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1.  Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial 
BMC Pediatrics  2013;13:85.
Background
Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome since obesity and insulin resistance are the main pathogenic contributors for both conditions. NAFLD carries increased risk of atherosclerosis and cardiovascular diseases. There is an urgent need to find effective and safe therapy for children and adults with NAFLD. Data from research and clinical studies suggest that omega-3 fatty acids may be beneficial in metabolic syndrome-related conditions and can reduce the risk of cardiovascular disease.
Methods/design
We are conducting a randomized, multicenter, double-blind, placebo-controlled trial of treatment with omega-3 fatty acids in children with NAFLD. Patients are randomized to receive either omega-3 fatty acids containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or placebo for 24 weeks. The dose of omega-3 (DHA+ EPA) ranges from 450 to 1300 mg daily. Low calorie diet and increased physical activity are advised and monitored using validated questionnaires. The primary outcome of the trial is the number of patients who decreased ALT activity by ≥ 0,3 of upper limit of normal. The main secondary outcomes are improvement in the laboratory liver tests, liver steatosis on ultrasound, markers of insulin resistance and difference in fat/lean body mass composition after 6 months of intervention.
Discussion
Potential efficacy of omega-3 fatty acids in the treatment of NAFLD will provide needed rationale for use of this safe diet supplement together with weight reduction therapy in the growing population of children with NAFLD.
Trial registration
NCT01547910
doi:10.1186/1471-2431-13-85
PMCID: PMC3672084  PMID: 23702094
Non-alcoholic fatty liver disease; Omega-3 fatty acids; Polyunsaturated fatty acids; Randomized controlled trial; Children
2.  CAN THE RAT LIVER MAINTAIN NORMAL BRAIN DHA METABOLISM IN THE ABSENCE OF DIETARY DHA?2,3 
Background
Docosahexaenoic acid (DHA) is required for normal brain function. The concentration of DHA in the brain depends on both diet and liver metabolism.
Objective
To determine rat brain DHA concentration and consumption in relation to dietary n-3 (omega-3) polyunsaturated fatty acid (PUFA) content and liver secretion of DHA derived from circulating α-linolenic acid (α-LNA).
Design
Following weaning, male rats were fed for 15 weeks either: (1) a diet with a high DHA and α-LNA content, (2) an n-3 PUFA “adequate” diet containing 4.6% α-LNA but no DHA, or (3) an n-3 PUFA “deficient” diet containing 0.2% α-LNA and no DHA. Brain DHA consumption rates were measured following intravenous infusion in unanesthetized rats of [1-14C]DHA, whereas liver and brain DHA synthesis rates were measured by infusing [1-14C]α-LNA.
Results
Brain DHA concentrations equaled 17.6 μm/g, 11.4 μm/g and 7.14 μm/g in rats on diets 1, 2 and 3, respectively. With each diet, the rate of brain DHA synthesis from α-LNA was much less than the brain DHA consumption rate, whereas the liver synthesis-secretion rate was 5-10 fold higher. Higher elongase 2 and 5 and desaturase Δ5 and Δ6 activities in liver than in brain accounted for the higher liver DHA synthesis rates; these enzymes were transcriptionally upregulated in liver but not in brain of rats fed the deficient diet.
Conclusions
While DHA is essential to normal brain function, this need might be covered by dietary α-LNA when liver metabolic conversion machinery is intact and the diet has a high α-LNA content.
doi:10.1016/j.plefa.2009.05.021
PMCID: PMC2967256  PMID: 19540098
docosahexaenoic acid; liver; brain; rat; n-3; omega-3; PUFA; imaging; metabolism; diet; synthesis; α-linolenic acid
3.  The essentiality of arachidonic acid and docosahexaenoic acid 
Objective
The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.
Background
Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (DHA, omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.
Design
Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene-tetraene ratio (Mead acid/AA >0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.
Results
No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene-tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when thirteen percent of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.
Conclusions
When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.
doi:10.1016/j.plefa.2009.05.020
PMCID: PMC3361712  PMID: 19540099
4.  Short term effects of different omega-3 fatty acid formulation on lipid metabolism in mice fed high or low fat diet 
Background
Bioactivities of Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) depend on their chemical forms. The present study was to investigate short term effects of triglyceride (TG), ethyl ester (EE), free fatty acid (FFA) and phospholipid (PL) forms of omega-3 fatty acid (FA) on lipid metabolism in mice, fed high fat or low fat diet.
