The anti-tussive, anti-inflammatory effects and sub-chronic toxicological evaluation of perilla seed oil.

BACKGROUND: Perilla seed oil (PSO) is the main constituent of perilla seeds currently being used in the food industry, however it also has great clinical potential in the regulation of lung function as a nutrition supplement because of the high content of α-linolenic acid (ALA). In this study, the pharmacological activities including anti-tussive, expectorant and anti-inflammatory effect of PSO were performed. Furthermore, the 90-day sub-chronic oral toxicity with a 30 day recovery period was evaluated in Wistar rats. RESULTS: The pharmacological studies demonstrated that PSO inhibited cough frequency induced by capsaicine in mice. PSO also inhibited the leukotriene B4 (LTB4) release from the calcium ionophore A23187-induced polymorphonuclear neutrophils (PMNs) to some extent. In this sub-chronic toxicity study, mortality, clinical signs, body weight, food consumption, hematology, serum biochemistry, urinalysis, organ weight, necropsy, and histopathology were used to evaluate the toxicity of PSO. Lower body weight and various negative impacts on liver related parameters without histopathological lesion were observed in the 16 g kg-1 groups. No clinically significant changes were discovered in the 4 g kg-1 group during the test period. CONCLUSION: In summary, PSO exhibited anti-tussive and anti-inflammatory activities in vivo and in vitro. These sub-chronic toxicity studies inferred that the 'no-observed adverse effect level' (NOAEL) of PSO in Wistar rats was determined to be 4 g kg-1 . These results may provide a safety profile and a valuable reference for the use of PSO. © 2020 Society of Chemical Industry.

Dietary Fats in Relation to Total and Cause-Specific Mortality in a Prospective Cohort of 521 120 Individuals With 16 Years of Follow-Up.

RATIONALE: Evidence linking saturated fat intake with cardiovascular health is controversial. The associations of unsaturated fats with total and cardiovascular disease (CVD) mortality remain inconsistent, and data about non-CVD mortality are limited. OBJECTIVE: To assess dietary fat intake in relation to total and cause-specific mortality. METHODS AND RESULTS: We analyzed data of 521 120 participants aged 50 to 71 years from the National Institutes of Health-American Association of Retired Persons Diet and Health Study with 16 years of follow-up. Intakes of saturated fatty acids (SFAs), trans-fatty acids, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were assessed via food frequency questionnaires. Hazard ratios and 95%CIs were estimated using the Cox proportional hazards model. Overall, 129 328 deaths were documented during 7.3 million person-years of follow-up. In the replacement of carbohydrates, multivariable-adjusted hazard ratios of total mortality comparing extreme quintiles were 1.29 (95% CI, 1.25-1.33) for SFAs, 1.03 (1.00-1.05) for trans-fatty acids, 0.98 (0.94-1.02) for MUFAs, 1.09 (1.06-1.13) for animal MUFAs, 0.94 (0.91-0.97) for plant MUFAs, 0.93 (0.91-0.95) for PUFAs, 0.92 (0.90-0.94) for marine omega-3 PUFAs, 1.06 (1.03-1.09) for α-linolenic acid, 0.88 (0.86-0.91) for linoleic acid, and 1.10 (1.08-1.13) for arachidonic acid. CVD mortality was inversely associated with marine omega-3 PUFA intake ( P trend <0.0001), whereas it was positively associated with SFA, trans-fatty acid, and arachidonic acid intake. Isocalorically replacing 5% of the energy from SFAs with plant MUFAs was associated with 15%, 10%, 11%, and 30% lower total mortality, CVD, cancer, and respiratory disease mortality, respectively. Isocaloric replacement of SFA with linoleic acid (2%) was associated with lower total (8%), CVD (6%), cancer (8%), respiratory disease (11%), and diabetes mellitus (9%) mortality. CONCLUSIONS: Intakes of SFAs, trans-fatty acids, animal MUFAs, α-linolenic acid, and arachidonic acid were associated with higher mortality. Dietary intake of marine omega-3 PUFAs and replacing SFAs with plant MUFAs or linoleic acid were associated with lower total, CVD, and certain cause-specific mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00340015.

