Doses Of Eicosapentaenoic Acid Research Articles

Omega-3 fatty acids and major depression: a Mendelian randomization study

Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega-3 to prevent major depressive disorder (MDD) have so far been unsuccessful. Whether this association is causal remains unclear. We used two sample Mendelian randomization (MR) to investigate causality. Genetic variants associated with circulating omega-3 and omega-6 fatty acids in UK Biobank (UKBB, n = 115,078) were selected as exposures. The Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWAS) of MDD (n = 430,775; cases = 116,209; controls = 314,566) and recurrent depression (rMDD, n = 80,933; cases = 17,451; controls = 62,482), were used as outcomes. Multivariable MR (MVMR) models were used to account for biologically correlated lipids, such as high- and low-density cholesterol and triglycerides, and to explore the relative importance of longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) using data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, n = 8866). Genetic colocalization analyses were used to explore the presence of a shared underlying causal variant between traits. Genetically predicted total omega-3 fatty acids reduced the odds of MDD (ORIVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93–0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OREPA 0.92; 95% CI 0.88–0.96; p = 0.0002). The effect of omega-3 fatty acids was robust to MVMR models accounting for biologically correlated lipids. ‘Leave-one-out’ analyses highlighted the FADS gene cluster as a key driver of the effect. Colocalization analyses suggested a shared causal variant using the primary outcome sample, but genomic confounding could not be fully excluded. This study supports a role for omega-3 fatty acids, particularly EPA, in the aetiology of depression, although pleiotropic mechanisms cannot be ruled out. The findings support guidelines highlighting the importance of EPA dose and ratio for MDD and question whether targeted interventions may be superior to universal prevention trials, as modest effect sizes will limit statistical power.

The disparate effects of omega-3 PUFAs on intestinal microbial homeostasis in experimental rodents under physiological condition

The health benefits of omega-3 polyunsaturated fatty acids (omega-3 PUFAs), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are linked to their regulatory effects on the composition of the gut microbiota. However, there is a lack of direct evidence on whether omega-3 PUFAs regulate the gut microbial homeostasis under physiological conditions. This study investigated the impact of equivalent doses of EPA, DHA, and fish oil (FO) with a DHA to EPA ratio of approximately 1:1 on the bacterial and fungal composition of normal young mice. This study also analyzed changes in key components of the gut microenvironment, including the colonic mucus barrier and short-chain fatty acids, to address the prebiotic potential of omega-3 PUFAs. The results showed that all three omega-3 PUFAs interventions induced significant fluctuations in the gut bacteria and fungi, leading to an increase in the abundance of some probiotics. Notably, DHA, EPA, and FO interventions significantly increased the abundance of the probiotic Lactobacillus, Bifidobacterium, and Akkermansia, respectively. Both DHA and fish oil interventions also significantly reduced the abundance of potentially pathogenic fungi, such as Aspergillus and Penicillium. Association analysis of the top 19 differential fungal and bacterial genera in abundance revealed a much more bacteria-bacteria and bacteria-fungi connections, but fewer fungi-fungi connections. This highlights the importance of bacteria in the gut microecological network. Furthermore, the levels of butyric acid and valeric acid in the colonic contents of DHA intervention group were significantly increased, and the colonic mucus layer thickness was increased in three treatment groups. In summary, DHA, EPA and FO interventions showed targeted enhancement of different probiotics and enhanced colon defense barrier (mucus barrier), showing potential prebiotic effects.

A Low Omega-3 Index and High AA/EPA Ratio in American College Football Players are Both Improved Following 5 Weeks of DHA-Rich Algae Oil Supplementation