Method
Male Balb/c mice were fed with 0.7% different Omega-3 fatty acid formulation: DHA bound free fatty acid (DHA-FFA), DHA bound triglyceride (DHA-TG), DHA bound ethyl ester (DHA-EE) and DHA bound phospholipid (DHA-PL) for 1 week, with dietary fat levels at 5% and 22.5%. Serum and hepatic lipid concentrations were analyzed, as well as the fatty acid composition of liver and brain.
Result
At low fat level, serum total cholesterol (TC) level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL were significantly lower than that in the control group (P < 0.05). Hepatic TG level decreased significantly in mice fed diets with DHA-TG (P < 0.05), DHA-EE (P < 0.05) and DHA-PL (P < 0.05), while TC level in liver was significantly lower in mice fed diets with TG and EE compared with the control group (P < 0.05). At high fat level, mice fed diets with DHA-EE and DHA-PL had significantly lower hepatic TC level compared with the control diet (P < 0.05). Hepatic PL concentration experienced a significant increase in mice fed the diet with PL at high fat level (P < 0.05). Furthermore, both at low and high fat levels, hepatic DHA level significantly increased and AA level significantly decreased in all forms of DHA groups (P < 0.05), compared to control groups at two different fat levels, respectively. Additionally, cerebral DHA level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL significantly increased compared with the control at high fat level (P < 0.05), but no significant differences were observed among dietary treatments for mice fed diets with low fat level.
Conclusion
The present study suggested that not only total dietary fat content but also the molecular forms of omega-3 fatty acids contributed to lipid metabolism in mice. DHA-PL showed effective bioactivity in decreasing hepatic and serum TC, TG levels and increasing omega-3 concentration in liver and brain.
doi:10.1186/1476-511X-11-70
PMCID: PMC3393618  PMID: 22676394
Omega-3 fatty acid; DHA; EPA; Lipid metabolism; Triglycerides; Ethyl ester; Phospholipids
5.  Omega-3 fatty acids: potential role in the management of early Alzheimer’s disease 
Omega-3 fatty acids are essential for brain growth and development. They play an important role throughout life, as critical modulators of neuronal function and regulation of oxidative stress mechanisms, in brain health and disease. Docosahexanoic acid (DHA), the major omega-3 fatty acid found in neurons, has taken on a central role as a target for therapeutic intervention in Alzheimer’s disease (AD). A plethora of in vitro, animal model, and human data, gathered over the past decade, highlight the important role DHA may play in the development of a variety of neurological and psychiatric disorders, including AD. Cross sectional and prospective cohort data have demonstrated that reduced dietary intake or low brain levels of DHA are associated with accelerated cognitive decline or the development of incipient dementia, including AD. Several clinical trials investigating the effects of omega-3 fatty acid supplementation in AD have been completed and all failed to demonstrate its efficacy in the treatment of AD. However, these trials produced intriguing data suggesting that the beneficial effects of omega-3 fatty acid supplementation may depend on the stage of disease, other dietary mediators, and apolipoprotein E status.
PMCID: PMC2854051  PMID: 20396634
Alzheimer’s disease; omega-3 fatty acids; oxidative stress; clinical studies; treatment
6.  Docosahexaenoic Acid, Inflammation, and Bacterial Dysbiosis in Relation to Periodontal Disease, Inflammatory Bowel Disease, and the Metabolic Syndrome 
Nutrients  2013;5(8):3299-3310.
Docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid, has been used to treat a range of different conditions, including periodontal disease (PD) and inflammatory bowel disease (IBD). That DHA helps with these oral and gastrointestinal diseases in which inflammation and bacterial dysbiosis play key roles, raises the question of whether DHA may assist in the prevention or treatment of other inflammatory conditions, such as the metabolic syndrome, which have also been linked with inflammation and alterations in normal host microbial populations. Here we review established and investigated associations between DHA, PD, and IBD. We conclude that by beneficially altering cytokine production and macrophage recruitment, the composition of intestinal microbiota and intestinal integrity, lipopolysaccharide- and adipose-induced inflammation, and insulin signaling, DHA may be a key tool in the prevention of metabolic syndrome.
doi:10.3390/nu5083299
PMCID: PMC3775255  PMID: 23966110
inflammation; periodontal disease; inflammatory bowel disease; metabolic syndrome; bacterial dysbiosis; microbiome; DHA; docosahexaenoic acid; omega-3; fattyacid
7.  Oral Supplementation with Docosahexaenoic Acid and Uridine-5’-Monophosphate Increases Dendritic Spine Density in Adult Gerbil Hippocampus 
Brain research  2007;1182:50-59.
Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is an essential component of membrane phosphatides and has been implicated in cognitive functions. Low levels of circulating or brain DHA are associated with various neurocognitive disorders including Alzheimer’s disease (AD), while laboratory animals, including animal models of AD, can exhibit improved cognitive ability with a diet enriched in DHA. Various cellular mechanisms have been proposed for DHA’s behavioral effects, including increases in cellular membrane fluidity, promotion of neurite extension, and inhibition of apoptosis. However, there is little direct evidence that DHA affects synaptic structure in living animals. Here we show that oral supplementation with DHA substantially increases the number of dendritic spines in adult gerbil hippocampus, particularly when animals are co-supplemented with a uridine source, uridine-5’-monophosphate (UMP), which increases brain levels of the rate-limiting phosphatide precursor CTP. The increase in dendritic spines (> 30%) is accompanied by parallel increases in membrane phosphatides, and in pre- and post-synaptic proteins within the hippocampus. Hence oral DHA may promote neuronal membrane synthesis to increase the number of synapses, particularly when co-administered with UMP. Our findings provide a possible explanation for the effects of DHA on behavior and also suggest a strategy to treat cognitive disorders resulting from synapse loss.
doi:10.1016/j.brainres.2007.08.089
PMCID: PMC2140951  PMID: 17950710
docosahexaenoic acid; uridine; membrane synthesis; spine formation; synaptogenesis; phosphatides
8.  Induction of lipid oxidation by polyunsaturated fatty acids of marine origin in small intestine of mice fed a high-fat diet 
BMC Genomics  2009;10:110.
Background
Dietary polyunsaturated fatty acids (PUFA), in particular the long chain marine fatty acids docosahexaenoic (DHA) and eicosapentaenoic (EPA), are linked to many health benefits in humans and in animal models. Little is known of the molecular response to DHA and EPA of the small intestine, and the potential contribution of this organ to the beneficial effects of these fatty acids. Here, we assessed gene expression changes induced by DHA and EPA in the wildtype C57BL/6J murine small intestine using whole genome microarrays and functionally characterized the most prominent biological process.
Results
The main biological process affected based on gene expression analysis was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR, and -in a second animal experiment- intestinal fatty acid oxidation measurements confirmed significant gene expression differences and showed in a dose-dependent manner significant changes at biological functional level. Furthermore, no major changes in the expression of lipid metabolism genes were observed in the colon.
Conclusion
We show that marine n-3 fatty acids regulate small intestinal gene expression and increase fatty acid oxidation. Since this organ contributes significantly to whole organism energy use, this effect on the small intestine may well contribute to the beneficial physiological effects of marine PUFAs under conditions that will normally lead to development of obesity, insulin resistance and diabetes.
doi:10.1186/1471-2164-10-110
PMCID: PMC2662879  PMID: 19284886
9.  Docosahexaenoic Acid Neurolipidomics 
Mediator lipidomics is a field of study concerned with the characterization, structural elucidation and bioactivity of lipid derivatives generated by enzymatic activity. Omega-3 fatty acids have beneficial effects for vision, brain function, cardiovascular function, and immune-inflammatory responses. Docosahexaenoic acid [DHA; 22:6(n-3)], the most abundant essential omega-3 fatty acid in the human body, is selectively enriched and avidly retained in the central nervous system as an acyl chain of phospholipids. Brain-ischemia reperfusion and seizures trigger rapid release of DHA and of arachidonic acid (AA) as free, unesterified fatty acids. AA in turn generates eicosanoids, and DHA forms docosanoids. The stereoselective docosanoid neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,15E,19Z hexaenoic acid) is formed early in brain-ischemia reperfusion. Supplementation of NPD1 (intracerebroventricularly; i.c.v.) or of DHA (i.c.v. or systemically) results in decreased infarct size, polymorphonuclear neutrophil infiltration, ischemia-induced nuclear factor kappa B (NFκB) activation, and cyclooxygenase-2 (COX-2) induction. DHA involvement in cell function includes enhancing Akt translocation and activation, and binding to a peroxisome proliferator-activated receptor-gamma (PPAR-γ) family of ligand-activated nuclear receptors. Here we present an overview of recent DHA-mediator lipidomic studies in experimental brain ischemia-reperfusion and other conditions.
