Disease relevance of Docosahexaenoic acid

• The highly unsaturated n-3 fatty acids from fish oils, eicosapentaenoic acid [EPA; C20:5 (n-3)] and docosahexanoic acid [DHA; C22:6 (n-3)], prevent the toxicity of high concentrations of the cardiac glycoside ouabain to isolated neonatal rat cardiac myocytes [1].
• The fatty acids that are able to reduce the beating rate, particularly EPA and DHA, could effectively prevent and terminate lethal tachyarrhythmias (contracture/fibrillation) induced by high extracellular calcium concentrations or ouabain [2].
• Omega 3 (omega3) fatty acids, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), can effectively reduce the risk of skin cancer whereas omega 6 (omega6) fatty acids such as arachidonic acid (AA) reportedly promote risk [3].
• Furthermore, high-dose DHA reversed the stimulation of MPNST cell growth by a number of growth factors suggested to have a pathogenic effect in NF1 and inhibited MPNST growth in vivo [4].
• Patients with generalized peroxisomal disorders have extremely low levels of DHA in the brain and other tissues [5].

Psychiatry related information on Docosahexaenoic acid

• Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder [6].
• Research is needed (1) to probe the effects of variable DHA exposure on infant and child development, (2) to measure outcomes that better relate to preschool and school-age cognitive function, and (3) to reinforce, and in some cases demonstrate, links between specific infant and preschool measures of cognitive development [7].
• Our own unpublished observations from the Framingham Heart Study suggest that > or =180 mg/d of dietary DHA (approximately 2.7 fish servings/wk) is associated with an approximately 50% reduction in dementia risk [8].
• CONCLUSIONS: The results of this study suggest that for full-term infants, breast-feeding is associated with enhanced stereopsis at age 3.5 y, as is a maternal DHA-rich antenatal diet, irrespective of later infant feeding practice [9].
• The amount of DHA in human milk varies widely and is positively correlated with visual and language development in breast-fed infants [10].

High impact information on Docosahexaenoic acid

• Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17R-HDHA that also proved a major route in hypoxic endothelial cells [11].
• These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17R-hydroxy series of docosanoids that are potent regulators [11].
• Only when the dose was increased to 15 capsules/d was there a reduction in the AA/DCHA ratio in neutrophil lipids [12].
• Exogenous eicosapentaenoic acid (EPA) and docosahexaenoic acid (DCHA) have been compared with exogenous arachidonic acid for their capacity to modulate the oxidative metabolism of membrane-derived arachidonic acid by the 5-lipoxygenase pathway in ionophore-activated human neutrophils and for their suitability as parallel substrates in this pathway [13].
• Erythrocyte DHA was the only fatty acid that consistently correlated with VEP acuity in all infants at both ages tested [14].

Chemical compound and disease context of Docosahexaenoic acid

• CONCLUSIONS: Higher combined dietary intake of DHA and EPA, and possibly alpha-linolenic acid, may lower the risk of fatal ischemic heart disease in older adults [15].
• In previous studies, we reported that neonates of women with gestational diabetes mellitus (GDM) have reduced blood levels of arachidonic acid (AA) and docosahexaenoic acid (DHA) that were unrelated to maternal status [16].
• Lipases from Mucor miehei (Lipozyme-IM), Pseudomonas sp. (PS-30), and Candida rugosa (AY-30) catalyzed optimum incorporation of EPA, DPA, and DHA into Laurical 35, respectively [17].
• Two human colorectal carcinoma cell lines (CX-1 and CCL-188) were grown in cell culture media supplemented with omega-3 (docosahexanoic acid) and omega-6 (linoleic acid) fatty acids [18].
• PPARalpha activator DHA attenuated the development of hypertension, corrected structural abnormalities, and improved endothelial dysfunction induced by Ang II [19].