Abstract Purpose Many athletes are deficient in long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA). A consequent low Omega-3 Index (O3I) and high arachidonic acid/eicosapentaenoic acid (AA/EPA) ratio increase cardiovascular disease risk and inflammation. Algae oil is a plant-based, sustainable source of LC n-3 PUFA, suitable for vegans and vegetarians. Effects of algae oil supplementation on whole blood fatty acids among athletes has not been previously reported. This study evaluated the effects of 5 weeks of DHA-rich algae oil supplementation on the whole blood fatty acid profile, O3I and AA/EPA ratio of omnivorous Division I American College Football (ACF) players. Methods: Data, including a spot blood sample, were collected at baseline for all participants (n = 47), then for a subset of players (n = 22) following a 5-week control period (usual diet) and 5 weeks of algae oil supplementation (usual diet + 1575 mg docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) 5 days/week; average 1125 mg/day). Results: Baseline O3I was 4.3% ± 0.1% and AA/EPA ratio was 45.6 ± 23.8. After 5 weeks of algae oil supplementation, the O3I was 6.1% ± 1.0% and the AA/EPA ratio was 25.1 ± 11.6. The O3I was significantly higher and the AA/EPA ratio was significantly lower (P < 0.0001 for both) compared with both baseline and the end of the control period. The increase in O3I from baseline was correlated with calculated DHA + EPA dose per unit body mass (R = 0.641, P = 0.001). Conclusions: Algae oil supplementation for 5 weeks improved both the low baseline O3I and high AA/EPA ratio among ACF players, with body mass specific dose effects.

Eicosapentaenoic Acid Alleviates Inflammatory Response and Insulin Resistance in Pregnant Mice With Gestational Diabetes Mellitus.

This study investigated the effect of eicosapentaenoic acid (EPA) on insulin resistance in pregnant mice with gestational diabetes mellitus (GDM) and underlying mechanism. C57BL/6 mice fed with a high-fat diet for 4 weeks and the newly gestated were selected and injected with streptozotocin for GDM modeling. We demonstrated that the fasting insulin levels (FINS) and insulin sensitivity index (ISI) in serum and blood glucose level were significantly higher in GDM group than in normal control (NC) group. The low or high dose of EPA intervention reduced these levels, and the effect of high dose intervention was more significant. The area under the curve in GDM group was higher than that of NC group, and then gradually decreased after low or high dose of EPA treatment. The serum levels of TC, TG and LDL were increased in GDM group, while decreased in EPA group. GDM induced down-regulation of HDL level, and the low or high dose of EPA gradually increased this level. The levels of p-AKT2Ser, p-IRS-1Tyr, GLUT4, and ratios of pIRS-1Tyr/IRS-1 and pAKT2Ser/AKT2 in gastrocnemius muscle were reduced in GDM group, while low or high dose of EPA progressively increased these alterations. GDM enhanced TLR4, NF-kappaB p65, IL-1beta, IL-6 and TNF-alpha levels in placental tissues, and these expressions were declined at different dose of EPA, and the decrease was greater at high dose. We concluded that EPA receded the release of inflammatory factors in the placental tissues by inhibiting the activation of TLR4 signaling, thereby alleviating the IR.

Omega-3 Fatty Acids for Depression in the Elderly and Patients with Dementia: A Systematic Review and Meta-Analysis.

This study aimed to evaluate the efficacy of omega-3 fatty acid supplementation interventions in improving depression in patients with dementia. To achieve this objective, randomized controlled trials (RCTs) were identified from primary electronic databases, focusing on the relationship between omega-3 fatty acids and depression in patients with dementia. The primary outcome was the impact of omega-3 fatty acids on post-intervention depression in patients with dementia, with subgroup analyses conducted based on the type of intervention (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) combination), duration of intervention (3 months, 6 months, 12 months, ≥24 months), cognitive function (ranging from mild cognitive impairment (MCI) to severe dementia), and daily dosage (high, medium, low, applicable to both DHA and EPA). The study has been duly registered with PROSPERO (registration ID: CRD42023408744). A meta-analysis of five studies (n = 517) included in nine systematic reviews showed that omega-3 supplementation had a non-significant trend toward affecting depressive symptoms in patients with dementia (standardized mean difference (SMD): 0.147; 95% confidence interval (CI): -0.324 to 0.049; p = 0.141). Subgroup analyses revealed that DHA supplementation significantly reduced depressive symptoms (SMD: -0.247; p = 0.039). There was no significant effect for high (SMD: -0.169; 95% CI: -0.454 to 0.116; p = 0.246) or medium (SMD: -0.061; 95% CI: -0.228 to 0.105; p = 0.470) doses of EPA. However, low doses of EPA were significantly effective (SMD: -0.953; 95% CI: -1.534 to -0.373; p = 0.001), with notable improvements in patients with MCI (SMD: -0.934; p < 0.001). The study concludes that omega-3 fatty acids, particularly through DHA supplementation, may alleviate depressive symptoms in patients with MCI. Given the limited sample size, further long-term RCTs are recommended to better understand the efficacy and optimal management of omega-3 supplementation in this population using different dosages.

