Omega-3 Docosahexaenoic Acid Research Articles

Acyl-CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging.

The omega-3 fatty acid docosahexaenoic acid (DHA) inversely relates to neurological impairments with aging; however, limited nondietary models manipulating brain DHA have hindered a direct linkage. We discovered that loss of long-chain acyl-CoA synthetase 6 in mice (Acsl6–/–) depletes brain membrane phospholipid DHA levels, independent of diet. Here, Acsl6–/– brains contained lower DHA compared with controls across the life span. The loss of DHA- and increased arachidonate-enriched phospholipids were visualized by MALDI imaging predominantly in neuron-rich regions where single-molecule RNA in situ hybridization localized Acsl6 to neurons. ACSL6 is also astrocytic; however, we found that astrocyte-specific ACSL6 depletion did not alter membrane DHA because astrocytes express a non–DHA-preferring ACSL6 variant. Across the life span, Acsl6–/– mice exhibited hyperlocomotion, impairments in working spatial memory, and increased cholesterol biosynthesis genes. Aging caused Acsl6–/– brains to decrease the expression of membrane, bioenergetic, ribosomal, and synaptic genes and increase the expression of immune response genes. With age, the Acsl6–/– cerebellum became inflamed and gliotic. Together, our findings suggest that ACSL6 promotes membrane DHA enrichment in neurons, but not in astrocytes, and is important for neuronal DHA levels across the life span. The loss of ACSL6 impacts motor function, memory, and age-related neuroinflammation, reflecting the importance of neuronal ACSL6-mediated lipid metabolism across the life span.

Differential Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Serum Metabolome

Abstract Objectives The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to have shared and independent effects on inflammation and on lipid and glucose metabolism. However, the differential effects of EPA and DHA on serum metabolome remain elusive in humans. Methods Twenty-one subjects (9 men and 12 women, 50–75 y) with chronic inflammation (C reactive protein > 2 μg/mL) were enrolled in a randomized, controlled crossover trial consisting of a 4-week lead-in phase (high oleic sunflower oil, 3 g/d; baseline) followed by randomization to two sequential 10-week supplementation phases with pure EPA and DHA (3 g/d each) separated by a 10-week washout. Primary metabolites (n = 129) were measured in fasting serum samples by gas chromatography-mass spectrometry. Linear-mixed model was created to compare changes in metabolites by EPA and DHA relative to baseline. Pathway analysis (MetaboAnalyst 4.0, https://www.metaboanalyst.ca) was performed to identify the biological pathways associated with affected metabolites. Results DHA altered a greater number of metabolites than EPA (19 vs 11). Both EPA and DHA significantly lowered constitutive metabolites of the TCA cycle and the alanine, aspartate and glutamate metabolism pathway, with DHA showing a greater reduction than EPA. EPA significantly increased UDP-glucuronic acid and glucuronic acid, and DHA increased only glucuronic acid, thus affecting pathways where these metabolites play key roles (ascorbate and aldarate metabolism; pentose and glucuronate interconversions). Conclusions DHA affected more metabolites than EPA. The greater impact of DHA on the TCA cycle and the larger effect of EPA on the glucose-derived glucuronic acid-related pathways suggest their differential ability to modulate metabolic pathways. Funding Sources Grant number: 2015–67,017-23,142 from the National Institute of Food and Agriculture, U.S. Department Of Agriculture.