doi:10.1016/j.prostaglandins.2009.09.005
PMCID: PMC2905848  PMID: 19804838
10.  Docosahexaenoic acid in maternal and neonatal plasma phospholipids and milk lipids of Taiwanese women in Kinmen: fatty acid composition of maternal blood, neonatal blood and breast milk 
Background
Docosahexaenoic acid (DHA) is a long-chain omega-3 polyunsaturated fatty acid (LCPUFA) that is critically important for the structure, development and function of the retina and central nervous system (CNS), ultimately contributing to improved cognition. It is known that the DHA content of breast milk is positively correlated with maternal DHA intake. Since there is a lack of information about the DHA status of pregnant and lactating women in rural Taiwan. The aims of the present study were to: 1) assess the DHA status of mothers and babies in urban setting, and 2) determine the content of DHA in the milk of nursing mothers.
Methods
All pregnant women who attended the Obstetrics and Gynecology Outpatient Clinic of Kinmen Hospital on Kinmen Island in Taiwan between May 1 and May 30, 2011 were invited by research nurses to enroll in the study. The maternal blood sample was obtained on the day of their delivery. Cord blood was collected by the obstetrician following delivery. Participants were asked to visit the doctor forty-two days after the delivery, at which time a nurse collected breast milk on the day mothers were visiting the doctor for post-natal well-baby check-up.
Results
The DHA percentages of maternal and neonatal plasma phospholipids were 5.16% and 6.36%, respectively, which are higher than values reported for most populations elsewhere in the world. The DHA percentage for the breast milk of Kinmen mothers was also high (0.98%) relation to international norms. The DHA proportions in maternal and neonatal plasma phospholipids were positively correlated (r = 0.46, p = 0.01).
Conclusions
We show that the DHA status of mothers and newborns on Kinmen Island is satisfactory, thereby providing an evidence-based argument for promoting breastfeeding in Taiwan.
doi:10.1186/1476-511X-12-27
PMCID: PMC3608933  PMID: 23496882
Breast milk; Lactation; Neonates; Fish intake; Kinmen; Docosahexaenoic acid; Pregnancy; Fatty acids
11.  Transgenic fat-1 mouse as a model to study the pathophysiology of cardiovascular, neurological and psychiatric disorders 
Polyunsaturated fatty acids (PUFAs) form an important constituent of all the cell membranes in the body. PUFAs such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) form precursors to both pro-inflammatory and anti-inflammatory compounds. Low-grade systemic inflammation occurs in clinical conditions such as insulin resistance, hypertension, type 2 diabetes mellitus, atherosclerosis, coronary heart disease, lupus, schizophrenia, Alzheimer's disease, and other dementias, cancer and non-alcoholic fatty liver disease (NAFLD) that are also characterized by an alteration in the metabolism of essential fatty acids in the form of excess production of pro-inflammatory eicosanoids and possibly, decreased synthesis and release of anti-inflammatory lipoxins, resolvins, protectins and maresins. We propose that low-grade systemic inflammation observed in these clinical conditions is due to an imbalance in the metabolism of essential fatty acids that is more in favour of pro-inflammatory molecules. In this context, transgenic fat-1 mouse that is designed to convert n-6 to n-3 fatty acids could form an ideal model to study the altered metabolism of essential fatty acids in the above mentioned conditions. It is envisaged that low-grade systemic inflammatory conditions are much less likely in the fat-1 mouse and/or these diseases will run a relatively mild course. Identifying the anti-inflammatory compounds from n-3 fatty acids that suppress low-grade systemic inflammatory conditions and understanding their mechanism(s) of action may lead to newer therapeutic strategies.
