improved renal and respiratory function suggests that the systemic response to pancreatic injury is attenuated.
JPEN J Parenter Enteral Nutr. 2002 Nov-Dec;26(6):351-6

Conversion of alpha-linolenic acid to eicosapen- taenoic, docosapentaenoic and docosahexaenoic acids in young women.
The extent to which women of reproductive age are able to convert the n-3 fatty acid alpha-linolenic acid (ALNA) to eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) was investigated in vivo by measuring the concentrations of labeled fatty acids in plasma for 21 days following the ingestion of [U-13C]ALNA (700 mg). [13C]ALNA excursion was greatest in cholesteryl ester (CE) (224 (sem 70) micromol/l over 21 d) compared with triacylglycerol (9-fold), non-esterified fatty acids (37-fold) and phosphatidylcholine (PC, 7-fold). EPA excursion was similar in both PC (42 (sem 8) micromol/l) and CE (42 (sem 9) micromol/l) over 21 days. In contrast both [13C]DPA and [13C]DHA were detected predominately in PC (18 (sem 4) and 27 (sem 7) micromol/l over 21 days, respectively). Estimated net fractional ALNA inter-conversion was EPA 21%, DPA 6% and DHA 9%. Approximately 22% of administered [13C]ALNA was recovered as 13CO2 on breath over the first 24 hours of the study. These results suggest differential partitioning of ALNA, EPA and DHA between plasma lipid classes, which may facilitate targeting of individual n-3 fatty acids to specific tissues. Comparison with previous studies suggests that women may possess a greater capacity for ALNA conversion than men. Such metabolic capacity may be important for meeting the demands of the fetus and neonate for DHA during pregnancy and lactation. Differences in DHA status between women both in the non-pregnant state and in pregnancy may reflect variations in metabolic capacity for DHA synthesis.

Br J Nutr. 2002 Oct;88(4):411-20

Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action.
The role of marine fish oil (n-3) polyunsaturated fatty acids in the prevention of fatal ventricular arrhythmia has been established in experimental animals. Prevention of arrhythmias arising at the onset of ischemia and reperfusion is important because if untreated, they result in sudden cardiac death. Animals supplemented with fish oils in their diet developed little or no ventricular fibrillation after ischemia was induced. Similar effects have also been observed in cultured neonatal cardiomyocytes. Several mechanisms have been proposed and studied to explain the antiarrhythmic effects of fish oil polyunsaturated fatty acids, but to date, no definite mechanism has been validated. The sequence of action of these mechanisms and whether more than one mechanism is involved is also not clear. Some of the mechanisms suggested to explain the antiarrhythmic action of fish oils include the incorporation and modification of cell membrane structure by (n-3) polyunsaturated fatty acids, their direct effect on calcium channels and cardiomyocytes and their role in eicosanoid metabolism. Other mechanisms that are currently being investigated include the role of (n-3) polyunsaturated fatty acids in cell signalling mediated through phosphoinositides and their effect on various enzymes and receptors. This article reviews these mechanisms and the antiarrhythmic studies using (n-3) polyunsaturated fatty acids.

J Nutr. 1997 Mar;127(3):383-93

Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease—a randomized, placebo-controlled, double-blind cross-over trial.
Thirty-nine patients with chronic inflammatory bowel disease were studied in a seven-month, double-blind, placebo controlled cross-over trial of dietary supplementation with fish oil, which provided about 3.2 g n-3 fatty acids per day. At control, biopsies from inflamed mucosa contained higher levels of arachidonic acid than uninvolved mucosa. Dietary n-3 fatty acids were well tolerated and incorporated into plasma and enteric mucosa phospholipids at the expense of n-6 fatty acids. The arachidonic acid-derived prostanoid generation was reduced by fish oil and the extension and severity of macroscopic bowel involvement was moderately improved. In patients with Crohn’s disease, clinical activity was unchanged by fish-oil supplementation. In patients with ulcerative colitis, clinical disease activity fell during fish oil supplementation and thereafter; this was not significant however. Despite a moderate reduction in inflammatory lipid mediators by dietary n-3 fatty acids and limited morphological improvement in chronic inflammatory bowel disease, the clinical benefit seems to be confined to patients with ulcerative colitis.

J Intern Med Suppl. 1989;225(731):225-32.