Transcriptome Analysis Reveals Docosahexaenoic Acid and α-Linolenic Acid Affect Cholesterol Metabolism and Migration of Monocytes via Common and Distinct Gene Pathways

ObjectivesOne of the earliest events in atherosclerotic plaque formation is the migration of monocytes to damaged blood vessels, and the accumulation of cholesterol in monocyte-derived macrophages. The omega-3 fatty acid docosahexaenoic acid (DHA) is known to inhibit this process. While there is limited evidence suggesting α-linolenic acid (ALA) has a similar effect, ALA has not been directly compared to DHA. The primary objective of this study was to compare the gene expression profiles of monocytes that have been exposed to either ALA or DHA and examine the effect of these fatty acids on monocyte cholesterol content and migration in a cell culture model. MethodsTranscriptome analysis was performed on total mRNA isolated from human THP-1 monocytes treated with ALA, DHA or vehicle for 48 h. Candidate genes identified via fold change and Ingenuity Pathway Analysis were validated by qPCR. Functional assays to measure total cholesterol content and migration were then performed on monocytes treated with ALA or DHA. ResultsTranscriptome analysis identified a series of genes associated with cholesterol metabolism and cell migration altered by ALA and DHA treatment. Changes in mRNA levels for candidate genes were validated by qPCR, with similar expression patterns as in the transcriptome analysis. Based on these data, both fatty acids were predicted to reduce cholesterol synthesis, ALA would increase migration and DHA would have no effect. Functional assays were then performed and revealed that ALA and DHA decreased cholesterol content to a similar extent. Additionally, contrary to our predictions, DHA significantly decreased migration, while ALA had no effect. ConclusionsThe results suggest ALA and DHA may influence monocyte migration through distinct gene pathways, while cholesterol metabolism may be regulated by a common mechanism. Furthermore, only DHA treatment reduced monocyte migration in functional assays, while both fatty acids reduced cholesterol content. Due to the critical role of monocyte migration and cholesterol content in the pathophysiology of atherosclerosis, it may be concluded from this study that both DHA and ALA may exert protective effects involving different mechanisms as they relate to individuals at risk for cardiovascular disease. Funding SourcesCIHR, NSERC

Omega-3 polyunsaturated fatty acid intake and plasma fatty acids of school going Indian children - a cross-sectional study

Long-chain omega-3 polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) play an essential role in cognitive and behavioural changes among school going children. This study delineates the dietary omega-3 PUFA [alpha-Linolenic acid (ALA), DHA, and EPA] intake and plasma fatty acids levels among school-going children. This is a cross-sectional study purely observational in nature, wherein 625 apparently healthy boys and girls aged between 7 and 13 years were selected from five different schools of Hyderabad. Dietary information on omega-3 PUFA (ALA, DHA, and EPA) intake was collected using a food frequency questionnaire. Plasma fatty acid concentrations were measured in 34% of sub-sample using standard gas chromatography. The study revealed that the average dietary intakes of omega-3 PUFA, ALA, DHA, and EPA were 55.46, 15.82, 35.59, 4.06 mg/day, respectively. There was a significant difference in mean DHA intake among gender and age group [girls (38.64±1.45 mg/day), boys (31.80±1.38 mg/day) p < 0.001] and [7–10 years (31.75±1.38 mg/day), 11–13 years (38.07±1.40 mg/day) p < 0.01]. The mean plasma DHA and DPA levels of overall subjects were 0.98 nmol% and 0.18nmol% respectively which was comparable among different gender, age and BMI-for age groups. There was a positive correlation between dietary DHA intake and plasma DHA level [ρ=0.376 (p < 0.001)]. The current study demonstrated that the omega-3 PUFA intake in school going children was less and reinforces the importance of increasing the omega-3 PUFA intake through diet and supplements.

Dietary soluble flaxseed oils as a source of omega-3 polyunsaturated fatty acids for laying hens