doi:10.1186/1476-511X-8-61
PMCID: PMC2811702  PMID: 20042103
12.  Omega-3 Fatty Acids and Cardiovascular Disease: A Case for Omega-3 Index as a New Risk Factor 
The omega-3 fatty acids (FAs) found in fish and fish oils (eicosapentaenoic and docosahexaenoic acids, EPA and DHA) have been reported to have a variety of beneficial effects in cardiovascular diseases. Ecological and prospective cohort studies as well as randomized, controlled trials have supported the view that the effects of these FAs are clinically-relevant. They operate via several mechanisms, all beginning with the incorporation of EPA and DHA into cell membranes. From here, these omega-3 FA alter membrane physical characteristics and the activity of membrane-bound proteins, and once released by intracellular phospholipases, can interact with ion channels, be converted into a wide variety of bioactive eicosanoids, and serve as ligands for several nuclear transcription factors thereby altering gene expression. In as much as blood levels are a strong reflection of dietary intake, it is proposed that an omega-3 FA biomarker, the omega-3 index (erythrocyte EPA+DHA) be considered at least a marker, if not a risk factor, for coronary heart disease, especially sudden cardiac death. The omega-3 index fulfils many of the requirements for a risk factor including consistent epidemiological evidence, a plausible mechanism of action, a reproducible assay, independence from classical risk factors, modifiability, and most importantly, the demonstration that raising tissue levels will reduce risk for cardiac events. For these and a number of other reasons, the omega-3 index compares very favourably with other risk factors for sudden cardiac death.
doi:10.1016/j.phrs.2007.01.013
PMCID: PMC1899522  PMID: 17324586
Eicosapentaenoic acid; docosahexaenoic acid; biomarkers; risk factors; cardiovascular disease; coronary heart disease; sudden cardiac death; fish oils
13.  Docosahexaenoic Acid Supplementation, Vascular Function and Risk Factors for Cardiovascular Disease: A Randomized Controlled Trial in Young Adults 
Background
A high consumption of omega‐3 long‐chain polyunsaturated fatty acids, and particularly docosahexaenoic acid (DHA), has been suggested to reduce the risk of cardiovascular disease (CVD). However, while DHA supplementation may have benefits for secondary prevention, few studies have investigated the role of DHA in the primary prevention of CVD. Here, we tested the hypothesis that DHA supplementation improves endothelial function and risk factors for CVD.
Methods and Results
Healthy volunteers (n=328), aged 18 to 37 years, were randomly assigned to 1.6 g DHA/day (from a microalgae source) together with 2.4 g/day carrier oil (index group) or to 4.0 g/day olive oil (control) (both given in eight 500‐mg capsules/day for 16 weeks). Flow‐mediated endothelium‐dependent vasodilation (FMD) of the brachial artery (primary outcome) was measured before and after the intervention (n=268) using high‐resolution vascular ultrasound. FMD was the same in both groups at randomization (mean, SD; 0.27, 0.1 mm), but postintervention was higher in the control group (0.29, 0.1 mm) compared with the DHA‐supplemented group (0.26, 0.1 mm; mean difference −0.03 mm; 95% CI −0.005 to −0.06 mm; P=0.02). Of other outcomes, only triglyceride (mean difference −28%, 95% CI −40% to −15%; P<0.0001) and very low‐density lipoprotein concentrations were significant lower in DHA‐supplemented individuals compared with controls.
Conclusions
DHA supplementation did not improve endothelial function in healthy, young adults. Nevertheless, lower triglyceride concentrations with DHA supplementation was consistent with previous reports and could have benefits for the prevention of CVD.
Clinical Trial Registration Information
URL: http://www.controlled-trials.com/ Unique identifier: ISRCTN no: 19987575.
doi:10.1161/JAHA.113.000283
PMCID: PMC3828816  PMID: 23817470
atherosclerosis; docosahexaenoic acid; endothelial function
14.  Distinguishing Health Benefits of Eicosapentaenoic and Docosahexaenoic Acids 
Marine Drugs  2012;10(11):2535-2559.
Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) are recommended for management of patients with wide-ranging chronic diseases, including coronary heart disease, rheumatoid arthritis, dementia, and depression. Increased consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is recommended by many health authorities to prevent (up to 0.5 g/day) or treat chronic disease (1.0 g/day for coronary heart disease; 1.2–4 g/day for elevated triglyceride levels). Recommendations for dietary intake of LC n-3 PUFAs are often provided for α-linolenic acid, and for the combination of EPA and DHA. However, many studies have also reported differential effects of EPA, DHA and their metabolites in the clinic and at the laboratory bench. The aim of this article is to review studies that have identified divergent responses to EPA and DHA, and to explore reasons for these differences. In particular, we review potential contributing factors such as differential membrane incorporation, modulation of gene expression, activation of signaling pathways and metabolite formation. We suggest that there may be future opportunity to refine recommendations for intake of individual LC n-3 PUFAs.
doi:10.3390/md10112535
PMCID: PMC3509534  PMID: 23203276
LC n-3 PUFAs; omega-3 fatty acids; eicosapentaenoic acid; docosahexaenoic acid; resolvin D1; differential response; omega-3 fatty acid metabolites
15.  Convergent functional genomic studies of omega-3 fatty acids in stress reactivity, bipolar disorder and alcoholism 
Translational Psychiatry  2011;1(4):e4-.
Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease-relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well-established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond.
doi:10.1038/tp.2011.1
PMCID: PMC3309466  PMID: 22832392
alcoholism; bipolar; DHA; genomics; omega-3; stress
16.  Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease 
Jama  2010;304(17):1903-1911.
Context
Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology.
Objective
To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease.
Design, Setting, and Patients
A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14–26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study.
Intervention
Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months.
Main Outcome Measures
Change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102).
Results
A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51–9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72–9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44–3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44–3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm3 (95% CI, 21.4–28.0 cm3) during 18 months and a 1.32% (95% CI, 1.14%–1.50%) volume decline per year compared with 24.0 cm3 (95% CI, 20–28 cm3) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%–1.51%) volume decline per year (P = .79).
Conclusion
Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.
doi:10.1001/jama.2010.1510
PMCID: PMC3259852  PMID: 21045096
17.  Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke 
Translational Stroke Research  2010;2(1):33-41.
We examined the neuroprotective efficacy of docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, in acute ischemic stroke; studied the therapeutic window; and investigated whether DHA administration after an ischemic stroke is able to salvage the penumbra. In each series described below, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo). In series 1, DHA or saline was administered i.v. at 3, 4, 5, or 6 h after stroke. In series 2, MRI was conducted on days 1, 3 and 7. In series 3, DHA or saline was administered at 3 h, and lipidomic analysis was conducted on day 3. Treatment with DHA significantly improved behavior and reduced total infarct volume by a mean of 40% when administered at 3 h, by 66% at 4 h, and by 59% at 5 h. Total lesion volumes computed from T2-weighted images were reduced in the DHA group at all time points. Lipidomic analysis showed that DHA treatment potentiates neuroprotectin D1 (NPD1) synthesis in the penumbra 3 days after MCAo. DHA administration provides neurobehavioral recovery, reduces brain infarction and edema, and activates NPD1 synthesis in the penumbra when administered up to 5 h after focal cerebral ischemia in rats.
doi:10.1007/s12975-010-0046-0
PMCID: PMC3037476  PMID: 21423332
Focal ischemia; Magnetic resonance imaging; Neuroprotection; Animal models
18.  DHA derivatives of fish oil as dietary supplements: a nutrition-based drug discovery approach for therapies to prevent metabolic cardiotoxicity 
Expert opinion on drug discovery  2012;7(8):711-721.
Introduction
During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA-enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease.
Areas covered
This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases.
Expert opinion
The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease.
doi:10.1517/17460441.2012.694862
PMCID: PMC3969443  PMID: 22724444
cardiovascular disease; dietary supplement; docosahexaenoic acid; eicosapentaenoic acid; fish oil; metabolic syndrome; obesity
19.  Potential Benefits of Icosapent Ethyl on the Lipid Profile: Case Studies 
The cardiovascular benefits of marine-derived omega-3 fatty acids are supported by epidemiologic and clinical studies. Both healthy patients and those with confirmed coronary heart disease are advised by the American Heart Association to consume omega-3 fatty acids either through dietary fatty fish or fish oil products. We present two case reports of patients with dyslipidemia who were switched from an omega-3 dietary supplement or a prescription omega-3 drug containing eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) to a new prescription EPA-only drug, icosapent ethyl (IPE). Products containing a combination of EPA and DHA, including dietary supplements and prescription products, are more likely to increase low-density lipoprotein cholesterol (LDL-C) levels compared with pure EPA-only products. The lipid profiles of these two patients were improved with IPE treatment, illustrating the potentially favorable effects of IPE compared with other products containing both EPA and DHA.
doi:10.4137/CMC.S13571
PMCID: PMC3914996  PMID: 24516343
omega-3 fatty acids; fish oil; eicosapentaenoic acid; docosahexaenoic acid; lipids; icosapent ethyl
20.  The Effects of Omega-3 Fatty Acids on Matrix Metalloproteinase-9 Production and Cell Migration in Human Immune Cells: Implications for Multiple Sclerosis 
Autoimmune Diseases  2011;2011:134592.