Effect of fish-oil supplementation on the glycemic and lipidemic profiles of pregnant women: a systematic review and meta-analysis.

Pregnant women have physiological metabolic changes in glycemic and lipid profiles that are essential for fetal development. The aim of this systematic review was to analyze the effects of fish-oil-capsule supplementation on the glycemic and lipid profiles of pregnant women. A systematic search was conducted of the MEDLINE (by PubMed), Embase, Cochrane Library (CENTRAL) databases and gray literature, including preprints for all relevant studies published in English, with no date restrictions. The estimated pooled results were analyzed using a random-effects model and represented by mean differences (MDs) and corresponding 95% confidence intervals (CIs). The analyses were performed with R software, version 4.2.1, using the "Meta" packages, versions 6.0-0. Fifteen eligible studies were included after screening. In a pooled analysis, overall fish-oil supplementation had no effect on parameters compared with placebo. In the subgroup analysis, fish-oil supplementation may be beneficial in insulin (MD: -2.11 IU/mL; 95% CI: -3.86, -0.36) and homeostasis model assessment of insulin resistance (HOMA-IR) (MD: -0.71; 95% CI: -1.14, -0.29) indices, with heterogeneity (I2 =0%) among pregnant women with diabetes mellitus. In the subgroup with doses of eicosapentaenoic acid (EPA) below 200 mg, there was a reduction in HOMA-IR in the intervention group (MD: -0.60; 95% CI: -1.14, -0.06). Pregnant women taking fish-oil capsules showed significant beneficial changes in the subgroups of type 2 diabetes and EPA dosages below 200 mg for insulin and HOMA-IR.

New perspectives on randomized controlled trials with omega-3 fatty acid supplements and cognition: A scoping review.

Long chain polyunsaturated omega-3 fatty acids (n-3 FA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are known to be important components in a healthy diet and contribute to healthy functioning of the heart and the brain, among other organs. Although there are epidemiological studies on the strong relationship between fish or n-3 FA consumption and lower risk of cognitive decline, results from randomized controlled trials (RCTs) are less consistent. Here, we performed a scoping review on RCTs with n-3 FA supplementation where cognition was evaluated. Seventy-eight RCTs published before April 2022 were included in this review. Among these RCTs, 43.6% reported a positive cognitive outcome after the consumption of n-3 FA compared to the placebo. However, there was a large diversity of populations studied (age ranges and health status), wide range of doses of EPA +DHA supplemented (79mg/day - 5200mg/day) and a multitude of tests evaluating cognition, mainly diagnostic tests, that were used to assess cognitive scores and overall cognitive status. RCTs were thereafter categorized into non-cognitively impaired middle-aged adults (n=24), non-cognitively impaired older adults (n=24), adults with subjective memory complaints (n=14), adults with mild cognitive impairments (MCI, n=9) and people with diagnosed dementia or other cognitive changes (n=7). Among these categories, 66.7% of RCTs conducted with MCI adults reported a positive cognitive outcome when supplemented with n-3 FA vs. the placebo. Therefore, this scoping review provides rationale and questions to a) strengthen the design of future RCTs with n-3 FA for cognitive outcomes, and b) generate more informative data to support clinicians in their practice in assessing cognition before and after a nutritional intervention.

Effect of local administration of eicosapentaenoic acid on the jaw-opening reflex in rats.