The present study investigated the effect of dietary soluble flaxseed oil (SFO), as a source of omega-3 polyunsaturated fatty acids, on the fatty acid composition of egg yolk and various indices including laying performance, egg quality, nutrient composition of eggs, egg stability upon storage, and serum characteristics in laying hens. A total of 210 52-week-old Hy-Line Brown laying hens were assigned to one of 5 experimental diets. A corn-soybean meal-based control diet was mixed without or with SFO to reach the concentrations of 0.2, 0.4, 0.6, and 0.8% in diets and fed for 4 wk. Dietary SFO did not affect laying performance and egg quality. Increasing dietary SFO linearly increased the pH of yolk at 7, 14, and 28 d following storage at room temperature (P < 0.05). Malondialdehyde contents in egg yolks were quadratically increased (P < 0.05) at 0, 7, and 21 d following storage as the inclusion levels of SFO increased in diets. A significant increase (P < 0.05) in total omega-3 polyunsaturated fatty acids and docosahexaenoic acid, but not α-linolenic acid and eicosapentaenoic acid, was deposited in egg yolks at 2 and 4 wk following the SFO feeding. Finally, dietary SFO did not affect serum parameters such as total cholesterol, triglyceride, high-density lipoprotein cholesterol, and nitric oxide. It is concluded that adding SFO into the diets of laying hens can be an efficient strategy to enrich the omega-3 polyunsaturated fatty acids, including docosahexaenoic acid in eggs.

Acyl‐CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging

The omega-3 fatty acid docosahexaenoic acid (DHA) inversely relates to neurological impairments with aging. However, limited non-dietary in vivo models specifically depleting brain DHA have limited direct linkage of DHA to neurological aging processes. We discovered that loss of long-chain acyl-CoA synthetase 6 (ACSL6) depletes brain membrane phospholipid DHA levels. Here, the effects of membrane phospholipid DHA depletion on behavioral and neurological outcomes across the natural progression of aging in control and Acsl6 knockout mice (Acsl6-/-) were determined. Across the lifespan, Acsl6-/- brains contained lower DHA compared to controls. The loss of DHA-enriched and increased arachidonic acid-enriched phospholipids was visualized by MALDI imaging, predominantly in neuronal rich regions where robust Acsl6 gene expression localized by smFISH to neurons across the brain, including pyramidal, Purkinje, and within the cerebellar granular layer. ACSL6 was also found in astrocytes; however, astrocyte-specific loss of ACSL6 did not regulate membrane DHA, a phenomenon attributed to astrocyte-specific expression of alternative-exon ACSL6 variants that do not prefer DHA as substrate. Total ACSL6 knockout mice exhibited hyperlocomotion across the lifespan, early-onset impairments in working spatial memory, and increased expression of cholesterol biosynthesis genes. In response to aging, cerebellar neuroinflammation and gliosis developed. Neuroinflammation was not accompanied by major alterations of lipid mediators but was preceded by decreased expression of synaptic proteins. Together our findings suggest that ACSL6 is enriched in neurons to promote membrane DHA enrichment, is important for brain DHA levels across the lifespan, protects against disordered motor function, memory, and age-related neuroinflammation reflecting the importance of DHA, and its metabolism by ACSL6, early in life and in age-related neuroprotection.

PLASMA FATTY ACIDS AND THE RISK OF VASCULAR AND MORTALITY OUTCOMES IN INDIVIDUALS WITH TYPE 2 DIABETES: RESULTS FROM THE ADVANCE STUDY

Objective: This study aimed to quantify the association of essential and other plasma fatty acids biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes. Design and method: A case cohort study (N = 3,576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of median follow-up was undertaken in participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. The fatty acids measured from baseline plasma samples, by proton nuclear magnetic resonance (NMR) analysis, were omega-3, docosahexaenoic acid (DHA), omega-6, linoleic acid (LA), polyunsaturated (PUFA), monounsaturated (MUFA) and saturated fatty acids (SFA). Hazard ratios (HRs) were modelled per standard deviation higher percentage fatty acid. C-statistics and net reclassification improvement were used to test the added value of fatty acids for risk prediction. Results: After adjustment for traditional cardiovascular risk factors, an inverse association was observed for omega-3 fatty acids and DHA (HR [95%CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively per 1SD higher percentage) with the risk of macrovascular events, and for omega-3 fatty acids (HR [95%CI]: 0.91 [0.84, 0.99] per 1SD higher percentage) with death. Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in predictive ability of models when any fatty acid was added. Conclusions: Plasma omega-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, whilst omega-3 fatty acids was also inversely associated with death. These results provide additional support for regular consumption of food rich in omega-3 fatty acids in type 2 diabetes.