Significantly reduced docosahexaenoic and docosapentaenoic acid concentrations in erythrocyte membranes from schizophrenic patients compared with a carefully matched control group.
BACKGROUND: Fatty acid research in schizophrenia has demonstrated an altered cell membrane phospholipid metabolism. Erythrocyte membrane phospholipid composition closest reflects that of neuronal membranes. METHODS: (Poly)(un)saturated fatty acid concentrations were measured in the erythrocyte membranes of 19, consecutively admitted, medicated young schizophrenic patients and then compared with matched control subjects. Psychiatric symptomatology was rated with the Positive and Negative Symptom Scale and Montgomery-Asberg Depression Rating Scale. Because diet, hormones, and cannabis influence fatty acid metabolism, we included these factors in our study. RESULTS: The most distinctive findings concerned the omega-3 series: C22:5 omega-3, C22:6 omega-3 (docosahexaenoic acid), and the sum of omega-3 fatty acids were significantly decreased. Interestingly, C20:4 omega-6 (arachidonic acid) was not lowered. In the omega-9 series, higher levels of C22:1 omega-9 and lower levels its elongation product, C24:1 omega-9 (nervonic acid), were found. Interestingly, the other arm of the desaturation-elongation sequence of C18:1 omega-9, C20:3 omega-9, was lower in patients. The total omega-9 fatty acid levels were also lower in patients. CONCLUSIONS: Significant differences in erythrocyte fatty acid composition were found. The differences were not due to diet or hormonal status and could not be explained by the medication or cannabis use. No consistent pattern emerged from the different fatty acid abnormalities and the clinical symptom scores.

Biol Psychiatry. 2001 Mar 15;49(6):510-22

Omega-3 but not omega-6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells.
Epidemiological and animal-based investigations have indicated that the development of skin cancer is in part associated with poor dietary practices. Lipid content and subsequently the derived fatty acid composition of the diet are believed to play a major role in the development of tumorigenesis. Omega-3 fatty acids, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), can effectively reduce the risk of skin cancer whereas omega-6 (omega-6) fatty acids such as arachidonic acid (AA) reportedly promote risk. To investigate the effects of fatty acids on tumorigenesis, we performed experiments to examine the effects of the omega-3 fatty acids EPA and DHA and of the omega-6 fatty acid AA on phorbol 12-tetradecanoate 13-acetate (TPA)-induced or epidermal growth factor (EGF)-induced transcription activator protein 1 (AP-1) transactivation and on the subsequent cellular transformation in a mouse epidermal JB6 cell model. DHA treatment resulted in marked inhibition of TPA- and EGF-induced cell transformation by inhibiting AP-1 transactivation. EPA treatment also inhibited TPA-induced AP-1 transactivation and cell transformation but had no effect on EGF-induced transformation. AA treatment had no effect on either TPA- or EGF-induced AP-1 transactivation or transformation, but did abrogate the inhibitory effects of DHA on TPA- or EGF-induced AP-1 transactivation and cell transformation in a dose-dependent manner. The results of this study demonstrate that the inhibitory effects of omega-3 fatty acids on tumorigenesis are more significant for DHA than for EPA and are related to an inhibition of AP-1. Similarly, because AA abrogates the beneficial effects of DHA, the dietary ratio of omega-6 to omega-3 fatty acids may be a significant factor in mediating tumor development.

Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7510-5

Effect of an eight-month treatment with omega-3 fatty acids (eicosapentaenoic and docosahexaenoic) in patients with cystic fibrosis.
BACKGROUND: Supplementation of the diet with eicosapentaenoic acid and docosahexaenoic acid, the main long-chain omega-3 fatty acids in cell membranes, may have beneficial effects in patients with cystic fibrosis. METHODS: A prospective study involving 30 patients and 20 control subjects was carried out; eicosapentaenoic plus docosahexaenoic acid was equal to 1.3% of caloric intake in the cystic fibrosis patients. Our present study included the evaluation of eicosapentaenoic and docosahexaenoic acid incorporation into erythrocyte membranes and biological and clinical effects in response to long-term (eight months) supplementation with fish oil as a source of eicosapentaenoic and docosahexaenoic acids in patients with cystic fibrosis. RESULTS: Baseline erythrocyte membrane fatty acids showed low levels of linoleic acid and eicosapentaenoic acid and mild elevation of 18:3n-6, but similar docosahexanoic acid and other fatty acids in cystic fibrosis patients compared with controls. Fish oil supplementation led to a 1.7-fold (p < .05) and 1.3-fold (not significant) increase of eicosapentaenoic acid in erythrocyte membrane phospholipids after 4 and 8 months of supplementation, respectively, and to a 1.67-fold (p < .05) and 1.38-fold (p < .05) increase of docosahexanoic acid, respectively. Along with these changes, there was a progressive decrease of arachidonic acid (from 8.51 to 6.67 g/100 fatty acids at four months and 4.83 g/100 fatty acids at eight months; p < .05) and an increase of linoleic acid (p < .05) in membrane phospholipids. Analysis of inflammatory markers showed a significant decrease of serum immunoglobulin G (IgG) and of alpha-1 antitrypsin (p < .05) concentrations. Pulmonary function testing showed mild but significant improvement of forced expiratory volume (FEV)-1 from 61% +/- 19% to 57% +/- 19% of predicted values (p < .05). The number of days of antibiotic therapy during the study period was markedly lower compared with the preceding eight-month period (392 versus 721 days; p < .05). CONCLUSION: Long-term eicosapentaenoic plus docosahexanoic acid supplementation (eight months) has positive effects, such as decreasing inflammation, in cystic fibrosis.