In multiple sclerosis (MS), compromised blood-brain barrier (BBB) integrity contributes to inflammatory T cell migration into the central nervous system. Matrix metalloproteinase-9 (MMP-9) is associated with BBB disruption and subsequent T cell migration into the CNS. The aim of this paper was to evaluate the effects of omega-3 fatty acids on MMP-9 levels and T cell migration. Peripheral blood mononuclear cells (PBMC) from healthy controls were pretreated with two types of omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Cell supernatants were used to determine MMP-9 protein and activity levels. Jurkat cells were pretreated with EPA and DHA and were added to fibronectin-coated transwells to measure T cell migration. EPA and DHA significantly decreased MMP-9 protein levels, MMP-9 activity, and significantly inhibited human T cell migration. The data suggest that omega-3 fatty acids may benefit patients with multiple sclerosis by modulating immune cell production of MMP-9.
doi:10.4061/2011/134592
PMCID: PMC3140187  PMID: 21799946
21.  Effects of Specific Multi-Nutrient Enriched Diets on Cerebral Metabolism, Cognition and Neuropathology in AβPPswe-PS1dE9 Mice 
PLoS ONE  2013;8(9):e75393.
Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AβPPswe-PS1dE9 mice. Starting from 2 months of age, male AβPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1β mRNA levels in AβPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AβPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AβPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders.
doi:10.1371/journal.pone.0075393
PMCID: PMC3782450  PMID: 24086523
22.  A role for docosahexaenoic acid–derived neuroprotectin D1 in neural cell survival and Alzheimer disease 
Journal of Clinical Investigation  2005;115(10):2774-2783.
Deficiency in docosahexaenoic acid (DHA), a brain-essential omega-3 fatty acid, is associated with cognitive decline. Here we report that, in cytokine-stressed human neural cells, DHA attenuates amyloid-β (Aβ) secretion, an effect accompanied by the formation of NPD1, a novel, DHA-derived 10,17S-docosatriene. DHA and NPD1 were reduced in Alzheimer disease (AD) hippocampal cornu ammonis region 1, but not in the thalamus or occipital lobes from the same brains. The expression of key enzymes in NPD1 biosynthesis, cytosolic phospholipase A2 and 15-lipoxygenase, was altered in AD hippocampus. NPD1 repressed Aβ42-triggered activation of proinflammatory genes while upregulating the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1). Soluble amyloid precursor protein-α stimulated NPD1 biosynthesis from DHA. These results indicate that NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Aβ42-induced neurotoxicity.
doi:10.1172/JCI25420
PMCID: PMC1199531  PMID: 16151530
23.  Oral bioavailability of the ether lipid plasmalogen precursor, PPI-1011, in the rabbit: a new therapeutic strategy for Alzheimer's disease 
Introduction
Docosahexaenoic acid (DHA) and DHA-containing ethanolamine plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing ether lipid precursor of plasmalogens. PPI-1011 is an alkyl-diacyl plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn).
Methods
Rabbits were dosed orally with PPI-1011 in hard gelatin capsules for time-course and dose response studies. Incorporation into PlsEtn and PtdEtn was monitored by LC-MS/MS. Metabolism of released lipoic acid was monitored by GC-MS. To monitor the metabolic fate of different components of PPI-1011, we labeled the sn-1 palmitic acid, sn-2 DHA and glycerol backbone with13C and monitored their metabolic fates by LC-MS/MS.
Results
PPI-1011 was not detected in plasma suggesting rapid release of sn-3 lipoic acid via gut lipases. This conclusion was supported by peak levels of lipoic acid metabolites in the plasma 3 hours after dosing. While PPI-1011 did not gain access to the plasma, it increased circulating levels of DHA-containing PlsEtn and PtdEtn. Labeling experiments demonstrated that the PtdEtn increases resulted from increased availability of DHA released via remodeling at sn-2 of phospholipids derived from PPI-1011. This release of DHA peaked at 6 hrs while increases in phospholipids peaked at 12 hr. Increases in circulating PlsEtn were more complex. Labeling experiments demonstrated that increases in the target PlsEtn, 16:0/22:6, consisted of 2 pools. In one pool, the intact precursor received a sn-3 phosphoethanolamine group and desaturation at sn-1 to generate the target plasmalogen. The second pool, like the PtdEtn, resulted from increased availability of DHA released during remodeling of sn-2. In the case of sn-1 18:0 and 18:1 plasmalogens with [13C3]DHA at sn-2, labeling was the result of increased availability of [13C3]DHA from lipid remodeling. Isotope and repeated dosing (2 weeks) experiments also demonstrated that plasmalogens and/or plasmalogen precursors derived from PPI-1011 are able to cross both the blood-retinal and blood-brain barriers.