Flaxseed Oil Attenuates Intestinal Damage and Inflammation by Regulating Necroptosis and TLR4/NOD Signaling Pathways Following Lipopolysaccharide Challenge in a Piglet Model.

SCOPE: Flaxseed oil is a rich source of α-linolenic acid (ALA), which is the precursor of the long-chain n-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This study investigates the protective effect of flaxseed oil against intestinal injury induced by lipopolysaccharide (LPS). MATERIALS AND RESULTS: Twenty-four weaned pigs were used in a 2 × 2 factorial experiment with dietary treatment (5% corn oil vs 5% flaxseed oil) and LPS challenge (saline vs LPS). On day 21 of the experiment, pigs were administrated with LPS or saline. At 2 h and 4 h post-administration, blood samples were collected. After the blood harvest at 4 h, all piglets were slaughtered and intestinal samples were collected. Flaxseed oil supplementation led to the enrichment of ALA, EPA, and total n-3 PUFAs in intestine. Flaxseed oil improved intestinal morphology, jejunal lactase activity, and claudin-1 protein expression. Flaxseed oil downregulated the mRNA expression of intestinal necroptotic signals. Flaxseed oil also downregulated the mRNA expression of intestinal toll-like receptors 4 (TLR4) and its downstream signals myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), and nucleotide-binding oligomerization domain proteins 1, 2 (NOD1, NOD2) and its adapter molecule, receptor-interacting protein kinase 2 (RIPK2). CONCLUSION: These results suggest that dietary addition of flaxseed oil enhances intestinal integrity and barrier function, which is involved in modulating necroptosis and TLR4/NOD signaling pathways.

Effect of dietary alpha-linolenic acid on blood inflammatory markers: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The aim of the current meta-analysis was to investigate the effect of increasing dietary ALA intake on the blood concentration of inflammatory markers including tumor necrosis factor (TNF), interleukin 6 (IL-6), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in adults. METHODS: After a systemic search on PubMed, Embase, and Cochrane library and bibliographies of relevant articles, 25 randomized controlled trials that met the inclusion criteria were identified. RESULTS: No significant effect of dietary ALA supplementation was observed on TNF (SMD: -0.03, 95% CI -0.36 to 0.29), IL-6 (SMD: -0.17, 95% CI -0.46 to 0.12), CRP (SMD: -0.06, 95% CI -0.24 to 0.12), sICAM-1 (SMD: -0.06, 95% CI -0.26 to 0.13), and sVCAM-1 (SMD: -0.24, 95% CI -0.56 to 0.09). Subgroup analysis revealed that increasing dietary ALA tends to elevate CRP concentration in healthy subjects. However, the null effect of ALA supplementation on other inflammatory markers was not changed in various subgroups, indicating that the results are stable. Meta-regression results revealed a negative relationship between the effect size on CRP and its baseline concentration. No significant publication bias was observed for all inflammatory markers as suggested by funnel plot and Begg's test. CONCLUSION: Our meta-analysis did not find any beneficial effect of ALA supplementation on reducing inflammatory markers including TNF, IL-6, CRP, sICAM-1, and sVCAM-1. However, in healthy subjects, ALA supplementation might increase CRP concentration.

Long-chain omega-3 fatty acids and cancer: any cause for concern?