Although eicosapentaenoic acid (EPA) application in vitro inhibits voltage-gated Na+ (Nav) channels in excitable tissues, the acute local effect of EPA on the jaw-opening reflex in vivo remains unknown. The aim of the present study was to determine whether local administration of EPA to adult male Wistar rats could attenuate the excitability of the jaw-opening reflex in vivo, including nociception. The jaw-opening reflex evoked by electrical stimulation of the tongue was recorded by a digastric muscle electromyogram (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG response was significantly increased in proportion to the electrical stimulation intensity (1×-5× threshold). At 3×, local administration of EPA dose-dependently inhibited the dEMG response, lasting 60min, with maximum inhibition observed within approximately 10min. The mean magnitude of dEMG signal inhibition by EPA was almost equal to that observed with a local anesthetic, 1% lidocaine, and with a half dose of lidocaine plus a half dose of EPA. These findings suggest that EPA attenuates the jaw-opening reflex, possibly by blocking Nav channels of primary nerve terminals, and strongly support the idea that EPA is a potential therapeutic agent and complementary alternative medicine for the prevention of acute trigeminal nociception.

Abstract 10905: Relationship of Eicosapentaenoic Acid and Docosahexaenoic Acid Dosage to Plaque Progression in Patients With Coronary Atherosclerosis Receiving Statin and Polyunsaturated Fatty Acid Therapy

Introduction: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 polyunsaturated fatty acids (PUFAs) extensively studied in atherosclerosis. Clinical endpoint and imaging studies have yielded convergent findings favoring pure EPA over mixed EPA/DHA formulations. The effects of EPA and DHA dose on coronary plaque dynamics, however, remain unknown, and could yield insights into the utility of these PUFAs in coronary artery disease. Methods: We considered longitudinal studies that compared coronary plaque change in patients receiving statin versus statin+PUFA therapy. Outcomes were % change in total and lipid plaque volume. Treatment effects were calculated as standardized mean difference (SMD), the mean % plaque volume change between statin and statin+PUFA cohorts divided by their pooled standard error. To isolate effects of EPA or DHA dose respectively, treatment arms were pooled by dosage of the PUFA of interest. To account for dependent samples, we fit hierarchical mixed effects models using robust variance estimation, assuming a correlation of 0.5 among treatment effects within multi-arm studies. Results: Among 555 screened articles, 11 studies met inclusion criteria. Among 1,070 patients, there were 14 treatment arms stratified by EPA dose, and 15 treatment arms stratified by DHA dose. Meta-regression revealed that EPA dose (g/day) correlated positively with treatment effect (β = 0.3 [0.1, 0.6], P = 0.02), while daily DHA dose correlated negatively with treatment effect (β = -0.4 [-0.7, -0.1], P = 0.01). We found no associations between EPA (β = 0.1 [-0.2, 0.4], P = 0.44) or DHA (β = -0.1 [-0.3, 0.2], P = 0.59) dose and treatment effects for lipid volume (Figure 1). Conclusions: Among cohorts receiving statin+PUFA therapy, we found a dose-dependent benefit of administered EPA on coronary plaque volume; the opposite was true for DHA. This adds to a growing body of evidence suggesting DHA may blunt beneficial effects of EPA in atherosclerosis.

Abstract 13395: Truth in Advertising? Health Claims and Contents of Fish Oil Supplements

Background: Fish oil supplement use continues to rise. Although prescription eicosapentaenoic acid (EPA) at 4 gm/day did lower cardiovascular risk, the vast majority of randomized trials have shown no benefit to fish oil dietary supplements. Information on health claims and contents of fish oil supplements is limited. Methods: Label information for on-market fish oil supplements was obtained from the National Institute of Health Dietary Supplement Label Database as of February 2022. Label text was analyzed to categorize health claims by type and organ system referenced. The total daily dose of EPA and docosahexaenoic acid (DHA) was evaluated for supplements made by 16 of the leading retailers and manufacturers of fish oil. Results: We evaluated 2,192 fish oil supplement labels, among which 1,647 (75.1%) made at least one health claim. Of these, only 22.0% (n=362) used from the FDA-approved qualified health claim for fish oil. The remaining 78.0% of labels made “structure &amp; function” claims (e.g., “promotes heart health”, “supports brain and vision function”, etc.) across a variety of organ systems (Figure). Heart-health related claims were the most common (n=1,390, 63.4% of labels). Across 16 different brands/manufacturers, 239 product labels were reviewed for dose information. Wide variation in the doses of EPA and DHA was observed (median EPA+DHA dose 600 mg, interquartile range 250-1100 mg). Only 9.2% of supplements reviewed contained at least 2 gm of EPA+DHA, the minimum recommended for triglyceride lowering, and none contained an EPA dose shown to prevent cardiovascular events (≥4 gm/day). Conclusions: Fish oil supplement labels commonly make vaguely worded claims that imply a range of health benefits, almost none of which are supported by randomized trial data. The doses of EPA and DHA available in commonly used fish oil supplements vary substantially, yet none contain levels shown to reduce cardiovascular risk.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

