Lipid Docosahexaenoic Acid Research Articles

TLR4 Blockade Using Docosahexaenoic Acid Restores Vulnerability of Drug-Tolerant Tumor Cells and Prevents Breast Cancer Metastasis and Postsurgical Relapse.

Nonmutational mechanisms were recently discovered leading to reversible drug tolerance. Despite the rapid elimination of a majority of tumor cells, a small subpopulation of "'drug-tolerant"' cells remain viable with lethal drug exposure, which may further lead to resistance or tumor relapse. Several signaling pathways are involved in the local or systemic inflammatory responses contributing to drug-induced phenotypic switch. Here, we report that Toll-like receptor 4 (TLR4)-interacting lipid docosahexaenoic acid (DHA) restores the cytotoxic effect of doxorubicin (DOX) in the lipopolysaccharide-treated breast tumor cell line 4T1, preventing the phenotypic switch to drug-tolerant cells, which significantly reduces primary tumor growth and lung metastasis in both 4T1 orthotopic and experimental metastasis models. Importantly, DHA in combination with DOX delays and inhibits tumor recurrence following surgical removal of the primary tumor. Furthermore, the coencapsulation of DHA and DOX in a nanoemulsion significantly prolongs the survival of mice in the postsurgical 4T1 tumor relapse model with significantly reduced systemic toxicity. The synergistic antitumor, antimetastasis, and antirecurrence effects of DHA + DOX combination are likely mediated by attenuating TLR4 activation, thus sensitizing tumor cells to standard chemotherapy.

Lipids in the origin of intracellular detail and speciation in the Cambrian epoch and the significance of the last double bond of docosahexaenoic acid in cell signaling

One of the great unanswered biological questions is the absolute necessity of the polyunsaturated lipid docosahexaenoic acid (DHA; 22:6n-3) in retinal and neural tissues. Everything from the simple eye spot of dinoflagellates to cephalopods to every class of vertebrates uses DHA, yet it is abundant only in cold water marine food chains. Docosapentaenoic acids (DPAs; 22:5n-6 and especially 22:5n-3) are fairly plentiful in food chains yet cannot substitute for DHA. About 600 million years ago, multi-cellular, air breathing systems evolved rapidly and 32 phyla came into existence in a short geological time span; the “Cambrian Explosion”. Eukaryotic intracellular detail requires cell membranes, which are constructed of complex lipids, and proteins. Proteins and nucleic acids would have been abundant during the first 2.5–5 billion years of anaerobic life but lipids, especially unsaturated fatty acids, would not. We hypothesize lipid biology was a key driver of the Cambrian Explosion, because it alone provides for compartmentalization and specialization within cellsDHA has six methylene interrupted double bonds providing controlled electron flow at precise energy levels; this is essential for visual acuity and truthful execution of the neural pathways which make up our recollections, information processing and consciousness. The last double bond is critical for the evolution and function of the photoreceptor and neuronal and synaptic signaling systems. It completes a quantum mechanical device for the regulation of current flow with absolute signal precision based on electron tunneling (ET). DHA's methylene interruption distance is < 6 Å, making ET transfer between the π-orbitals feasible throughout the molecule. The possibility fails if one double bond is removed and replaced by a saturated bond as in the DPAs.The molecular biophysical foundation of neural signaling can also include the discrete pattern of paired spin states that arise in the DHA double bond and methylene regions. The complexity depends upon the number of C13 and H1 molecular sites in which spin states are coupled. Electron wave harmonics with entanglement and cohesion provide a mechanism for learning and memory, and power cognition and complex human brain functions.

Suitability of Tisochrysis lutea at different growth phases as an enrichment diet for Brachionus plicatilis sp. complex rotifers

In larviculture of marine finfish, Tisochrysis lutea cultured cells have a potential to be a sustainable enrichment diet for rotifers due to its de novo synthesis of docosahexaenoic acid (DHA). To improve its effectiveness in rotifer enrichment for later larviculture, we determined which growth phase of T. lutea can enhance DHA in polar lipids (PLs) in Brachionus plicatilis sp. complex rotifers without reducing their vigor. Tisochrysis lutea was harvested at logarithmic growth phase, deceleration growth phase, and stationary phase. The ambient concentrations of phosphorus (P) and nitrogen (N), and fatty acid composition of microalgae were measured. P was limited between logarithmic and deceleration growth phases, followed by N starvation in stationary phase. Total lipid DHA was lowest in logarithmic growth phase, whereas DHA levels increased in deceleration growth phase and maintained at high levels even in stationary phase. PL-DHA also increased during deceleration growth phase, although its abundance dropped during stationary phase. In a rotifer enrichment trial, T. lutea harvested in each phase were fed to B. plicatilis sp. complex rotifers for 12 h. The highest PL-DHA value for cells in deceleration growth phase reflected the concentrations of the rotifers. No significant differences were found in rotifer growth rate and egg ratio. Rotifers fed cells in deceleration growth phase exhibited higher swimming speeds than those fed the other cells, potentially linking to increased larval capture success. Therefore, we recommend the deceleration growth phase as an optimal timing for T. lutea harvest for the effective enrichment of B. plicatilis sp. complex rotifers.

