Showing papers in "Prostaglandins Leukotrienes and Essential Fatty Acids in 2006"

Polyunsaturated fatty acids and inflammation

Abstract: The n-6 polyunsaturated fatty acid arachidonic acid gives rise to the eicosanoid family of mediators (prostaglandins, thromboxanes, leukotrienes and related metabolites). These have inflammatory actions in their own right and also regulate the production of other mediators including inflammatory cytokines. Consumption of long chain n-3 polyunsaturated fatty acids decreases the amount of arachidonic acid in cell membranes and so available for eicosanoid production. Thus, n-3 polyunsaturated fatty acids decrease production of arachidonic acid-derived eicosanoids. These fatty acids also decrease the production of the classic inflammatory cytokines tumour necrosis factor, interleukin-1, and interleukin-6 and the expression of adhesion molecules involved in inflammatory interactions between leukocytes and endothelial cells. These latter effects may occur by eicosanoid-independent mechanisms including modulation of the activation of transcription factors involved in inflammatory processes. The anti-inflammatory actions of long chain n-3 fatty acid-induced effects may be of therapeutic use in conditions with an acute or chronic inflammatory component.

Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology

Abstract: The principle omega-3 fatty acid in brain, docosahexaenoic acid (DHA), accumulates in the brain during perinatal cortical expansion and maturation. Animal studies have demonstrated that reductions in perinatal brain DHA accrual are associated with deficits in neuronal arborization, multiple indices of synaptic pathology including deficits in serotonin and mesocorticolimbic dopamine neurotransmission, neurocognitive deficits, and elevated behavioral indices of anxiety, aggression, and depression. In primates and humans, preterm delivery is associated with deficits in fetal cortical DHA accrual, and children/adolescents born preterm exhibit deficits in cortical gray matter maturation, neurocognitive deficits particularly in the realm of attention, and increased risk for attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. Individuals diagnosed with ADHD or schizophrenia exhibit deficits in cortical gray matter maturation, and medications found to be efficacious in the treatment of these disorders increase cortical and striatal dopamine neurotransmission. These associations in conjunction with intervention trials showing enhanced cortical visual acuity and cognitive outcomes in preterm and term infants fed DHA, suggest that perinatal deficits in brain DHA accrual may represent a preventable neurodevelopmental risk factor for the subsequent emergence of psychopathology.

Omega-3 fatty acids and monoamine neurotransmission

Abstract: We proposed several years ago that the behavioral effects of n -3 PUFA deficiency observed in animal models might be mediated through the dopaminergic and serotonergic systems that are very involved in the modulation of attention, motivation and emotion. We evaluated this hypothesis in an extended series of experiments on rats chronically diet-deficient in α -linolenic acid, the precursor of long-chain n -3 PUFA, in which we studied several parameters of these neurotransmission systems. The present paper synthesizes the main data we obtained on interactions between n -3 PUFA status and neurotransmission in animal models. We demonstrated that several parameters of neurotransmission were affected, such as the vesicular pool of dopamine and serotonin, thus inducing several regulatory processes such as modification of cerebral receptors in specific brain areas. We also demonstrated that (i) a reversal diet with adequate n -6 and n -3 PUFA given during the lactating period to rats originating from α -linolenic acid-deficient dams was able to restore both the fatty acid composition of brain membranes and several parameters of the dopaminergic and serotonergic neurotransmission, and (ii) when given from weaning, this reversal diet allowed partial recovery of biochemical parameters, but no recovery of neurochemical factors. The occurrence of profound n -3 PUFA deficiency during the lactating period could therefore be an environmental insult leading to irreversible damage to specific brain functions. Strong evidence is now showing that a profound n -3 PUFA experimental deficiency is able to alter several neurotransmission systems, at least the dopaminergic and serotonergic. Whether these experimental findings can be transposed to human pathophysiology must be taken cautiously, but reinforces the hypothesis that strong links exist between the PUFA status, aspects of brain function such as neurotransmission processes and behavior.

