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Where does the developing brain obtain its docosahexaenoic acid? Relative contributions of dietary alpha-linolenic acid, docosahexaenoic acid, and body stores in the developing rat.

Docosahexaenoic acid (DHA), a 22-carbon, highly unsaturated, n-3 fatty acid, is important for optimal nervous system function. In this study, designed to quantify how preformed dietary DHA regulates metabolic pathways in vivo, 8-d-old rat pups were divided into four groups and fed artificial rat milk diets. One group was fed formula with deuterium-labeled LNA (d5-LNA) as the only source of n-3 fatty acids, and a second group was fed formula that contained d5-LNA and unlabeled DHA. Two additional groups were dam-reared to permit analysis of fatty acyl pool sizes at postnatal days 8 and 28. The dams were fed a diet that contained 3% unlabeled LNA. DHA in brain and liver was analyzed. Our study demonstrated that preformed DHA in the diet markedly decreased the amount of biosynthesized DHA that accumulated in the brain and the liver. Surprisingly, 40% of the DHA that was newly acquired during this period in the "LNA" group was unlabeled. Because there were no unlabeled n-3 fatty acids in this diet, this DHA must have been derived from body stores of n-3 fatty acids. Thus, body stores can be a significant source of brain DHA in animals that are fed LNA as the only source of n-3 fatty acids.

Animal Feed↗

Exposure to the n-3 polyunsaturated fatty acid docosahexaenoic acid impairs alpha 1-adrenoceptor-mediated contractile responses and inositol phosphate formation in rat cardiomyocytes.

The beneficial effects of n-3 polyunsaturated fatty acids of fish oil in the prevention of fatal arrhythmias in myocardial ischemia were suggested to be at least in part mediated by a modulation of dihydropyridine-sensitive L-type calcium channels. As cardiac alpha 1-adrenoceptor stimulation has been suggested to have no significant effect on L-type calcium channels, the aim of this study using cultured neonatal rat cardiomyocytes was to investigate whether chronic n-3 polyunsaturated fatty acid exposure may have an influence on alpha 1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias. Pretreatment of the rat cardiomyocytes for 3 days in the presence of the n-3 polyunsaturated fish oil-derived fatty acid docosahexaenoic acid (60 mumol/l) markedly decreased alpha 1-adrenoceptor-stimulated increase in contraction velocity and induction of arrhythmias. The increase in contraction velocity of the cardiomyocytes induced by the beta-adrenoceptor agonist isoprenaline was also markedly reduced by the n-3 fatty acid pretreatment. Basal contractile amplitude and spontaneous beating frequency of the cardiomyocytes were not significantly altered by the docosahexaenoic acid exposure. The pretreatment of the rat cardiomyocytes for 3 days in the presence of docosahexaenoic acid (60 mumol/l) decreased alpha 1-adrenoceptor-stimulated formation of the calcium-mobilizing second messenger IP3 and its metabolites IP2 and IP1 by 55%. The depression of IP3 formation by docosahexaenoic acid treatment was not mediated by a decreased uptake of myo-inositol into the cardiomyocytes nor by a decreased synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of phospholipase C. The level of glycerol-3-phosphate, an important substrate of the phosphoinositide cycle, was unaltered by the docosahexaenoic acid pretreatment. Receptor binding studies revealed that the dissociation constant and maximal binding capacity of the alpha 1-adrenoceptor antagonist (3H)prazosin was unchanged by the n-3 polyunsaturated fatty acid exposure. Beta-Adrenoceptor-and forskolin-stimulated adenylyl cyclase activities were not diminished by the docosahexaenoic acid pretreatment. Chronic exposure of the cardiomyocytes to the n-6 polyunsaturated fatty acid arachidonic acid (60 mumol/l) did neither significantly alter alpha 1-adrenoceptor-induced inositol phosphate formation nor alpha 1-adrenoceptor-stimulated increase in contraction velocity. The results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat cardiomyocytes leads to a marked impairment of alpha 1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation. This derangement of the phosphoinositide pathway by chronic n-3 fatty acid exposure may, thus, contribute to the beneficial effects of fish oil-derived fatty acids in the prevention of fatal arrhythmias in myocardial ischemia.

Adenylyl Cyclases↗

Biotechnological production and applications of the omega-3 polyunsaturated fatty acid docosahexaenoic acid.