Regression of human coronary artery plaque is associated with a high ratio of (18-hydroxy-eicosapentaenoic acid + resolvin E1) to leukotriene B4.

Inflammation in arterial walls leads to coronary artery disease (CAD). We previously reported that a high omega-3 fatty index was associated with prevention of progression of coronary atherosclerosis, a disease of chronic inflammation in the arterial wall. However, the mechanism of such benefit is unclear. The two main omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of specialized pro-resolving lipid mediators (SPMs)-resolvins and maresins-which actively resolve chronic inflammation. To explore whether SPMs are associated with coronary plaque progression, levels of SPMs and proinflammatory mediators (leukotriene B4 [LTB4 ] and prostaglandins) were measured using liquid chromatography-tandem mass spectrometry in 31 statin-treated patients with stable CAD randomized to either EPA and DHA, 3.36 g daily, or no EPA/DHA (control). Coronary plaque volume was measured by coronary computed tomographic angiography at baseline and at 30-month follow-up. Higher plasma levels of EPA+DHA were associated with significantly increased levels of two SPMs-resolvin E1 and maresin 1-and 18-hydroxy-eicosapentaenoic acid (HEPE), the precursor of resolvin E1. Those with low plasma EPA+DHA levels had a low (18-HEPE+resolvin E1)/LTB4 ratio and significant plaque progression. Those with high plasma EPA+DHA levels had either low (18-HEPE+resolvin E1)/LTB4 ratios with significant plaque progression or high (18-HEPE+resolvin E1)/LTB4 ratios with significant plaque regression. These findings suggest that an imbalance between pro-resolving and proinflammatory lipid mediators is associated with plaque progression and potentially mediates the beneficial effects of EPA and DHA in CAD patients.

Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation

Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). The primary outcome was incident AF confirmed by medical record review. Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.

Fish Oil Enriched in EPA, but Not in DHA, Reverses the Metabolic Syndrome and Adipocyte Dysfunction Induced by a High-Fat Diet

This study aimed to investigate the effects of two commercially available fish oils (FOs) containing different proportions of two omega-3 fatty acids (FA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the metabolic and endocrine dysfunctions of white adipose tissue resulting from obesity. Male C57BL/6J mice, 8 weeks old, received a control or high-fat diet (CO and HF groups, with 9% and 59% energy from fat, respectively) for 8 weeks. The next 8 weeks, the HF group was subdivided into HF, HF+FO/E (HF+5:1 EPA:DHA), and HF+FO/D (HF+5:1 DHA:EPA). Supplementation was performed by gavage, three times a week. All groups that received the HF diet had lower food and caloric intake, but a higher fat intake, body weight (BW) gain, glucose intolerance, and a significant increase in inguinal (ING), retroperitoneal (RP), and epididymal (EPI) adipose tissues when compared to the CO group. Additionally, HF and HF+FO/D groups showed insulin resistance, adipocyte hypertrophy, increased lipolysis and secretion of TNF-α, resistin and IL-10 adipokines by ING and RP adipocytes, and adiponectin only by the HF+FO/D group in ING adipocytes. All of these effects were completely reversed in the HF+FO/E group, which also showed partial reversion in BW gain and glucose intolerance. Both the HF+FO/E and HF+FO/D groups showed a reduction in ING and RP adipose depots when compared to the HF group, but only HF+FO/E in the EPI depot. HF+FO/E, but not HF+FO/D, was able to prevent the changes triggered by obesity in TNF-α, Il-10, and resistin secretion in ING and RP depots. These results strongly suggest that different EPA:DHA ratios have different impacts on the adipose tissue metabolism, FO being rich in EPA, but not in DHA, and effective in reversing the changes induced by obesity.