PURPOSE OF REVIEW: Recently, concerns have been raised with regard to the recommended doses of marine long-chain omega-3 polyunsaturated fatty acids (LC-omega-3 PUFAs) especially in relation to cancer risk and treatment. There is urgent need to clarify this point. This review considers the most recent evidence related to the potential risk of developing cancer with high LC-omega-3 PUFA intakes, and possible research strategies to better elucidate this matter. RECENT FINDINGS: The latest published recommendations have still highlighted the usefulness of an increased dietary intake of LC-omega-3 PUFAs for the prevention of some cardiovascular diseases. However, LC-omega-3 PUFAs have been related to the potential development and progression of cancer, and considerable debate exists on this issue. SUMMARY: The use of biomarkers reflecting the intake of LC-omega-3 PUFAs as cancer risk markers is discussed, as well as the possibility that the reported beneficial/deleterious effects may be confined to specific subpopulations on the basis of genetic, metabolic, and nutritional characteristics. Recent advances on new strategies for a safer intake of LC-omega-3 PUFAs will be considered, as their dietary sources may be contaminated by toxic/carcinogenic compounds. Potentially future directions in this important research area are also discussed.

α-Lipoic acid ameliorated oxidative stress induced by perilla oil, but the combination of these dietary factors was ineffective to cause marked deceases in serum lipid levels in rats.

Dietary perilla oil rich in α-linolenic acid and α-lipoic acid lowers the serum lipid level through changes in hepatic fatty acid metabolism. We therefore hypothesized that the combination of these dietary factors may ameliorate lipid metabolism more than the factors individually. Moreover, α-lipoic acid exerts strong anti-oxidative activity. Hence, we also hypothesized that α-lipoic acid may attenuate perilla oil-mediated oxidative stress. We therefore studied the combined effects of perilla oil and α-lipoic acid on lipid metabolism and parameters of oxidative stress. Male rats were fed diets supplemented with 0 or 2.0 g/kg R-α-lipoic acid and containing 120 g/kg of palm (saturated fat), corn (linoleic acid), or perilla oil (α-linolenic acid) for 23 days. Perilla oil compared with other fats decreased serum lipid concentrations in rats fed α-lipoic acid-free diets; however, the combination of perilla oil with α-lipoic acid was ineffective for observing more marked decreases in serum lipid levels. Alterations in hepatic fatty acid synthesis and oxidation may account for the observed changes. Perilla oil, compared with palm and corn oils, strongly increased the malondialdehyde level in the serum and liver. α-Lipoic acid counteracted the increases in these parameters even though the effects were attenuated in the liver. α-Lipoic acid increased the parameters of the anti-oxidant system. The results suggested that α-lipoic acid can ameliorate oxidative stress induced by perilla oil, but the combination of these dietary factors was ineffective for additionally reducing serum lipid levels.

Dietary intake of α-linolenic acid and risk of age-related macular degeneration.

Background: The relation between α-linolenic acid (ALA), a plant-derived omega-3 (n-3) fatty acid, and age-related macular degeneration (AMD) is unclear. European researchers reported that ≤40% of ALA can be present as trans forms.Objective: We aimed to evaluate the associations between intake of ALA and intermediate and advanced AMD.Design: Seventy-five thousand eight hundred eighty-nine women from the Nurses' Health Study and 38,961 men from Health Professionals Follow-Up Study were followed up from 1984 to 2012 and from 1986 to 2010, respectively. We assessed dietary intake by a validated food-frequency questionnaire at baseline and every 4 y thereafter. One thousand five hundred eighty-nine incident intermediate and 1356 advanced AMD cases (primarily neovascular AMD) were confirmed by medical record review.Results: The multivariable-adjusted HR for intermediate AMD comparing ALA intake at the top quintile to the bottom quintile was 1.28 (95% CI: 1.05, 1.56; P-trend = 0.01) in the analyses combining 2 cohorts. The HR in each cohort was in the positive direction but reached statistical significance only in the women. However, the positive association was apparent only in the pre-2002 era in each cohort and not afterward (P-time interaction = 0.003). ALA intake was not associated with advanced AMD in either time period. Using gas-liquid chromatography, we identified both cis ALA (mean ± SD: 0.13% ± 0.04%) and trans ALA isomers (0.05% ± 0.01%) in 395 erythrocyte samples collected in 1989-1990. In stepwise regression models, mayonnaise was the leading predictor of erythrocyte concentrations of cis ALA and one isomer of trans ALA. We also found trans ALA in mayonnaise samples.Conclusions: A high intake of ALA was associated with an increased risk of intermediate AMD before 2002 but not afterward. The period before 2002 coincides with the same time period when trans ALA was found in food and participants' blood; this finding deserves further study.

Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features.

The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, ω-3) and gamma-linolenic acid (GLA, 18:3, ω-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect.

Intake of n-3 fatty acids and long-term outcome in renal transplant recipients: a post hoc analysis of a prospective cohort study.

Supplementation with n-3 fatty acids may improve long-term outcomes of renal transplant recipients (RTR). Recent evidence suggests that EPA and DHA have different outcomes compared with α-linolenic acid (ALA). We examined the prospective associations of EPA-DHA and ALA intakes with graft failure and all-cause mortality in 637 RTR. During 3·1 years (interquartile range 2·7, 3·8) of follow-up, forty-one developed graft failure and sixty-seven died. In age- and sex-adjusted analyses, EPA-DHA and ALA intakes were not associated with graft failure. EPA-DHA intake was not significantly associated with mortality (hazard ratio (HR) 0·79; 95% CI 0·54, 1·15 per 0·1 energy% difference). ALA intake was significantly associated with mortality (HR 1·17; 95% CI 1·04, 1·31 per 0·1 energy% difference). This association remained following adjustments for BMI, proteinuria and intakes of fat, carbohydrate and protein. RTR in the highest tertile of ALA intake exhibited about 2-fold higher mortality risk (HR 2·21; 95% CI 1·23, 3·97) compared with the lowest tertile. In conclusion, ALA intake may be associated with increased mortality in RTR. Future RCT are needed to confirm these results.

Comparative effects of plant oils on the cerebral hemorrhage in stroke-prone spontaneously hypertensive rats.

OBJECTIVES: Since oils and fats can induce metabolic syndrome, leading to cardiovascular and cerebrovascular diseases, the present study was performed to find out whether the plant oils affect the cerebral hemorrhage in stroke-prone spontaneously hypertensive (SHR-SP) rats. METHODS: From 47 days of age, male SHR-SP rats were given drinking water containing 1% NaCl to induce hypertension, and simultaneously fed semi-purified diets containing 10% perilla oil, canola oil, or shortening. The onset time of convulsion following cerebral hemorrhage was recorded, and the areas of hemorrhage and infarction were analyzed in the stroke brains. RESULTS: In comparison with 58-day survival of SHR-SP rats during feeding NaCl alone, perilla oil extended the survival time to 68.5 days, whereas canola oil shortened it to 45.7 days. Feeding perilla oil greatly reduced the total volume of cerebral hemorrhage from 17.27% in the control group to 4.53%, while shortening increased the lesions to 21.23%. In a microscopic analysis, perilla oil also markedly decreased the hemorrhagic and infarction lesions to 1/10 of those in control rats, in contrast to an exacerbating effect of shortening. In blood analyses, perilla oil reduced blood total cholesterol and low-density lipoproteins which were increased in SHR-SP, but canola oil further increased them and markedly lowered platelet counts. DISCUSSION: Perilla oil delayed and attenuated cerebral hemorrhage by improving hyperlipidemia in hypertensive stroke animals, in contrast to the aggravating potential of canola oil and shortening. It is suggested that perilla oil should be the first choice oil for improving metabolic syndrome in hypertensive persons at risk of hemorrhagic stroke.

The HYPERFlax trial for determining the anti-HYPERtensive effects of dietary flaxseed in newly diagnosed stage 1 hypertensive patients: study protocol for a randomized, double-blinded, controlled clinical trial.