Effect of Omega-3 Fatty Acids on Coronary Plaque Morphology - A Serial Computed Tomography Angiography Study.

Omega-3 fatty acids have been proposed to be useful in the prevention of cardiac events. High-risk plaque (HRP) and plaque progression on serial coronary computed tomography angiography (CTA) have been suggested to be the predecessor of acute coronary syndrome (ACS). The purpose of this study was to investigate whether addition of omega-3 fatty acids to statin therapy for secondary prevention would lead to change in plaque characteristics detected by using serial CTA. This study enrolled 210 patients with ACS: no eicosapentaenoic acid (EPA)/ docosahexaenoic acid (DHA; EPA/DHA), low-dose EPA+DHA, high-dose EPA+DHA, and high-dose EPA alone. HRP was significantly more frequent in patients with plaque progression (P=0.0001). There was a significant interaction between plaque progression and EPA dose regardless of the DHA dose; 20.3% in EPA-none (no EPA/DHA), 15.7% in EPA-low (low-dose EPA+DHA), and 5.6% in EPA-high (high-dose EPA+DHA and high-dose EPA alone). On multivariate logistic regression analysis, HRP (OR 6.44, P<0.0001), EPA-high (OR 0.13, P=0.0004), and Rosvastatin (OR 0.24, P=0.0079) were the independent predictors for plaque progression. In quantitative analyses (n=563 plaques), the interval change of low attenuation plaque (LAP) volume was significantly different based on EPA dose; LAP was significantly increased in the EPA-none group and significantly decreased in the EPA-high group. In patients with ACS, addition of high-dose EPA (EPA-high) to statin therapy, compared to statin therapy without EPA, was associated with a lower rate of plaque progression.

Dose-related meta-analysis for Omega-3 fatty acids supplementation on major adverse cardiovascular events

Omega-3 supplements are widely used for cardiovascular (CV) protection. We performed an updated meta-analysis for omega-3 and CV outcomes. Random-effects meta-analysis including double-blind RCTs with duration ≥1 year, evaluating omega-3 supplements in 4 a priori defined categories (<1, 1, 2, ≥3 of 1g capsules/day) on all-cause mortality, cardiac death, myocardial infarction and stroke, reporting the relative risk (RR) as the measure of interest. Complementary approaches were Trial Sequential Analysis (TSA) and sensitivity analyses for triglycerides, prevention setting, intention-to-treat analysis, eicosapentaenoic acid (EPA), sample size, statin use and study duration. Nineteen randomized controlled trials (RCTs) with 97,709 participants were included. Omega-3 supplements were not statistically significantly associated with reduced all-cause mortality, cardiac death, MI, or stroke, with the exception of reduced cardiac mortality only for the equivalent dose of 2 capsules/day (RR 0.55, 95%CI 0.33, 0.90, p=0.0169, I2=0%). TSA reached the required information size only for the lower doses regarding all-cause and cardiac mortality, where they show no significant association. Meta-regression on EPA dose, as well as the majority of sensitivity analyses did not show any statistically significant association. Compared to the robust evidence for low doses, higher doses and particularly for the unique type of omega-3 icosapent ethyl ester should be further addressed.