Randomized open-label trial of docosahexaenoic acid-enriched fish oil and fish meal on cognitive and behavioral functioning in Omani children.

This study aimed to examine the effect of docosahexaenoic acid (DHA)-enriched fish oil supplement and meal of grilled fish on cognitive and behavioral functioning manifested as attention-deficit/hyperactivity disorder in primary school students 9 to 10 y of age in Muscat, Oman. This randomized open-label trial involved two types of interventions: fish oil supplement or one serving (100 g) of grilled fish per day (Sunday through Friday) for 12 weeks. Red cell total lipid DHA levels were assessed. The Verbal Fluency Test, Buschke Selective Reminding Test, and Trail Making Test were used to measure cognitive functioning. Behavioral functioning was assessed using a standardized Arabic version of the National Initiative for Children's Health Quality Vanderbilt Assessment Scales. All measurements were carried out before and after intervention. DHA levels increased by 72% and 64% in the fish oil (mean, 3.6%-6.2%) and fish-meal (mean, 3.4%-5.6%) groups, respectively (P = 0.000). The Trail Making Test was the only cognitive test that demonstrated marked differences between groups: Median interquartile range difference between pre- and postintervention in the Trail Making Part B score was 61.5 (SE, 19.3, 103.2) in the fish oil versus fish-meal group, 24.5 (SE, -15.2, 74.7, P = 0.005). The Vanderbilt Assessment Scales also showed significant differences between groups (P < 0.001). This study contributed to available evidence on the cognitive and behavioral benefits of DHA in healthy school children. Expanding the food fortification program with DHA-enriched fish oil should be considered as part of broader policy to improve child health.

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [(18)F]GE-180 and effect of docosahexaenoic acid.

PurposeTraumatic spinal cord injury (SCI) is a devastating condition which affects millions of people worldwide causing major disability and substantial socioeconomic burden. There are currently no effective treatments. Modulating the neuroinflammatory (NI) response after SCI has evolved as a major therapeutic strategy. PET can be used to detect the upregulation of the 18-kDa translocator protein (TSPO), a hallmark of activated microglia in the CNS. We investigated whether PET imaging using the novel TSPO tracer [18F]GE-180 can be used as a clinically relevant biomarker for NI in a contusion SCI rat model, and we present data on the modulation of NI by the lipid docosahexaenoic acid (DHA).MethodsA total of 22 adult male Wistar rats were subjected to controlled spinal cord contusion at the T10 spinal cord level. Six non-injured and ten T10 laminectomy only (LAM) animals were used as controls. A subset of six SCI animals were treated with a single intravenous dose of 250 nmol/kg DHA (SCI-DHA group) 30 min after injury; a saline-injected group of six animals was used as an injection control. PET and CT imaging was carried out 7 days after injury using the [18F]GE-180 radiotracer. After imaging, the animals were killed and the spinal cord dissected out for biodistribution and autoradiography studies. In vivo data were correlated with ex vivo immunohistochemistry for TSPO.ResultsIn vivo dynamic PET imaging revealed an increase in tracer uptake in the spinal cord of the SCI animals compared with the non-injured and LAM animals from 35 min after injection (P < 0.0001; SCI vs. LAM vs. non-injured). Biodistribution and autoradiography studies confirmed the high affinity and specific [18F]GE-180 binding in the injured spinal cord compared with the binding in the control groups. Furthermore, they also showed decreased tracer uptake in the T10 SCI area in relation to the non-injured remainder of the spinal cord in the SCI-DHA group compared with the SCI-saline group (P < 0.05), supporting a NI modulatory effect of DHA. Immunohistochemistry showed a high level of TSPO expression (38 %) at the T10 injury site in SCI animals compared with that in the non-injured animals (6 %).Conclusion[18F]GE-180 PET imaging can reveal areas of increased TSPO expression that can be visualized and quantified in vivo after SCI, offering a minimally invasive approach to the monitoring of NI in SCI models and providing a translatable clinical readout for the testing of new therapies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3391-8) contains supplementary material, which is available to authorized users.