The placental lipidome of maternal antenatal depression predicts socio-emotional problems in the offspring

While maternal mental health strongly influences neurodevelopment and health in the offspring, little is known about the determinants of inter-individual variation in the mental health of mothers. Likewise, the in utero biological pathways by which variation in maternal mental health affects offspring development remain to be defined. Previous studies implicate lipids, consistent with a known influence on cognitive and emotional function, but the relevance for maternal mental health and offspring neurodevelopment is unclear. This study characterizes the placental and circulatory lipids in antenatal depression, as well as socio-emotional outcomes in the offspring. Targeted liquid chromatography-mass spectrometry covering 470 lipid species was performed on placenta from 186 women with low (n = 70) or high (n = 116) levels of antenatal depressive symptoms assessed using the Edinburgh Postnatal Depression Scale at 26 weeks’ gestation. Child socio-emotional outcomes were assessed from the Child Behavior Check List (CBCL) at 48 months. Seventeen placental lipid species showed an inverse association with antenatal EPDS scores. Specifically, lower levels of phospholipids containing LC-PUFAs: omega-3 docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-6 arachidonic acid (AA) were significantly associated with depressive symptoms. Additional measurement of LC-PUFA in antenatal plasma samples at mid-gestation confirmed the reduced circulation of these specific fatty acids in mothers. Reduced concentration of the placental phospholipids also predicted poorer socio-emotional outcomes in the offspring. This study provides new insights into the role of the materno-fetal lipid cross-talk as a mechanism linking maternal mental health to that of the offspring. These findings show the potential utility of nutritional approaches among pregnant women with depressive symptoms to reduce offspring risk for later socio-emotional problems.

Docosahexaenoic fatty acid reduces the pro\u2010inflammatory response induced by IL-1\u03b2 in astrocytes through inhibition of NF-\u03baB and AP-1 transcription factor activation

BackgroundAstrocytes are responsible for a broad range of functions that maintain homeostasis in the brain. However, their response to the pro-inflammatory cytokines released by activated microglia in various neurological pathologies may exacerbate neurodegenerative processes. Accumulating evidence suggests that omega-3 docosahexaenoic fatty acid (DHA) has an anti-inflammatory effect in various cell cultures studies and in a variety of neurological disorders. In this study we examined the mechanism involved in the inhibition of the pro-inflammatory response by DHA in astrocytes treated with IL-1β.Methods and resultsActivation of the transcription factors NF-κB and AP-1 was measured in IL-1β-treated primary astrocytes incubated with various concentrations of DHA. COX-2 and iNOS protein expression was determined by Western blot, and TNF-α and IL-6 secretion was measured using ELISA-based assays. DHA treatment inhibited translocation of p65NF-κB to the nucleus, significantly lowered p65NF-κB protein level and fluorescence of p65NF-κB in the nucleus, reduced dose-dependently IκB protein phosphorylation, and the binding of the AP-1 transcription factor members (c-Jun/c-Fos) to the specific TPA-response element (TRE) of DNA. In addition, the expression of pro-inflammatory COX-2 and iNOS proteins was downregulated and TNF-α and IL-6 secretion was also reduced.ConclusionsThese results indicate that DHA is a powerful factor that reduces the pro-inflammatory response in astrocytes. Consequently, successful introduction of DHA into the astrocyte membranes can attenuate neuroinflammation, which is a key factor of age-related neurodegenerative disorders.

The Influence of Long-Chain Omega-3 Fatty Acids on Eccentric Exercise-Induced Delayed Muscle Soreness: Reported Outcomes Are Compromised by Study Design Issues.