BACKGROUND: In 2013 the World Health Organization deemed hypertension as a global crisis as it is the leading risk factor attributed to global mortality. Therefore, there is a great need for effective alternative treatment strategies to combat a condition that affects 40% of adults worldwide. Recently, the FlaxPAD Trial observed a significant reduction in systolic and diastolic blood pressure in hypertensive patients with peripheral arterial disease that consumed 30 g of milled flaxseed per day for one year. However, these patients were already on anti-hypertensive medication. Therefore, there is a need to assess if dietary flaxseed can effectively reduce blood pressure in the absence of peripheral arterial disease and anti-hypertensive medication in newly diagnosed hypertensive patients. METHODS/DESIGN: The HYPERFlax Trial is a parallel, superiority, phase II/III, randomized, double-blinded, controlled clinical trial. St. Boniface Hospital and the Health Sciences Centre of Winnipeg, Canada, will recruit 100 participants newly diagnosed with stage 1 hypertension who have yet to be administered anti-hypertensive medication. Participants will be randomly allocated with a 1:1 ratio into a flaxseed or control group and provided food products to consume daily for six months. At baseline, two, four, and six months, participant assessments will include the primary outcome measure, averaged automated blood pressure, and secondary measures: 24-hour food recall, international physical activity questionnaire, anthropometrics, and blood and urine sampling for biochemical analysis. Plasma will be assessed for lipids, metabolomics profiling, and molecules that regulate vascular tone. Urine will be collected for metabolomics profiling. With an estimated dropout rate of 20%, the trial will have a power of 0.80 to detect differences between groups and across time, out of an effect size of 0.7 (SD) at an α level of 0.05. DISCUSSION: This trial will determine if dietary flaxseed is efficacious over six months as an anti-hypertensive therapy in subjects newly diagnosed with hypertension. If flaxseed can effectively reduce blood pressure as a monotherapy, then flaxseed will provide individuals on a global basis with a cost-effective food-based strategy to control hypertension. TRIAL REGISTRATION: NCT01952340, Registered 24 September 2013.

α-Linolenic acid: nutraceutical, pharmacological and toxicological evaluation.

α-Linolenic acid (ALA), a carboxylic acid with 18 carbons and three cis double bonds, is an essential fatty acid needed for human health and can be acquired via regular dietary intake of foods that contain ALA or dietary supplementation of foods high in ALA, for example flaxseed. ALA has been reported to have cardiovascular-protective, anti-cancer, neuro-protective, anti-osteoporotic, anti-inflammatory, and antioxidative effects. ALA is the precursor of longer chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), but its beneficial effects on risk factors for cardiovascular diseases are still inconclusive. The recommended intake of ALA for cardiovascular health is reported to be 1.1-2.2g/day. Although there are limited toxicological data for ALA, no serious adverse effects have been reported. The evidence on an increased prostate cancer risk in association with dietary ALA is not conclusive. Based on the limited data currently available, it may be concluded that ALA may be beneficial as a nutraceutical/pharmaceutical candidate and is safe for use as a food ingredient.

High-fat diet from perilla oil induces insulin resistance despite lower serum lipids and increases hepatic fatty acid oxidation in rats.

BACKGROUND: The purpose of this study is to investigate the effects of a high-fat diet from perilla oil on serum lipids, hepatic lipid metabolism and insulin sensitivity. METHODS: Male Sprague-Dawley (SD) rats were fed either a control (CT) diet or a diet high in perilla oil (HP). After 16 weeks of feeding, the serum lipids were measured, and the gene expressions involved in hepatic fatty acid oxidation and synthesis were determined. In addition, hepatic fat deposition was detected, and insulin sensitivity was evaluated by means of euglycemic-hyperinsulinemic clamp. RESULTS: Compared with the rats in the CT group, the HP-feeding significantly decreased the levels of triglyceride (TG), total cholesterol (TCH) and HDL-cholesterol (HDL-c). HP-feeding did not change the levels of LDL-cholesterol (LDL-c), free fatty acid (FFA), intrahepatic lipids or body weight. Moreover, the HP-feeding dramatically increased the mRNA expressions of fatty acid oxidation markers (PPAR-alpha, CPT1A) and fatty acid synthesis markers (SREBP-1, FASN and ACC) in the liver. The HP-feeding induced increased protein levels of CPT1A, while reducing the protein levels of FASN and ACC in the liver. However, the glucose infusion rate significantly increased in the HP group compared with the CT group. CONCLUSIONS: Our data show that, in rats, excessive perilla oil intake may significantly lower serum lipids, strengthen hepatic fatty acid oxidation, and inhibit hepatic fatty acid synthesis, but at the same time may also lead to insulin resistance.