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid composed of 22 carbon atoms and six double bonds. Because the first double bond, as counted from the methyl terminus, is at position three, DHA belongs to the so-called omega-3 group. In recent years, DHA has attracted much attention because of its beneficial effect on human health. At present, fish oil is the major source of DHA, but alternatively it may be produced by use of microorganisms. Marine microorganisms may contain large quantities of DHA and are considered a potential source of this important fatty acid. Some of these organisms can be grown heterotrophically on organic substrates without light. These processes can be well controlled and DHA with constant quality can be produced all year round. This paper reviews recent advances in the biotechnological production of DHA by marine microorganisms.

Animals↗

Role of Ca2+-independent phospholipase A2 and n-3 polyunsaturated fatty acid docosahexaenoic acid in prostanoid production in brain: perspectives for protection in neuroinflammation.

Various diseases of the central nervous system are characterized by induction of inflammatory events, which involve formation of prostaglandins. Production of prostaglandins is regulated by activity of phospholipases A(2) and cyclooxygenases. These enzymes release the prostaglandin precursor, the n-6 polyunsaturated fatty acid, arachidonic acid and oxidize it into prostaglandin H(2). Docosahexaenoic acid, which belongs to the n-3 class of polyunsaturated fatty acids, was shown to reduce production of prostaglandins after in vivo and in vitro administration. Nevertheless, the fact that in brain tissue cellular phospholipids naturally have a uniquely high content of docosahexaenoic acid was ignored so far in studies of prostaglandin formation in brain tissue. We consider the following possibilities: docosahexaenoic acid might attenuate production of prostaglandins by direct inhibition of cyclooxygenases. Such inhibition was found with the isolated enzyme. Another possibility, which has been already shown is reduction of expression of inducible cyclooxygenase-2. Additionally, we propose that docosahexaenoic acid could influence intracellular Ca(2+) signaling, which results in changes of activity of Ca(2+)-dependent phospholipase A(2), hence reducing the amount of arachidonic acid available for prostaglandin production. Astrocytes, the main type of glial cells in the brain control the release of arachidonic acid, docosahexaenoic acid and the formation of prostaglandins. Our recently obtained data revealed that the release of arachidonic and docosahexaenoic acids in astrocytes is controlled by different isoforms of phospholipase A(2), i.e. Ca(2+)-dependent phospholipase A(2) and Ca(2+)-independent phospholipase A(2), respectively. Moreover, the release of arachidonic and docosahexaenoic acids is differently regulated through Ca(2+)- and cAMP-dependent signal transduction pathways. Based on analysis of the current literature and our own data we put forward the hypothesis that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid are promising targets for treatment of inflammatory related disorders in brain. We suggest that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid might be crucially involved in brain-specific regulation of prostaglandins.

Animals↗

Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: the Kuopio ischaemic heart disease risk factor study.

BACKGROUND: Previous findings concerning the serum levels of fish-derived (n-3) fatty acids and coronary heart disease are inconsistent. The purpose of this study was to investigate the association between the serum n-3 end-product fatty acids docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid and the risk of acute coronary events in middle-aged men. METHODS AND RESULTS: We studied this association in the Kuopio Ischaemic Heart Disease Risk Factor Study, a prospective population study in Eastern Finland. Subjects were randomly selected and included 1871 men aged 42 to 60 years who had no clinical coronary heart disease at baseline examination. A total of 194 men had a fatal or nonfatal acute coronary event during follow-up. In a Cox proportional hazards' model adjusting for other risk factors, men in the highest fifth of the proportion of serum DHA+DPA in all fatty acids had a 44% reduced risk (P=0.014) of acute coronary events compared with men in the lowest fifth. Men in the highest fifth of DHA+DPA who had a low hair content of mercury (</=2.0 microgram/g) had a 67% reduced risk (P=0.016) of acute coronary events compared with men in the lowest fifth who had a high hair content of mercury (>2.0 microgram/g). There was no association between proportion of eicosapentaenoic acid and the risk of acute coronary events. CONCLUSIONS: Our data provide further confirmation for the concept that fish oil-derived fatty acids reduce the risk of acute coronary events. However, a high mercury content in fish could attenuate this protective effect.

Acute Disease↗

A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.