Delayed onset muscle soreness (DOMS) following eccentric exercise is associated with increased inflammation which can be debilitating. Incorporation of long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA), eicosapentaenoic acid, and docosahexaenoic acid into membrane phospholipids provides anti-inflammatory, proresolving, and analgesic effects. This systematic review aims to examine both the quality of studies and the evidence for LC n-3 PUFA in the attenuation of DOMS and inflammation following eccentric exercise, both which of course are empirically linked. The Scopus, Embase, and Web of Science electronic databases were searched to identify studies that supplemented fish oil for a duration of ≥7 days, which included DOMS outcomes following an eccentric exercise protocol. Fifteen (n = 15) studies met inclusion criteria. Eccentric exercise protocols varied from single to multijoint activities. Risk of bias, assessed using either the Cochrane Collaboration tool or the Risk of Bias in Nonrandomized Studies of Interventions tool, was judged as "unclear" or "medium," respectively, for the majority of outcomes. Furthermore, a custom 5-point quality assessment scale demonstrated that only one (n = 1) study satisfied current recommendations for investigating LC n-3 PUFA. In combination, this highlights widespread inappropriate design protocols among studies investigating the role of LC n-3 PUFA in eccentric exercise. Notwithstanding these issues, LC n-3 PUFA supplementation appears to have favorable effects on eccentric exercise-induced DOMS and inflammatory markers. However, the optimal LC n-3 PUFA supplemental dose, duration, and fatty acid composition will only become clear when study design issues are rectified and underpinned by appropriate hypotheses.

Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A2s

Human phospholipase A2s (PLA2) constitute a superfamily of enzymes that hydrolyze the sn-2 acyl-chain of glycerophospholipids, producing lysophospholipids and free fatty acids. Each PLA2 enzyme type contributes to specific biological functions based on its expression, subcellular localization, and substrate specificity. Among the PLA2 superfamily, the cytosolic cPLA2 enzymes, calcium-independent iPLA2 enzymes, and secreted sPLA2 enzymes are implicated in many diseases, but a central issue is the preference for double-bond positions in polyunsaturated fatty acids (PUFAs) occupying the sn-2 position of membrane phospholipids. We demonstrate that each PLA2 has a unique preference between the specific omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the omega-6 arachidonic acid (AA), which are the precursors of most proinflammatory and anti-inflammatory or resolving eicosanoids and related oxylipins. Surprisingly, we discovered that human cPLA2 selectively prefers AA, whereas iPLA2 prefers EPA, and sPLA2 prefers DHA as substrate. We determined the optimal binding of each phospholipid substrate in the active site of each PLA2 to explain these specificities. To investigate this, we utilized recently developed lipidomics-based LC-MS/MS and GC/MS assays to determine the sn-2 acyl chain specificity in mixtures of phospholipids. We performed μs timescale molecular dynamics (MD) simulations to reveal unique active site properties, especially how the precise hydrophobic cavity accommodation of the sn-2 acyl chain contributes to the stability of substrate binding and the specificity of each PLA2 for AA, EPA, or DHA. This study provides the first comprehensive picture of the unique substrate selectivity of each PLA2 for omega-3 and omega-6 fatty acids.

Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk

It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%). Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. ClinicalTrials.gov Identifier: NCT02104817.

Dietary supplementation with docosahexaenoic acid rich fish oil increases circulating levels of testosterone in overweight and obese men