The Potential of Docosahexaenoic Acid (DHA) in SARS-CoV-2 Management: DHA Reduces ACE2 Levels in Endothelial Cells

ObjectivesAngiotensin-converting enzyme 2 (ACE2) is a transmembrane protein located on the surface of endothelial cells that promotes vasodilation by promoting the hydrolysis of angiotensin II. However, ACE2 also serves as the cellular receptor for SARS-CoV-2. Infection by SARS-CoV-2 can promote endothelial dysfunction which in turn is associated with greater infection severity. Long chain omega-3 fatty acids (n3 PUFA) like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are reported to prevent endothelial dysfunction. Thus, we hypothesize that treatment with n3 PUFA may suppress the actions of SARS-CoV-2 on endothelial cells, potentially through endothelial ACE2. The objective of the study was therefore to investigate whether changes in ACE2 levels occur as part of the endothelial response to n3 PUFA treatment.MethodsMale fa/fa Zucker rats were randomised into 4 PUFA-based diet groups: α-linoleic acid (ALA), EPA, DHA, and linoleic acid (LA), for 8 weeks. EA.hy926 cells were cultured to sub-confluent and quiescent states and treated with various doses of DHA, EPA, and ALA for 8 or 24 h. ACE2 levels in tissues and cells were quantified by Western blotting.ResultsIn contrast to ALA and EPA, DHA treatment significantly reduced ACE2 levels in rat heart, aorta, and kidney but not lungs after 8 weeks of diet intervention. EPA only showed this reduction compared to ALA in kidney. Interestingly, when applied to human endothelial cells in culture, DHA decreased ACE2 levels of growing EA.hy926 cells even at relatively low doses, but no significant effect was observed in quiescent cells. EPA also had an effect, but only at an extremely high dose.ConclusionsDHA reduced ACE2 levels in key organs and human endothelial cells, which should produce beneficial effects by lowering the susceptibility of cells to SARS-CoV-2.Funding SourcesSt Boniface Hospital Foundation - Research Without Borders and University of Manitoba - GETS

The ratio of eicosapentaenoic acid to docosahexaenoic acid as a modulator for the cardio-metabolic effects of omega-3 supplements: A meta-regression of randomized clinical trials

BackgroundA large number of studies have demonstrated the effects of omega- 3 supplements containing mixtures of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), known to favorably affect many modifiable risk factors of coronary heart disease (CHD). These studies have used diverse ratios and doses of EPA and DHA. However, it is not known whether the ratio of EPA to DHA in omega-3 supplements affect their efficacy as modulators for cardiovascular risk factors. This meta-regression aimed to investigate the effect of different ratios of EPA to DHA on risk factors associated with CHD including lipid profile, blood pressure, heart rate, and inflammation. MethodA regression analysis was carried out on 92 clinical trials with acceptable quality (Jadad score ≥ 3) that were previously identified from two databases (PubMed and Cochrane Library). ResultsData from studies that met the inclusion criteria for this analysis showed that the ratio of EPA to DHA was not associated with lipid profile, diastolic blood pressure, or heart rate. With all studies, the ratio of EPA to DHA was associated with C-reactive protein (CRP) (β = -1.3121 (95 % CI: -1.6610 to -0.9543), that is, the higher the EPA to DHA ratio, the greater the reduction. Using only studies that supplied EPA and DHA in the range of 2 g–6 g, the ratio of EPA to DHA was also associated with CRP (β = -2.10429 and 95 % CI: -3.89963 to -0.30895); that is, an even more pronounced reduction in CRP with a higher EPA to DHA ratio. Systolic blood pressure was only associated with an increasing EPA to DHA ratio in the 2 g–6 g range (β = 5.47129 and 95 % CI: 0.40677–10.53580), that is, a higher EPA to DHA ratio within this dose range, the greater the increase in SBP. ConclusionCurrent data suggest that the EPA to DHA ratio only correlates to the modulation of CRP by omega-3 supplementation of EPA and DHA, and SBP in studies that supplemented EPA and DHA in the range of 2 g–6 g, shedding light on potential differential effects of EPA vs. DHA on inflammation and systolic blood pressure.

Effect of Omega-3 Long Chain Polyunsaturated Fatty Acids (n-3 LCPUFA) Supplementation on Cognition in Children and Adolescents: A Systematic Literature Review with a Focus on n-3 LCPUFA Blood Values and Dose of DHA and EPA.

Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) supplementation in the cardiovascular field is effective if a certain Omega-3 index (O3I) is achieved or the daily n-3 LCPUFA dose is high enough. Whether this applies to studies on cognition in children and adolescents is unclear. The aims of the current review were to investigate whether: (1) a certain O3I level and (2) a minimum daily n-3 LCPUFA dose are required to improve cognition in 4–25 year olds. Web of Science and PubMed were searched. Inclusion criteria: placebo controlled randomized controlled trial; participants 4–25 years; supplementation with docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA); assessing cognition; in English and ≥10 participants per treatment arm. Thirty-three studies were included, 21 in typically developing participants, 12 in those with a disorder. A positive effect on cognitive measures was more likely in studies with an increase in O3I to >6%. Half of the studies in typically developing children with daily supplementation dose ≥450 mg DHA + EPA showed improved cognition. For children with a disorder no cut-off value was found. In conclusion, daily supplementation of ≥450 mg DHA + EPA per day and an increase in the O3I to >6% makes it more likely to show efficacy on cognition in children and adolescents.

Dose‐Dependent Anti‐Inflammatory and Metabolic Effects of Eicosapentaenoic Acid in Diet‐Induced Obese Mice

Obesity is a widespread epidemic that increases the risk for several metabolic diseases such as diabetes and cardiovascular diseases. Long‐chain omega‐3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) possess anti‐inflammatory and potent triglyceride‐lowering properties at high doses (4–6 g/day). However, whether lower doses are effective in reducing metabolic alterations associated with obesity has not been investigated. The objective of this study is to determine dose‐dependent effects of EPA in diet‐induced obese mice. We used B6 male mice fed for 14 weeks a high‐fat diet (HF, 45% kcal fat) or HF diet supplemented with 36, 18, or 9 g/kg of AlaskOmega EPA‐enriched fish oil (800mg EPA/g fish oil), kindly provided by Organic Technologies. We conducted metabolic phenotyping during the feeding period, and harvested tissues and blood at termination. There were no differences in food intake across the four treatment groups. Only 36 g/kg of EPA significantly lowered body weight, fat content and epididymal fat pad weight (P&lt;0.05), compared to HF. However, EPA at both 18 and 36 g/kg doses significantly increased glucose clearance and insulin sensitivity (P&lt;0.05), compared to mice fed HF or 9 g/kg of EPA. Locomotor activity was significantly increased (P&lt;0.05) in mice fed EPA 36 and 18 g/kg compared to other groups. Interestingly, compared to HF with all doses of EPA, energy expenditure and oxygen consumption were significantly increased (P&lt;0.05); while serum insulin and leptin levels were significantly decreased (p&lt;0.05). These results validate weight‐ and adiposity‐ independent metabolic benefits of EPA in obesity and demonstrate that doses of EPA comparable to those currently used to treat hypertriglyceridemia (18g/kg mouse diet, ~5g/d human diet) confer several metabolic benefits.Support or Funding InformationUSDA NIFA Postdoctoral Fellowship Grant # 2017‐07139

PUFAs, BDNF and lipoxin A4 inhibit chemical-induced cytotoxicity of RIN5F cells in vitro and streptozotocin-induced type 2 diabetes mellitus in vivo