OBJECTIVE: This study was an evaluation of the omega-3 fatty acid docosahexaenoic acid (DHA) for the treatment of major depression. METHOD: Thirty-six depressed patients were randomly assigned to receive DHA, 2 g/day, or placebo for 6 weeks. Response was defined a priori as a > or =50% reduction in the score on the Montgomery-Asberg Depression Rating Scale. Thirty-five participants were evaluable; 18 received DHA, and 17 received placebo. RESULTS: Response rates were 27.8% in the DHA group and 23.5% in the placebo group. The difference in response rates between groups did not reach statistical significance. CONCLUSIONS: This trial failed to show a significant effect of DHA monotherapy in subjects with major depression.

Adolescent↗

Some effects of the essential fatty acids linoleic acid and alpha-linolenic acid and of their metabolites gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and of prostaglandins A1 and E1 on the proliferation of human osteogenic sarcoma cells in culture.

Gamma-linolenic acid has been shown to suppress the rate of proliferation of a number of malignant cell lines in culture. To test the proposal that this was a specific prostaglandin 1- or 2-series effect, 379 batches of MG63 human osteogenic sarcoma cells were seeded in Greiner flasks and cultured in media supplemented with a range of unsaturated fatty acids and prostaglandins. The monounsaturated fatty acid oleic acid enhanced the rate of cancer cell proliferation. The polyunsaturated fatty acids linoleic acid, gamma-linolenic acid, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid, as well as prostaglandins E1 and A1 suppressed the rate of cell proliferation. Total suppression of colony forming and cell proliferation occurred at high levels of polyunsaturated fatty acid supplementation. In addition gamma-linolenic in the form of evening primrose seed oil and vitamin C has been given to 6 patients with histologically diagnosed primary liver cell cancer. Some clinical improvement and reduction in tumor size occurred in 3 cases. One patient has shown remarkable improvement in reduction of liver and tumor size on the CAT scan and reduction of the serum alkaline phosphatase from 2830 to 295 units and gamma-glutamyl transaminase from 274 to 82 units. Thus preliminary clinical results suggest that gamma-linolenic acid may be effective in the management of human cancer patients and further trials should be conducted. However, the cell culture results suggest that although the essential fatty acids suppress proliferation, eicosanoids of all 3 series may be involved. The proliferation suppressive effect of docosahexaenoic acid suggests that other aspects than only eicosanoid activity may also be important in the suppression of cancer cell proliferation.

Alprostadil↗

A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.

Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. beta-Amyloid (Abeta) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total Abeta by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased Abeta42 levels below those seen with control chow. Image analysis of brain sections with an antibody against Abeta (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both alpha- and beta-APP C-terminal fragment products and full-length APP. BACE1 (beta-secretase activity of the beta-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against beta-amyloid production, accumulation, and potential downstream toxicity.

Administration, Oral↗

Differential effects of all-trans-retinoic acid, docosahexaenoic acid, and hexadecylphosphocholine on cisplatin-induced cytotoxicity and apoptosis in a cisplantin-sensitive and resistant human embryonal carcinoma cell line.

Apart from modulation of tumor-cell drug sensitivity, induction of differentiation might be an alternative in the treatment of tumors resistant to cytotoxic drugs. In this report the capacity to induce differentiation and to modulate the cis-diamminedichloroplatinum(II) (CDDP) sensitivity of all-trans-retinoic acid (RA), docosahexaenoic acid (DCHA), and hexadecylphosphocholine (HePC) is examined in human germ-cell tumor cell lines. In the embryonal carcinoma cell line Tera-2 and its 3.7-fold CDDP-resistant subline Tera2-CP, we evaluated the effects of 96 h of pretreatment with RA (0.1 microM), DCHA (23 microM), and HePC (25 microM) on differentiation induction and on CDDP-induced cytotoxicity, DNA platination (4-h incubation), and apoptosis (continuous incubation). Without drug treatment, Tera2-CP showed less apoptosis than Tera-2. Pretreatment with RA decreased the cytotoxicity and apoptosis induced by CDDP without resulting in decreased DNA platination and increased differentiation in both cell lines. DCHA enhanced CDDP-induced cytotoxicity and apoptosis and did not affect the embryonal character of either cell line. HePC did not affect CDDP cytotoxicity or differentiation in either cell lines. Effects of the modulators on differentiation and on CDDP-induced cytotoxicity, DNA platination, and apoptosis did not differ between Tera-2 and Tera2-CP. RA can be applied for differentiation induction in CDDP-resistant germ-cell tumor models. However, in this model, RA reduced the apoptotic susceptibility. DCHA potentiated CDDP cytotoxicity in vitro; its in vivo modulatory capacity in germ-cell tumor cells deserves further study.