Lipid and protein oxidation of α-linolenic acid-enriched pork during refrigerated storage as influenced by diet supplementation with olive leaves (Olea europea L.) or α-tocopheryl acetate.

The objective of this study was to evaluate the effect of diet supplementation with olive leaves or α-tocopheryl acetate on lipid and protein oxidation of raw and cooked n-3 enriched-pork during refrigerated storage. Enrichment of pork with α-linolenic acid through diet supplementation with linseed oil enhanced (p≤0.05) lipid oxidation in both raw and cooked chops but had no effect (p>0.05) on protein oxidation during refrigerated storage while decreasing (p≤0.05) the sensory attributes of cooked pork. Diet supplementation with olive leaves or α-tocopheryl acetate had no effect (p>0.05) on the fatty acid composition of pork but decreased (p≤0.05) lipid oxidation while exerting no effect (p>0.05) on protein oxidation in both raw and cooked α-linolenic acid-enriched chops stored and chilled for 9 days. Moreover, olive leaves and α-tocopheryl acetate supplemented at 10 g/kg and 200mg/kg diet, respectively, exerted (p≤0.05) a beneficial effect on the sensory attributes of cooked α-linolenic acid-enriched pork chops.

n-3 fatty acids and cardiovascular events after myocardial infarction.

BACKGROUND: Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases. We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant-derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction. METHODS: In a multicenter, double-blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA-DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models. RESULTS: The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA-DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups. CONCLUSIONS: Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy. (Funded by the Netherlands Heart Foundation and others; ClinicalTrials.gov number, NCT00127452.).

Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder.

OBJECTIVES: This clinical trial evaluated whether supplementation with flax oil, containing the omega-3 fatty acid alpha-linolenic acid (alpha-LNA), safely reduced symptom severity in youth with bipolar disorder. METHODS: Children and adolescents aged 6-17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg alpha-LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale-Revised, and Clinical Global Impressions-Bipolar ratings using Kaplan-Meier survival analyses. RESULTS: There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician-rated Global Symptom Severity was negatively correlated with final serum omega-3 fatty acid compositions: %alpha-LNA (r = -0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = -0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n-6 (r = 0.48, p < 0.004). The mean duration of treatment for alpha-LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for alpha-LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms. CONCLUSIONS: Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and/or decreased AA and DPA n-6 levels, individual variations in conversion of alpha-LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone.

Elevated plasma fibrinogen caused by inadequate alpha-linolenic acid intake can be reduced by replacing fat with canola-type rapeseed oil.

The effects of canola-type rapeseed oil (RSO) on serum lipids, plasma fibrinogen, lipid oxidation and fatty acids were studied in three groups of subjects, two of which had not been consuming fish in their habitual diets. Forty-two volunteers (35 women, 7 men, 16-62 years) replaced fat with RSO for 6 weeks in a parallel design. The average cholesterol and fibrinogen concentrations were 5.0 mmol/l and 2.6 g/l, respectively. The intake of alpha-linolenic acid (alpha-LLA) was doubled. Efficient competitive inhibition by alpha-LLA was seen as a decrease in long-chain (LC) n-6 PUFA at 3 weeks. Elevated fibrinogen (2.6-3.9 g/l) decreased by 0.95 g/l at 6 weeks. Docosahexaenoic acid (22:6n-3) in plasma phospholipids increased at low fibrinogen levels only. The associations and changes in plasma C18 and LC PUFA followed the competitive and metabolic principles of the body, and especially in the case of n-3 PUFA according to the recycling pathway.

Effect of baseline plasma fatty acids on eicosapentaenoic acid levels in individuals supplemented with alpha-linolenic acid.