Biological context of Docosahexaenoic acid

• Biophysical experiments have shown that lipid unsaturation and cholesterol both have significant effects on rhodopsin's stability and function; omega-3 polyunsaturated chains, such as docosahexaenoic acid (DHA), destabilize rhodopsin and enhance the kinetics of the photocycle, whereas cholesterol has the opposite effect [20].
• To determine the effects of n-3 fatty acids on aged rat brain, 2-year-old rats were fed fish oil (27% DHA content) for 1 month, and gene expression analysis and fatty acid and molecular species composition of the major phospholipid species were assessed [21].
• This lipid imbalance was observed in organs pathologically affected by CF including lung, pancreas, and ileum and was not secondary to impaired intestinal absorption or hepatic biosynthesis of DHA [22].
• DHA treatment resulted in marked inhibition of TPA- and EGF-induced cell transformation by inhibiting AP-1 transactivation [3].
• DHA is involved in memory formation, excitable membrane function, photoreceptor cell biogenesis and function, and neuronal signaling, and has been implicated in neuroprotection [23].

Anatomical context of Docosahexaenoic acid

• An n-3 polyunsaturated fatty acid (docosahexaenoic acid (DHA)) suppressed NFkappaB activation and cyclooxygenase-2 expression induced by the agonist for TLR2, 3, 4, 5, or 9 in a macrophage cell line (RAW264.7) [24].
• Pharmacoepidemiological data, analytical data from human tissue and body fluids, and mechanistic data mostly from murine models all have implicated oxidation products of two fatty acids, arachidonic acid (AA) and docosahexaenoic acid (DHA), in the pathogenesis of neurodegeneration [25].
• The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor [6].
• EPA/DHA increased plasma adiponectin levels, independent of food intake, reflecting the stimulation of Adipoq expression in adipocytes and the release of adiponectin from WAT, particularly from epididymal fat [26].
• Plasma phospholipid AA and DHA increased approximately 18% and 50%, respectively, with the 1 x dose, similar to that expected at intakes provided by human milk [27].

Associations of Docosahexaenoic acid with other chemical compounds

• By analyzing the results of 26 independent 100-ns simulations of dark-adapted rhodopsin, we found that DHA routinely forms tight associations with the protein in a small number of specific locations qualitatively different from the nonspecific interactions made by saturated chains and cholesterol [20].
• EPA and DHA were subjected to an in vitro free radical oxidation process that models in vivo conditions [28].
• Consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can mitigate the progression of diseases in which oxidative stress represents a common underlying biochemical process [28].
• RESULTS: In mice with free access to food, plasma triacylglycerols, NEFA, and insulin levels were lower in the presence of EPA/DHA, while glucose and leptin levels were not significantly altered [26].
• METHODS: The effects of pregnancy and lactation on brain phospholipid fatty acid content were determined in female rats fed diets containing sufficient (control) or negligible (deficient) alpha-linolenic acid (18:3n-3), the dietary precursor of DHA, beginning at conception [29].

Gene context of Docosahexaenoic acid

• Additionally, DHA and EPA significantly suppressed COX-2 expression induced by a synthetic lipopeptide, a TLR2 agonist [30].
• These results indicate that EPA and DHA act in opposition to AA by modulating various steps of the inflammatory process induced by IL1 beta, probably by reducing mitogen-activated protein kinase p42/p44 activity [31].
• The target of inhibition by DHA is TLR itself or its associated molecules, but not downstream signaling components [30].
• Palmitate, but not DHA or laurate, induced nuclear factor kappaB (NF-kappaB)-driven luciferase activity and interleukin-6 (IL-6) expression (P < 0.05) [32].
• Finally, we have shown that the incorporation of EPA and DHA also increased the concentration of caveolin-1 and caveolin-3 in caveolae, which correlated with n-3 PUFA inhibition of SMC proliferation through the mitogen-activated protein kinase pathway [33].

Analytical, diagnostic and therapeutic context of Docosahexaenoic acid

• As proof of concept, oral administration of DHA to cftr(-/-) mice corrected this lipid imbalance and reversed the observed pathological manifestations [22].
• Expression of Lep and the release of leptin from WAT, while being extremely sensitive to caloric restriction, was unaltered by EPA/DHA [26].
• By ages 17 and 39 wk, the red blood cell DHA concentration in the LCP-supplemented group was more than double and more than triple, respectively, that in the control group [34].
• Erythrocyte DHA concentrations were 30-40% higher after the n-3 egg intervention than after treatment with regular eggs or no eggs in both breast-fed and formula-fed infants [35].
• Pregravid body mass index was negatively associated with plasma phospholipid DHA (% by wt) in control subjects (r = -0.55, P = 0.04) and in women with GDM with a body mass index (in kg/m2) <30 (r = -0.76, P = 0.007) [36].

References