Apoptosis↗

Exogenous supplementation with omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA; 22:6n-3) synergistically enhances taxane cytotoxicity and downregulates Her-2/neu (c-erbB-2) oncogene expression in human breast cancer cells.

Omega-3 polyunsaturated fatty acid (PUFA), docosahexaenoic acid (DHA; 22:6n-3) and other omega-3 and omega-6 PUFAs have raised interest as novel anticancer agents by exerting selective cytotoxic effects on human cancer cells without affecting normal tissues. Here, we examined the in vitro relationship between exogenous supplementation with DHA and breast cancer chemosensitivity to taxanes. We measured cell viability in the highly metastatic human breast cancer cell line MDA-MB-231 exposed sequentially to DHA followed by paclitaxel (Taxol) or docetaxel (Taxotere). As DHA by itself showed cytotoxic effects, possible synergistic interactions between DHA and taxanes were assessed, employing the combination index (CI) method and the isobologram analysis. Both methods showed a strong synergism (CI approximately 0.5; P<0.005) between DHA and taxanes in MDA-MB-231 cells. When the increase in taxanes efficacy was measured by dividing the IC50 values (50% inhibitory concentrations) obtained when the cells were exposed to taxanes alone by those after DHA pre-exposure, we found that DHA enhanced the cytotoxic activity of taxanes against MDA-MB-231 cells in a dose-dependent manner (up to 13- and 5-fold increase in Taxol and Taxotere efficacy, respectively). Importantly, sequential exposure to DHA followed by taxanes also yielded strong synergism in Her-2/neu (c-erbB-2)-overexpressing and taxanes-resistant SK-Br3 and BT-474 breast cancer cells. Moreover, exogenous supplementation with DHA significantly decreased the expression of Her-2/neu-codified p185(Her-2/neu) oncoprotein (up to 78% reduction in BT-474 cells). Our results provide experimental support to the hypothesis that omega-3 PUFAs can be used as modulators of tumor cell chemosensitivity and provide the rationale for in vivo preclinical investigation. In addition, this is the first study demonstrating that omega-3 PUFA DHA downregulates Her-2/neu oncogene expression in human breast cancer cells.

Antineoplastic Agents, Phytogenic↗

Effects of arachidonic acid, docosahexaenoic acid and prostaglandin E(2) on cell proliferation and morphology of MG-63 and MC3T3-E1 osteoblast-like cells.

During bone remodelling bone is resorbed by osteoclasts and replaced again by osteoblasts through the process of bone formation. Clinical trials and in vivo animal studies suggest that specific polyunsaturated fatty acids (PUFAs) might benefit bone health. As the number of functional osteoblasts is important for bone formation the effects of specific PUFAs on in vitro osteoblastic cell proliferation were investigated. Morphological studies were conducted to determine whether exposure of the cells to these agents caused structural damage to the cells thereby yielding invalid results. Results from this study showed that arachidonic acid (AA) and docosahexaenoic acid (DHA) both inhibit cell growth significantly at high concentrations. The anti-mitotic effect of AA is possibly independent of PGE(2) production, as PGE(2) per se had little effect on proliferation. Further study is required to determine whether reduced proliferation due to fatty acids could be due to increased differentiation of osteoblasts to the mature mineralising osteoblastic phenotype.

Animals↗

Gas chromatography/mass spectrometry analysis of very long chain fatty acids, docosahexaenoic acid, phytanic acid and plasmalogen for the screening of peroxisomal disorders.

Very long chain fatty acids (VLCFAs) and docosahexaenoic acid (DHA), phytanic acid, and plasmalogens are usually measured individually. A novel method for the screening of peroxisomal disorders, using gas chromatography/mass spectrometry (GC/MS), was developed. Saturated and unsaturated fatty acids, including VLCFAs and DHA, phytanic acid, and plasmalogen were detected by a selected ion monitoring-electron impact method, using 100 microl of serum or plasma. Methyl-esterification and extraction could be done in one tube, and data were obtained within 4 h. All patients with Zellweger syndrome (ZS), X-linked adrenoleukodystrophy (ALD), isolated deficiency of peroxisomal beta-oxidation enzyme, and most ALD carriers showed increased VLCFA ratios, including C24:0/C22:0, C25:0/C22:0 and C26:0/C22:0. The ratio of DHA to palmitic acid (C16:0) and plasmalogen (measured as hexadecanal dimethyl acetal) to C16:0 in ZS patients was significantly lower than for the controls (P<0.001 for healthy high school students, P<0.05 for infants with other disorders). Plasmalogen was also decreased in patients with isolated deficiency of plasmalogen biosynthesis. Two of eight patients with ZS, two of four with RCDP, and all of three classical Refsum patients showed increased levels of phytanic acid. This method will simplify the screening for peroxisomal disorders.