We previously reported a >50% increase in mean plasma eicosapentaenoic acid levels in a general medicine clinic population after supplementation with alpha-linolenic acid. In the current analysis, we evaluate the variability of changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid and evaluated the impact of baseline plasma fatty acids levels on changes in eicosapentaenoic acid levels in these individuals. Changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid ranged from a 55% decrease to a 967% increase. Baseline plasma fatty acids had no statistically significant effect on changes in eicosapentaenoic levels acid after alpha-linolenic acid supplementation. Changes in eicosapentaenoic acid levels varied considerably in a general internal medicine clinic population supplemented with alpha-linolenic acid. Factors that may impact changes in plasma eicosapentaenoic acid levels after alpha-linolenic acid supplementation warrant further study.

The influence of short-chain essential fatty acids on children with attention-deficit/hyperactivity disorder: a double-blind placebo-controlled study.

Essential fatty acids (EFA) are needed for normal sensory, cognitive, and motor function. The EFA blood profile seems to be different in children with attention-deficit/hyperactivity disorder (ADHD) as compared to matched controls. Previous open EFA supplementation trials were successful in demonstrating significant therapeutic effects in this population, whereas most of the randomized controlled trials failed to show any benefit over placebo. The current randomized, double-blind, placebo-controlled trial tested the influence of short-chain EFA supplementation on ADHD children, using parent and teacher questionnaires and a computerized continuous performance test. A total of 73 unmedicated children aged 7-13 years with a diagnosis of ADHD participated in the study; 63 children completed the study. The EFA supplement contained 480 mg of linoleic acid and 120 mg of alpha-linolenic acid, and the placebo contained 1000 mg of vitamin C (daily amounts); both were given for a 7-week supplementation period. Analysis of variance for repeated measures revealed that both treatments ameliorated some of the symptoms, but no significant differences were found between the groups in any of the treatment effects.

Bioavailability of alpha-linolenic acid in subjects after ingestion of three different forms of flaxseed.

BACKGROUND: Dietary flaxseed may have significant health-related benefits due to its high content of the omega-3 fatty acid, alpha-linolenic acid (ALA). However, before extensive work can be undertaken in clinical populations to determine its efficacy, basic information on ALA bioavailability from flaxseed and the physiological effects of its ingestion need to be examined. OBJECTIVE: The purpose of this study, therefore, was to determine the bioavailability of ALA when the flaxseed was ingested in the form of whole seed, milled seed or as flaxseed oil. DESIGN: The flaxseed components (30 g of seed or 6 g of ALA in the oil) were baked into muffins for delivery over a 3 month test period in healthy male and female subjects. RESULTS: Flaxseed ingestion over a 1 month period resulted in significant (P = 0.005) increases in plasma ALA levels in the flaxseed oil and the milled flaxseed supplemented groups. The former group had significantly (P = 0.004) higher ALA levels than the milled flaxseed group. The subjects supplemented with whole flaxseed did not achieve a significant (P > 0.05) increase in plasma ALA levels. An additional two months of flaxseed ingestion did not achieve significantly higher levels of plasma ALA in any of the groups. However, no significant increase was detected in plasma eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) levels in any of the flax-fed groups. There were no changes in plasma cholesterol or triglycerides or in platelet aggregation at any time point in any of the groups. Subjects in all of the groups exhibited some symptoms of gastro-intestinal discomfort during the early stages of the study but these disappeared in the oil and milled seed groups. However, compliance was a problem in the whole flaxseed group. CONCLUSION: In summary, ingestion of flax oil and milled flaxseed delivered significant levels of ALA to the plasma whereas whole flaxseed did not. Whole seed and oil preparations induced adverse gastrointestinal effects within 4 weeks and these were severe enough to induce the withdrawal of some subjects from these two groups. No one withdrew from the group that ingested milled flaxseed and, therefore, may represent a good form of flaxseed to avoid serious side-effects and still provide significant increases in ALA to the body.