Fatty acid composition, sarcoplasmic reticular lipid oxidation, and immunity of hard clam (Meretrix lusoria) fed different dietary microalgae

Fatty acid profiles, activities of biomembrane lipid peroxidation, and immunity of a seawater clam (Meretrix lusoria) fed three species of dietary microalgae were investigated. Clams of a marketable size (25 g mean weight) were fed Tetraselmis chui, Chaetoceros muelleri, or Isochrysis galbana for 8 weeks. Fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the polar lipid fractions of clams reflected those of the dietary algae species. Clams fed with T. chui and C. muelleri contained higher proportion of non-methylene interrupted (NMI) fatty acids than those fed I. galbana. Proportion of DHA in lipids of the clams fed with I. galbana was the highest among test groups. The NADH-dependent sarcoplasmic reticular lipid peroxidation activity of clams fed I. galbana was significantly greater (p < 0.05) than that of clams fed T. chui or C. muelleri. The hemocyte adhesion capacity of clams fed C. muelleri or I. galbana was significantly higher (p < 0.05) than that of clams fed T. chui. No significant differences (p ≥ 0.05) in total hemocyte count, phenoloxidase activity, clearance efficiency hemocyte and phagocytosis were detected among clams fed different microalgae.

Children’s docosahexaenoic acid (DHA), but not maternal DHA in pregnancy, is associated with psychometric tests scores at 5‐6 years of age (124.2)

Docosahexaenoic acid (DHA) is an important component of neural lipids, affecting neural function throughout life. However, the dietary, genetic and other variables that impact DHA transfer to the brain, and the potential for early deficiency to have lasting effects remains unclear. We addressed the effect of DHA in gestation and children’s intake and blood lipid DHA on cognition at 5.75 years of age. Pregnant women, n=271 were enrolled at 16 weeks gestation and randomized to 400 mg DHA/day or placebo until infant delivery; 95 children returned for follow up, and were assessed with 153 additional children. Diet was assessed using 3 day records and frequency questionnaires, and venous blood was collected. Cognitive tests included the Peabody Picture Vocabulary Test (PPVT) and Kaufman Assessment Battery for Children (KABC). The median (IQR) DHA intake was 49.4 (23.8‐102) mg/day. The red blood cell mean ± SD DHA was 5.14 ± 1.50 percent total fatty acids. No evidence of persisting effects of DHA in pregnancy on child development were found. Children’s own DHA status, but not DHA intake, was associated with better PPVT and KABC Sequential, Learning, Simultaneous, and Mental Performance scores (P &lt;0.05). Child blood lipid 22:5n‐6 and the 22:5n‐6/DHA ratio were associated with poorer PPVT and KABC performance. DHA intake explained only 15% of variability in RBC DHA, raising complex questions on the relationship between diet, DHA transfer to membrane lipids, and neural function.

A cross‐sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria

Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R = .32, P = .03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA.

Article Commentary: The Emerging Role of Eicosapentaenoic Acid as an Important Psychoactive Natural Product: Some Answers but a Lot more Questions

Omega-3 polyunsaturated fatty acids play important roles in both the structure and communication processes of cells. Dietary deficiences of these fatty acids have been implicated in cardiac dysfunction, cancer and mood disorders. In the latter, clinical trials have strongly suggested that not all types of omega-3 PUFA are equally efficacious. In particular eicosapentaenoic acid (EPA) appears to be the most useful in ameliorating the symptoms of major depressive disorder. The mechanism by which omega-3 PUFA have these effects, and why EPA is apparently more effective in this role than the much more abundant brain lipid docosahexaenoic acid, is unclear. The available data do suggest various biologically plausible mechanisms all of which are amenable to study using straightforward experimental approaches. To progress further, a better understanding of how EPA and other omega-3 PUFA effect neurophysiological and neurosignalling processes is required.

Monitoring the oxidation of docosahexaenoic acid in lipids

The oxidation of free DHA, DHA mixed with PC, and DHA incorporated into PC, PE, or TG was evaluated to determine which lipid provided DHA with the best protection against oxidation. DHA was either situated at the sn-1 position, sn-2 position, or both positions of the phospholipid, whereas the TG contained DHA at all positions. All lipids were incubated as bulk lipids, in chloroform, or as an emulsion in contact with air at 25-30 degrees C for 28 d. Since DHA, which is highly sensitive to oxidation, has a great impact on our health and is desired as a food additive, the stability of this FA is of great importance. This study was mainly focused on the primary oxidation products, which were monitored as eight monohydroperoxy-DHA isomer groups, the total amount of polyhydroperoxides, and the PV. However, a measure of secondary oxidation products, the carbonyl value, was also monitored. We found that DHA was most protected against hydroperoxide formation when it was incorporated at one position of either PC or PE. In these lipids, hydroperoxide formation at carbon atoms 4, 7, 8, and 11 was completely prevented. DHA mixed with PC was also protected, although to a lesser extent, and all hydroperoxide isomers were detected. In contrast, PC and TG containing DHA at all positions should be avoided, since they were highly oxidized.