JPEN J Parenter Enteral Nutr. 2003 Jan-Feb;27(1):52-7

Homocysteine as a risk factor for cognitive impairment in stroke patients.
BACKGROUND: Elevated total homocysteine (tHcy) levels are associated with an increased risk of cerebrovascular disease. It is uncertain whether tHcy is also an independent risk factor for cognitive impairment. METHODS: We examined 95 stroke subjects three months after their strokes, and 55 healthy comparison subjects, with a detailed neuropsychological assessment, and MRI brain scans in a proportion (n = 97). Baseline measurements of tHcy, serum folate and B(12), creatinine and plasma fibrinogen levels were obtained. RESULTS: tHcy levels were higher in the stroke subjects by a mean 34%. These levels were significantly correlated with the first factor of a principal component analysis of the neuropsychological data, after controlling for age, folate, B(12) and creatinine levels. The correlation of Hcy levels was particularly significant with frontal-executive functioning and attention. tHcy levels were significantly correlated with number of infarcts and total stroke volume in the stroke group, but not with T(2)-weighted deep white matter hyperintensity scores, after correction for age. In the control group, tHcy levels were significantly correlated with ventricle-to-brain ratios as measures of brain atrophy. CONCLUSION: This study provides evidence that high tHcy levels are associated with cognitive impairment, in particular that of frontal-executive function. The major component of this association is accounted for by small and large strokes, but non-vascular neurotoxic effects of tHcy also appear to play a role. tHcy must receive greater attention as a risk factor for cognitive impairment.

Dement Geriatr Cogn Disord. 2003;15(3):155-62

Plasma chain-breaking antioxidants in Alzheimer’s disease, vascular dementia and Parkinson’s disease.
We studied the plasma chain-breaking antioxidants alpha carotene, beta carotene, lycopene, Vitamin A, Vitamin C, Vitamin E and a measure of total antioxidant capacity, TAC, in 79 patients with Alzheimer’s disease (AD), 37 patients with vascular dementia (VaD), 18 patients with Parkinson’s disease and dementia (PDem), and 58 matching controls, together with 41 patients with Parkinson’s disease (PD) and 41 matching controls. Significant reductions in individual antioxidants were observed in all dementia groups. When compared to controls, the following were reduced: Vitamin A in AD (p < 0.01) and VaD (p < 0.001); Vitamin C in AD (p < 0.001), VaD (p < 0.001) and PDem (p < 0.01); Vitamin E in AD (p < 0.01) and VaD (p < 0.001); beta carotene in VaD (p = 0.01); lycopene in PDem (p < 0.001). Lycopene was also reduced in PDem compared to AD (p < 0.001) and VaD (p < 0.001). Antioxidant levels in PD were not depleted. No significant change in TAC was seen in any group. The reduction in plasma chain-breaking antioxidants in patients with dementia may reflect an increased free-radical activity, and a common role in cognitive impairment in these conditions. Increased free-radical activity in VaD and PDem could be associated with concomitant AD pathology. Individual antioxidant changes are not reflected in TAC.

QJM. 1999 Jan;92(1):39-45
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Alzheimer’s disease: protective factors.
Approximately 6-8% of all persons aged >65 years have Alzheimer’s disease and the prevalence of the disease is increasing. Any intervention strategy aimed at decreasing risks or delaying the onset of the disease will therefore have a substantial effect on health care costs. Nutrition seems to be one of the factors that may play a protective role in Alzheimer’s disease. Many studies suggest that oxidative stress and the accumulation of free radicals are involved in the pathophysiology of the disease. Several studies have shown the existence of a correlation between cognitive skills and the serum concentrations of folate, vitamin B-12, vitamin B-6, and, more recently, homocysteine. However, nutritional factors have to be studied not alone but with the other factors related to Alzheimer’s disease: genetics, estrogen, antiinflammatory drug use, and socioeconomic variables. The objective of this article was to review recent studies in this field.