Adolescent↗

Photoaffinity labeling of human retinoid X receptor beta (RXRbeta) with 9-cis-retinoic acid: identification of phytanic acid, docosahexaenoic acid, and lithocholic acid as ligands for RXRbeta.

We utilized [20-methyl-(3)H]-9-cis-retinoic acid ([(3)H]9-cis-RA) as a direct photoaffinity probe for the characterization of human recombinant retinoid X receptor beta protein (RXRbeta). The photoaffinity labeling was light- and concentration-dependent, saturable, and protected by unlabeled 9-cis-RA in a concentration-dependent manner, indicating that binding occurred in the RXR retinoid binding site. all-trans-Retinoic acid (atRA) did not affect labeling with the 9-cis derivative, confirming that atRA does not compete for the 9-cis-RA binding site. Several retinoid, fatty acid, and bile acid ligands were evaluated for their ability to recognize the 9-cis-RA binding site. Retinol, atRA glucuronide, 13-cis-RA, dolichol, 5,6-epoxy-RA, and vitamin D(3) did not compete for the 9-cis-RA binding site. However, the saturated diterpenoid phytanic acid (PA) and docosahexaenoic acid, which have been recently shown to activate the nuclear receptor, RXR, competed with 9-cis-RA labeling, showing high affinity for the 9-cis-RA binding site. Oleic acid, arachidonic acid, and butyric acid did not interact. However, the bile acid lithocholic acid competed efficiently with 9-cis-RA for the binding site. These data validated the photoaffinity assay as an excellent system for the identification and evaluation of ligands for RXR.

Alitretinoin↗

Effects of low-dose eicosapentaenoic acid, docosahexaenoic acid and dietary fat on the incidence, growth and cell kinetics of mammary carcinomas in rats.

This study investigated the effects of low-dose eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) on the incidence, tumor growth and cell kinetics of a 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats fed either a high-fat (20% corn oil) or low-fat (0.5% corn oil) diet. Low-dose EPA and DHA completely blocked the stimulatory effect of fat on tumorigenesis, as demonstrated by a decreased number of tumors per group and per tumor-bearing rat. While EPA and DHA inhibited cell kinetics as evidenced by a decreased bromodeoxyuridine-labeling index, their inhibitory effects on tumor size and tumor doubling time were not significant. These data suggest that low-dose EPA and DHA inhibit tumorigenesis rather than tumor growth in the high-fat group.

9,10-Dimethyl-1,2-benzanthracene↗

Effects of arachidonic acid, docosahexaenoic acid, prostaglandin E(2) and parathyroid hormone on osteoprotegerin and RANKL secretion by MC3T3-E1 osteoblast-like cells.

Bone is continuously remodeled through resorption by osteoclasts and the subsequent synthesis of the bone matrix by osteoblasts. Cell-to-cell contact between osteoblasts and osteoclast precursors is required for osteoclast formation. RANKL (receptor activator of nuclear factor-kappaB ligand) expressed on osteoblastic cell membranes stimulates osteoclastogenesis, while osteoprotegerin (OPG) secreted by osteoblasts inhibits osteoclastogenesis. Although polyunsaturated fatty acids (PUFAs) have been implicated in bone homeostasis, the effects thereof on OPG and RANKL secretion have not been investigated. MC3T3-E1 osteoblasts were exposed to the n-6 PUFA arachidonic acid (AA) and the n-3 PUFA docosahexaenoic acid (DHA); furthermore, the bone-active hormone parathyroid hormone (PTH) and the effects thereof were tested on OPG and RANKL secretion. Prostaglandin E(2) (PGE(2)), a product of AA metabolism that was previously implicated in bone homeostasis, was included in the study. AA (5.0-20 microg/ml) inhibited OPG secretion by 25-30%, which was attenuated by pretreatment with the cyclooxygenase blocker indomethacin, suggesting that the inhibitory effect of AA on OPG could possibly be PGE(2)-mediated. MC3T3-E1 cells secreted very low basal levels of RANKL, but AA stimulated RANKL secretion, thereby decreasing the OPG/RANKL ratio. DHA suppressed OPG secretion to a smaller extent than AA. This could, however, be due to endogenous PGE(2) production. No RANKL could be detected after exposing the MC3T3-E1 cells to DHA. PTH did not affect OPG secretion, but stimulated RANKL secretion. This study demonstrates that AA and PTH reduce the OPG/RANKL ratio and may increase osteoclastogenesis. DHA, however, had no significant effect on OPG or RANKL in this model.