An optical fibre photobioreactor for enhanced production of the marine unicellular alga Isochrysis aff. galbana T-Iso (UTEX LB 2307) rich in docosahexaenoic acid

We have screened six species of marine microalga for their ability to produce the important dietary lipid docosahexaenoic acid (DHA). Isochrysis aff. galbana T-Iso (UTEX LB 2307), which produced DHA in the highest quantities (5.4 mg-g−1), was grown in a new type of closed photobioreactor in which efficient light distribution was achieved using light-diffusing optical fibres. The optimal temperature and light intensity for DHA production were determined and a maximal DHA production of 4.3 mg-l was achieved, twofold greater than that obtained using conventional culture methods. In addition, the DHA content could be enhanced by low temperature or dark incubation of the culture after growth.

Docosahexaenoic Acid Status of Term Infants Fed Breast Milk or Infant Formula Containing Soy Oil or Corn Oil

The objective of this study was to compare circulating lipid docosahexaenoic acid [22:6(n-3), DHA] levels in term infants fed a powdered (CORN oil) or liquid (SOY oil) infant formula or human milk (HM). Infants whose mothers chose not to breast feed were randomly assigned to the CORN or SOY formula group. The formula fat differed in linolenic acid [18:3(n-3)] content: it was 0.8% for the CORN and 4.8% for the SOY. Linoleic acid [18:2(n-6)] was 31.5 and 34.2% fatty acids in the CORN and SOY formula, respectively. The formulas or HM were fed from birth through 8 wk of age, and growth and the plasma and red blood cell (RBC) phospholipid fatty acid composition was determined at 3 d, 4 wk, and 8 wk of age. Growth did not differ among groups. The plasma phospholipid and RBC phosphatidylethanolamine DHA was similar in the CORN and SOY formula groups at all ages. Plasma and RBC phosphatidylethanolamine levels of DHA were significantly lower in infants fed the CORN or SOY formula than in infants fed HM during wk 4 and 8. Plasma and RBC 22:5(n-6) was not increased in the formula groups at any age. The formula content of linolenic acid had no effect on the RBC or plasma DHA levels of the infants. The biologic or functional significance of the lower plasma and RBC DHA in infants fed formula rather than HM is unknown. The need for a dietary source of DHA and specificity of plasma or RBC phospholipid DHA as a measure of desaturation and elongation of linolenic acid in developing organs remains uncertain.

Production of docosahexaenoic acid by Thraustochytrium aureum

Thraustochytrium aureum ATCC 34 304 contained approximately 50% of total fatty acids as docosahexaenoic acid (DHA). Lipid content of the biomass was dramatically influenced by medium composition and ranged from 0.3 to 16% of the biomass weight. Increasing the culture medium glucose concentration from 5 to 20 g/l caused the lipid content of the biomass to increase from 2.7 to 16.5% and the DHA yield to increase from 26 to 270 mg/l of whole culture broth. The proportion of DHA in lipids was independent of glucose concentration. The fatty acid profile observed in the high-yielding DHA culture was: 16:0, 19.2%; 18:1, 9.8%; 18:2, 2.4%; 20:4, 4.9%; 20:5, 3.6%; 22:6, 48.5% and others, 7.1%. For DHA production, fungal cultures were incubated on an orbital shaker under light at 25° C for 6 days.

Optimization of production of docosahexaenoic acid (DHA) byThraustochytrium aureum ATCC 34304

AbstractBy varying culture carbon source, lipid content in mycelium ofThraustochytrium aureum ATCC 34304 varied widely in the range 1–25% of biomass weight. Docosahexaenoic acid (DHA) content of mycelium lipid was higher (65–76%) when biomass lipid content was very low (1–2%) and lower (40–50%) when biomass contained a high lipid content (14–18%). DHA yields from glucose, starch and maltose were 270, 325 and 334 mg/L, respectively. DHA yield and content of biomass was optimal at an initial culture pH of 6.0. During the culture cycle ofT. aureum, DHA content in lipids remained relatively constant with optimal DHA yield being observed after six days. Biomass, lipid content in biomass, DHA content in biomass and DHA yield were all optimal at a cultivation temperature of 28°C. However, the proportion of DHA in lipids declined with increase in temperature. Biomass, lipids in biomass and DHA yields were 13%, 42% and 47% higher, respectively, din light‐exposed cultures as compared to dark cultures. A maximum yield of DHA of 511 mg/L was observed in light‐ exposed cultures containing 2.5% starch, where lipids accounted for over 20% of biomass dry weight.