Pre-clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs), in particular, docosahexaenoic acid (DHA) have been shown to affect testosterone synthesis in males. This study is a secondary analysis of a randomized controlled trial which determined the effect of a DHA-enriched fish oil supplement on insulin resistance. The aim of the current study was to determine whether testosterone levels change in response to a DHA-enriched fish oil intervention. Overweight and obese men and women without diabetes were recruited to the study. Participants were stratified by sex and randomly allocated to intervention (860 mg DHA + 120 g EPA/day; FO) or an isocaloric control (corn oil; CO) for 12 weeks. A fasted blood sample was collected pre- and post-intervention. Fatty acid composition of erythrocyte membranes was measured using gas chromatography. Total testosterone and metabolic parameters were measured by an accredited commercial pathology laboratory. Sixty-one participants (CO/FO: n = 29/32) were included in the current analysis (male: n = 22, 36.07%). DHA-enriched fish oil supplementation increased total testosterone levels in males after adjusting for baseline levels, age and BMI. There was no treatment effect in females. Changes in testosterone levels in males were positively associated with changes to omega-3 PUFAs EPA and DHA and inversely correlated with omega-6 PUFA, arachidonic acid and dihomo-gamma-linolenic acid content in erythrocyte membranes, and was associated with beneficial changes to fasting insulin and HOMA-IR across the course of the study. DHA-enriched fish oil supplementation increases testosterone levels in overweight and obese men. Further research is warranted to substantiate these findings with a larger sample size and a longer follow-up period.

A step to shell biorefinery—Extraction of astaxanthin-rich oil, protein, chitin, and chitosan from shrimp processing waste

Management of waste generated in fish processing industries is of great concern worldwide. Shrimp processing waste can be used for the generation of various biobased products along with its remediation. The present work was carried out to valorize shrimp processing waste using biorefinery approach. Ridgeback shrimp (Solenocera choprai) waste was used to produce commercially important biomolecules such as astaxanthin-rich oil, protein, chitin, and chitosan. Supercritical carbon dioxide extraction was performed for the extraction of astaxanthin and oil. Astaxanthin yield using super critical fluid extraction method was 30.26 ± 0.06 mg/kg dry shell weight. Extracted oil was found to have high content of health promoting polyunsaturated fatty acids, in particular omega-3 fatty acids, viz, eicosapentaenoic acid and docosahexaenoic acid. The remaining waste after the supercritical fluid extraction was used for protein extraction and the recovery yield was found to be 22.25 ± 0.15%. The residue left after extraction of astaxanthin and protein was used to extract chitin and the extracted chitin was used to produce chitosan. The yield of chitin and chitosan was 224.36 ± 0.32 g/kg and 156.99 ± 0.16 g/kg, respectively. The significant findings of the study suggest the potential of biorefinery in utilizing shrimp processing waste to produce commercially important products.

Lipid class and fatty acid composition of oil extracted from Atlantic salmon by-products under different optimization parameters of enzymatic hydrolysis

Abstract Six operational parameters, including fish part, antioxidant use, water addition, enzyme types, enzyme concentration and hydrolysis time, were studied about their effect on nutritional composition of oil enzymatically extracted from farmed Atlantic salmon by-products. Compared to the oil extracted from salmon viscera, the oil extracted from mixture of salmon heads and frames had higher amounts of triacylglycerols (TAGs), omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and lower amounts of omega-6 PUFAs. The interaction between water and high levels of hydrolysis time (4 h) or enzyme concentration (1%) resulted in decreased TAG content, increased content of phospholipids (PLs) and increased omega-6 PUFA content. The addition of antioxidant significantly increased the average content of omega-6 PUFAs, but decreased EPA and DHA amounts in viscera oil due to the pro-antioxidant activity of ascorbic acid. The use of Alcalase, Flavourzyme or SEBPRo didn't result in any significant difference in oil composition under studied conditions. The negative correlation between amounts of TAG and free fatty acid (FFA) indicates that the increase of FFA content resulted in the decrease of TAG content, mainly due to the oxidation of TAG promoted by FFAs.