Animals↗

Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder.

BACKGROUND: Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls. METHODS: We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann's Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography. RESULTS: After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (-22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (-32%) than in male MDD patients (-16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables. CONCLUSIONS: These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.

Adult↗

Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells.

Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 polyunsaturated fatty acids reduces the risk of colon cancer. Inhibition of colon carcinogenesis by omega-3 polyunsaturated fatty acids is mediated through modulation of more than one signaling pathway that alters the expression of genes involved in colon cancer growth. In our earlier studies on global gene expression with cDNA microarrays, we have shown that treatment of CaCo-2 colon cancer cells with docosahexaenoic acid (DHA) down-regulated the prostaglandin family of genes, as well as cyclooxygenase 2 expression and several cell cycle-related genes, whereas it up-regulated caspases 5, 8, 9, and 10 that are associated with apoptosis. It is known that nitric oxide activates the cyclooxygenase 2 enzyme, which plays a pivotal role in the progression of colon cancer via prostaglandin synthesis and angiogenesis. The present study was undertaken to examine the multifaceted role of DHA in the expression of inducible nitric oxide synthase (iNOS) and of related proinflammatory genes, as those have been shown to play a role in tumor progression. In addition, we aimed to identify associated target genes by DNA microarray, reverse transcription-PCR analysis, and cellular localization of iNOS expression in CaCo-2 cells. Results of this study demonstrate that treatment with DHA down-regulates iNOS in parallel with a differential expression and down-regulation of IFNs, cyclic GMP, and nuclear factor kappa B isoforms. More importantly, our findings clearly demonstrate the up-regulation of cyclin-dependent kinase inhibitors p21((Waf1/Cip1)) and p27, differentiation-associated genes such as alkaline phosphatases, and neuronal differentiation factors. These finding strongly suggest that the antitumor activity of DHA may be attributed, at least in part, to an effect on iNOS regulatory genes. In addition, our results indicate the presence of specific gene expression profiles in human colon cancer that can be used as molecular targets for chemopreventive agents.

Apoptosis↗

Low doses of eicosapentaenoic acid, docosahexaenoic acid, and hypolipidemic eicosapentaenoic acid derivatives have no effect on lipid peroxidation in plasma.

It was of interest to investigate the influence of both high doses of eicosapentaenoic acid (EPA) and low doses of 2- or 3-methylated EPA on the antioxidant status, as they all cause hypolipidemia, but the dose required is quite different. We fed low doses (250 mg/d/kg body wt) of different EPA derivatives or high doses (1500 mg/d/kg body wt) of EPA and DHA to rats for 5 and 7 d, respectively. The most potent hypolipidemic EPA derivative, 2,2-dimethyl-EPA, did not change the malondialdehyde content in liver or plasma. Plasma vitamin E decreased only after supplementation of those EPA derivatives that caused the greatest increase in the fatty acyl-CoA oxidase activity. Fatty acyl-CoA oxidase activity increased after administration of both EPA and DHA at high doses. High doses of EPA and DHA decreased plasma vitamin E content, whereas only DHA elevated lipid peroxidation. In liver, however, both EPA and DHA increased lipid peroxidation, but the hepatic level of vitamin E was unchanged. The glutathione-requiring enzymes and the glutathione level were unaffected, and no significant changes in the activities of xanthine oxidase and superoxide dismutase were observed in either low- or high-dose experiments. In conclusion, increased peroxisomal beta-oxidation in combination with high amounts of polyunsaturated fatty acids caused elevated lipid peroxidation. At low doses of polyunsaturated fatty acids, lipid peroxidation was unchanged, in spite of increased peroxisomal beta-oxidation, indicating that polyunsaturation is the most important factor for lipid peroxidation.

Acyl-CoA Oxidase↗