Conclusions
Our data demonstrate that PPI-1011, an ether lipid precursor of plasmalogens is orally bioavailable in the rabbit, augmenting the circulating levels of unesterified DHA and DHA-containing PlsEtn and PtdEtn. Other ethanolamine plasmalogens were generated from the precursor via lipid remodeling (de-acylation/re-acylation reactions at sn-2) and phosphatidylethanolamines were generated via de-alkylation/re-acylation reactions at sn-1. Repeated oral dosing for 2 weeks with PPI-1011 resulted in dose-dependent increases in circulating DHA and DHA-containing plasmalogens. These products and/or precursors were also able to cross the blood-retinal and blood-brain barriers.
doi:10.1186/1476-511X-10-227
PMCID: PMC3260122  PMID: 22142382
24.  Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids 
Journal of hepatology  2008;49(2):262-273.
Background/Aims
We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6, omega-6) and docosahexaenoic (DHA,22:6n3, omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet prevents alcohol-induced fatty liver.
Methods
Male Long-Evans rats were fed an ethanol or control liquid-diet with or without DHA/AA for 9 weeks. Plasma transaminase levels, liver histology, oxidative/nitrosative stress markers, and activities of oxidatively-modified mitochondrial proteins were evaluated.
Results
Chronic alcohol administration increased the degree of fatty liver but fatty liver decreased significantly in rats fed the alcohol-DHA/AA-supplemented diet. Alcohol exposure increased oxidative/nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. However, these increments were normalized in rats fed the alcohol-DHA/AA-supplemented diet. The number of oxidatively-modified mitochondrial proteins was markedly increased following alcohol exposure but significantly reduced in rats fed the alcohol-DHA/AA-supplemented diet. The suppressed activities of mitochondrial aldehyde dehydrogenase, ATP synthase, and 3-ketoacyl-CoA thiolase in ethanol-exposed rats were also recovered in animals fed the ethanol-DHA/AA-supplemented diet.
Conclusions
Addition of DHA/AA prevents alcohol-induced fatty liver and mitochondrial dysfunction in an animal model by protecting various mitochondrial enzymes most likely through reducing oxidative/nitrosative stress.
doi:10.1016/j.jhep.2008.04.023
PMCID: PMC2532851  PMID: 18571270
Alcoholic fatty liver; polyunsaturated fatty acids; Long-Evans rat; Oxidative/nitrosative stress; Protein oxidation; β-oxidation of fatty acids; Mitochondrial dysfunction
25.  High potency fish oil supplement improves omega-3 fatty acid status in healthy adults: an open-label study using a web-based, virtual platform 
Nutrition Journal  2013;12:112.
Background
The health benefits of omega-3 fatty acids from fish are well known, and fish oil supplements are used widely in a preventive manner to compensate the low intake in the general population. The aim of this open-label study was to determine if consumption of a high potency fish oil supplement could improve blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and impact SF-12 mental and physical health scores in healthy adults.
Methods
A novel virtual clinical research organization was used along with the HS-Omega-3 Index, a measure of EPA and DHA in red blood cell membranes expressed as a percentage of total fatty acids that has been shown to correlate with a reduction in cardiovascular and other risk factors. Briefly, adult subjects (mean age 44 years) were recruited from among U.S. health food store employees and supplemented with 1.1 g/d of omega-3 from fish oil (756 mg EPA, 228 mg DHA, Minami Nutrition® MorEPA® Platinum) for 120 days (n = 157).
Results
Omega-3 status and mental health scores increased with supplementation (p < 0.001), while physical health scores remained unchanged.
Conclusions
The use of a virtual, web-based platform shows considerable potential for engaging in clinical research with normal, healthy subjects. A high potency fish oil supplement may further improve omega-3 status in a healthy population regularly consuming an omega-3 supplement.
doi:10.1186/1475-2891-12-112
PMCID: PMC3751074  PMID: 23924406
Omega-3 index; Eicosapentaenoic acid; Docosahexaenoic acid; Fish oil; Open-label

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