Am J Clin Nutr. 2000 Feb;71(2):643S-649S

Homocysteine and Alzheimer’s disease.
BACKGROUND: A high circulating concentration of the amino acid homocysteine is an independent risk factor for stroke. Alzheimer’s disease (AD) commonly co-occurs with stroke. Epidemiological studies found associations between hyperhomocysteinaemia and both histologically confirmed AD and disease progression and revealed that dementia in AD was associated with evidence of brain infarcts on autopsy. Thus, hyperhomocysteinaemia and AD could be linked by stroke or microvascular disease. However, given known relations between B-group-vitamin deficiency and both hyperhomocysteinaemia and neurological dysfunction, direct causal mechanisms are also plausible. RECENT DEVELOPMENTS: A recent prospective study (S. Seshadri and colleagues N Engl J Med; 2002 346: 476-83) showed hyperhomocysteinaemia to be a strong, independent risk factor for dementia and AD. The researchers found a graded increase in risk of both outcomes with rising plasma concentration of homocysteine after multivariate control for putative risk factors for AD. In conjunction with demonstration of a fall in homocysteine concentrations in response to increasing B-group-vitamin status, these findings give hope that mental decline, or AD itself, could be prevented by dietary modification or food fortification. WHERE NEXT? 25% of dementia cases are attributed to stroke. The possibility that some of the other 75% might be prevented by the lowering of homocysteine concentrations greatly increases the hope of maintaining self-sufficiency into old age. If homocysteine lowering can reduce the incidence of dementia or AD, decreased incidence of these disorders may be seen in Canada and the USA, where government-mandated folate-fortification programmes are in effect. Future research should focus on early detection of AD and on the possibility that the disease itself, or its primary symptom, could be prevented by folate supplementation.

Lancet Neurol. 2003 Jul;2(7):425-8

Plasma total homocysteine in a representative sample of 972 British men and women aged 65 and over.
OBJECTIVES: To provide a reference range for plasma total homocysteine (tHcy), an independent risk factor for vascular disease, and to explore relationships with nutritional indices for people aged 65 years and over, in the UK National Diet and Nutrition Survey (NDNS). DESIGN: The survey procedures described in the National Diet and Nutrition Survey Report (1997) included a health-and-lifestyle interview, a four-day weighed diet record, anthropometric and blood pressure measurements and a fasting blood sample for biochemical indices, including tHcy. SETTING: Eighty randomly selected postcode sectors from mainland Britain during 1995-1996. SUBJECTS: Of 2,060 people interviewed, 1,527 were visited by the nurse, 1,276 gave a blood sample and 972 had tHcy measured. About 80% were in their own homes and the remainder were in nursing homes or similar institutions. RESULTS: Significant cross-sectional relationships, both univariate and multivariate were found between tHcy and index concentrations of folate and vitamin B12 (P < 0.0001), and between tHcy and plasma creatinine, urea, calcium, zinc, alpha 1-antichymotrypsin, lutein and cysteine (P = 0.013 to < 0.0001). Dietary nutrient analyses showed an association with folate intake. tHcy was also correlated with age and with domicile (free-living or institution), with history of vascular disease and with use of four classes of drugs, two of which are prescribed for vascular diseases. There was a north-south gradient in tHcy (P = 0.005), and also in food choices, blood micronutrient indices and vascular disease prevalence. CONCLUSIONS: The concentrations of tHcy found in this study provide a reference range for people aged 65 years and over, in mainland Britain. tHcy is a valuable functional index of micronutrient status and intakes for British people aged 65 years and over, which can assist the development of health-promotion strategies.

Eur J Clin Nutr. 1997 Oct;51(10):691-7

Homocysteine: a marker for cognitive performance? A longitudinal follow-up study.
The present prospective study investigated whether elevated total serum homocysteine concentration is a risk factor for cognitive decline. The outcomes were compared to the possible relation between cognition and vitamin B12 or folic acid. Cognitive performance of 144 normal aging individuals (aged 30-80 years) was tested at baseline and after six years of follow-up. Domains of cognitive function addressed were cognitive speed (Letter-Digit Coding test), attention and information processing (Stroop test) and verbal learning and memory (Word Learning Test Total; Delayed Recall). Serum concentrations of homocysteine, folic acid and vitamin B12 were determined. Serum concentrations of homocysteine correlated negatively with cognitive performance on the Word Learning tests at baseline, independent of age, sex, education level or folic acid concentration. Homocysteine concentration at baseline correlated negatively with cognitive performance on the Stroop and Word Learning tests during the whole six-year follow-up period. The folic acid concentration correlated to the Delayed Recall test at baseline only and no correlations were observed for vitamin B12. Thus, while a relation between vitamin B12 or folic acid and cognition was almost absent, elevated homocysteine concentrations were associated with prolonged lower cognitive performance in this normal aging population.

J Nutr Health Aging. 2003;7(3):153-9