340P Omega-3 fatty acids for cancer cachexia in advanced non-small cell lung cancer: A meta-analysis

Cancer cachexia is a common debilitating weight loss syndrome in advanced cancer, particularly in lung cancer patients. The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), because of their immune-modulating effects, have been used to improve the nutritional status of patients with cancer cachexia. This meta-analysis evaluated the effect of omega-3 fatty acids in change in weight and lean body mass or skeletal mass, and in health-related quality of life (HRQoL) scores in patients with advanced non-small cell lung cancer. Electronic databases were extensively searched for randomized controlled trials investigating omega-3 fatty acids in cancer cachexia among patients with advanced non-small cell lung cancer. Unpublished literature was also searched through manual handsearching and accessing online databases. Two review authors independently evaluated the methodological quality of the trials and analyzed the data. Six trials (394 patients) were included in the analysis. Five trials assessed change in weight, while two trials assessed change in lean body mass or skeletal mass, and HRQoL scores (Global Health and Physical Functioning Subscales). There is a significant difference in change in weight (mean difference [MD]: 1.22, 95% CI: 1.05 to 1.38; ƶ: 14.49, p<0.01) and HRQoL scores (Global Health subscale [MD: 14.40, 95% CI: 9.22 to 19.59, ƶ: 5.44, p<0.01] and Physical Functioning subscale [MD: 10.38, 95% CI: 8.50 to 12.27, ƶ: 10.78, p<0.01]) favoring the omega-3 fatty acids group. However, there is no sufficient evidence to support the association of change in lean body mass or skeletal mass, and the said intervention (MD: 2.05, 95% CI: -0.55 to 4.66; ƶ: 1.54, p: 0.12). Among patients with advanced non-small lung cancer with cancer cachexia, there is a significant increase in weight and HRQoL scores in the omega-3 fatty acids group. However, there is no sufficient evidence to support the association of change in lean body mass or skeletal mass, and the said intervention.

Increased Neuroanatomic Risk for Alzheimer’s Disease: Exploring the Interaction of Fine Particle Exposure and Long-Chain Omega-3 Polyunsaturated Fatty Acids

Background/Aim: Ambient fine particulate matter (PM2.5) may increase Alzheimer’s disease (AD) risk. Although epidemiologic and experimental studies have shown neurotrophic effects of long-chain omega-3 polyunsaturated fatty acids (LCn3FAs), no studies have investigated whether LCn3FAs modify the neurotoxic effect of PM2.5 on neuroanatomic risk for AD. Methods: Community-dwelling older women (aged 71-89) from the Women’s Health Initiative Memory Study of MRI completed two structural brain scans (MRI-1: 2005-6; MRI-2: 2010-11). The AD pattern similarity (AD-PS) score, developed by supervised machine learning and validated with AD Neuroimaging Initiative data, was used to measure neuroanatomic risk determined by the degree of high-dimensional gray matter atrophy in brain areas vulnerable to AD. Residential three-year average PM2.5 exposure preceding MRI-1 was aggregated from daily estimates, based on nationwide spatiotemporal modeling. Red blood cell fatty acid composition was analyzed using gas chromatography, with the omega-3 index defined as the sum of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We examined whether omega-3 index, EPA, and DHA modified the association between PM2.5 and AD-PS scores (5-year standardized difference) using generalized linear models, adjusting for geographic region, sociodemographics, lifestyle factors, clinical characteristics, intracranial volume, and total energy intake. Results: Among 627 women, PM2.5 (per 2.82-µg/m3) was significantly associated with increased AD-PS scores (β=0.026; p=0.003; equivalent to a 24% increase in AD risk) over 5 years. This association with PM2.5 was greater among women with lower (β=0.042; p=0.001) vs. higher (β=0.006; p=0.660) omega-3 index (median=0.050-g/1,000-kcal; pinteraction=0.056) and among women with lower (β=0.042; p=0.001) vs. higher (β=0.007; p=0.577) DHA (median=0.044-g/1,000-kcal; pinteraction=0.064). There was no evidence that EPA modified the association (pinteraction=0.340). Conclusions: Our findings support potential interactions between PM2.5 neurotoxicity and neurotrophic effects of LCn3FAs, though tests of interactions did not reach statistical significance. Higher LCn3FAs, achievable by dietary intervention, may reduce the AD risk associated with long-term PM2.5 exposure.