ObjectiveTo study whether minimal doses of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and lipoxin A4 (LXA4) and brain-derived neurotrophic factor (BDNF), when used in combination can protect RIN5F cells from chemical-induced cytotoxicity. As a corollary, to know whether plasma BDNF and LXA4 are altered in STZ-induced type 2 DM animals.Materials and methodsRIN5F cells, alloxan (AL), streptozotocin (STZ), doxorubicin (DB), and benzo(a)pyrene (BP) were used in this study. Chemical-induced apoptosis and changes in antioxidants, lipid peroxides and nitric oxide (NO) and LXA4 and BDNF levels in RIN5F cells were studied. Alterations in plasma concentrations of BDNF and LXA4 in STZ-induced type 2 diabetes animals was estimated.ResultsBDNF, LXA4 and AA, EPA and DHA protected (P < 0.001 and P < 0.01 respectively) against AL/STZ/DB/BP-induced toxicity to RIN5F cells in vitro. AL/ STZ/DB/BP inhibited BDNF and LXA4 production by RIN5F cells and were restored to normal by AA, EPA and DHA. Sub-optimal doses of BDNF, LXA4, AA and EPA when used in combination protected against cytotoxic action of AL/STZ/DB/BP on RIN5F cells in vitro by restoring LXA4/BDNF levels and altered antioxidant/lipid peroxides/NO levels (P < 0.01) to normal. STZ (65 mg/kg)-induced type 2 diabetes mellitus animals showed reduced plasma BDNF and LXA4 levels (P < 0.001).DiscussionAL/STZ/DB/BP-induced cytotoxicity to RIN5F cells in vitro can be prevented by BDNF, LXA4 and AA. AL/STZ/DB/BP are cytotoxic, possibly, by suppressing the production of LXA4 and BDNF in RIN5F cells. STZ-induced type 2 DM animals have decreased plasma levels of LXA4 and BDNF.ConclusionThe results of the present study suggest that BDNF, LXA4, EPA, DHA, AA, GLA and BDNF protect pancreatic β cells from the cytotoxic action of various chemicals and prevent development of diabetes mellitus. LXA4 seems to be the mediator of these cytoprotective actions of BDNF and PUFAs suggesting a close interaction exists among these molecules (BDNF, PUFAs and LXA4). Hence, methods developed to deliver a combination of PUFAs (especially AA), LXA4 and BDNF may prevent development of diabetes mellitus (both type 1 and type 2).

Eight weeks of fish oil supplementation does not prevent sitting-induced leg endothelial dysfunction.

Prolonged sitting impairs leg endothelial function and this impairment is thought to be mediated by a sustained reduction in blood flow-induced shear stress. However, whether nutritional strategies can be used to prevent sitting-induced leg endothelial dysfunction remains unknown. Herein, we tested the hypothesis that 8 weeks of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation would prevent endothelial dysfunction associated with sitting. Nineteen healthy men were randomly assigned to a placebo group or EPA+DHA group in a double-blind fashion. The EPA+DHA group was administered EPA-rich fish oil, containing 600 mg EPA and 260 mg DHA per day for 8 weeks. The placebo group received matching capsules for the same duration of time. Popliteal artery flow-mediated dilation (FMD) was measured at baseline and before and after a 3-h sitting period. During sitting, blood pressure, popliteal artery diameter, and blood velocity were measured every hour. Throughout the sitting period, popliteal artery blood flow and shear rate were markedly and similarly reduced in both groups (P < 0.05). However, counter to the hypothesis, 3 h of sitting impaired popliteal artery FMD to the same extent in both groups (P < 0.05). In conclusion, daily EPA and DHA supplementation is not effective at preventing the detrimental effects of prolonged sitting on leg endothelial function. Novelty We provide evidence that sitting-induced leg endothelial dysfunction in young healthy subjects cannot be remediated by a nutritional strategy known to produce cardiovascular benefits. This could be partially due to the low total dose of EPA and DHA administered.

Anti-pain and anti-inflammation like effects of Neptune krill oil and fish oil against carrageenan induced inflammation in mice models: Current statues and pilot study

Although inflammation is a reactive to injurious stimuli and considered as beneficial process in body, but it causes some discomforts, such as pain. Murine dietary contains appreciable amounts of fatty acids and antioxidants which encourages researchers to focus on their potential therapeutic effects. This study is aimed to examine the analgesic and anti-inflammatory activity of Neptune krill oil (NKO) and fish oil (FO) in rodent model which are two well-known sources of rich content of n-3 polyunsaturated fatty acids (n-3 PUFAs), mostly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). NKO and FO were used at the same dose of 500 mg and also balanced at similar doses of EPA: 12 in NKO vs. 12 in FO wt%, DHA: 7 NKO vs. 8 FO wt%. Application of NKO and FO in acetic acid-induced writhing effect, hot plate, and formalin induced test, indicated the nociceptive activity of the two tested drugs in comparison with normal saline. Also, the anti-inflammatory effect of these supplements was confirmed by carrageenan test. Analysis of cytokines levels in the blood samples of the mice after induction inflammation by carrageenan indicated decreased levels of those proteins compared to that in the normal groups. Both tested drugs, effectively could reduce severe inflammation and pain in rodents in comparison with the references drugs (depends on the tests); however, NKO was found to be more effective.