Metabolism of α-linolenic acid in humans

Abstract: Alpha-linolenic acid (18:3n-3) is essential in the human diet, probably because it is the substrate for the synthesis of longer-chain, more unsaturated n-3 fatty acids eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) which are required for tissue function. This article reviews the recent literature on 18:3n-3 metabolism in humans, including fatty acid beta-oxidation, recycling of carbon by fatty acid synthesis de novo and conversion to longer-chain polyunsaturated fatty acids (PUFA). In men, stable isotope tracer studies and studies in which volunteers increased their consumption of 18:3n-3 show conversion to 20:5n-3 and 22:5n-3, but limited conversion to 22:6n-3. However, conversion to 18:3n-3 to 20:5n-3 and 22:6n-3 is greater in women compared to men, due possibly to a regulatory effect of oestrogen, while partitioning of 18:3n-3 towards beta-oxidation and carbon recycling was lower than in men. These gender differences may be an important consideration in making dietary recommendations for n-3 PUFA intake.

Omega-3 fatty acids and rodent behavior.

Abstract: This paper reviews the role of the n-3 fatty acids in the regulation of cognitive functions, locomotor and exploratory activity and emotional status in rodents. There are disparate data on the performance of n-3 fatty acid deficient animals in the open field test and elevated plus maze. Results obtained in our laboratory indicated slower habituation to the open field in deficient mice, which affects total locomotor and exploratory parameters. We also observed no change in plus maze performance of deficient mice under low-stress but elevated anxiety under high-stress conditions. There is some evidence of elevated aggression and increased immobility time in the forced swimming test caused by n-3 fatty acid deficiency in rodents. Effects of n-3 fatty acid deficiency and supplementation on learning in several tests such as the Morris water maze, two odor olfactory discriminations, radial arm maze performance and avoidance tasks are reviewed in detail. There is some evidence of an enhanced vulnerability to stress of n-3 fatty acid deficient animals and this factor can influence performance in a variety of tests. Thus, behavioral tasks that involve a higher level of stress may better differentiate behavioral effects related to brain docosahexaenoic acid (DHA) status. It is suggested that a fruitful area for future investigations of functional alterations related to brain DHA status will be the delineation of the factors underlying changes in performance in behavioral tasks. The possible role of non-cognitive factors like emotionality and attention in the impaired performance of n-3 fatty acid deficient animals also requires further investigation.

Omega-3 fatty acid status in attention-deficit/hyperactivity disorder.

Abstract: Lower levels of long-chain polyunsaturated fatty acids, particularly omega-3 fatty acids, in blood have repeatedly been associated with a variety of behavioral disorders including attention-deficit/hyperactivity disorder (ADHD). The exact nature of this relationship is not yet clear. We have studied children with ADHD who exhibited skin and thirst symptoms classically associated with essential fatty acid (EFA) deficiency, altered plasma and red blood cell fatty acid profiles, and dietary intake patterns that do not differ significantly from controls. This led us to focus on a potential metabolic insufficiency as the cause for the altered fatty acid phenotype. Here we review previous work and present new data expanding our observations into the young adult population. The frequency of thirst and skin symptoms was greater in newly diagnosed individuals with ADHD (n = 35) versus control individuals without behavioral problems (n = 112) drawn from the Purdue student population. A follow up case-control study with participants willing to provide a blood sample, a urine sample, a questionnaire about their general health, and dietary intake records was conducted with balancing based on gender, age, body mass index, smoking and ethnicity. A number of biochemical measures were analyzed including status markers for several nutrients and antioxidants, markers of oxidative stress, inflammation markers, and fatty acid profiles in the blood. The proportion of omega-3 fatty acids was found to be significantly lower in plasma phospholipids and erythrocytes in the ADHD group versus controls whereas saturated fatty acid proportions were higher. Intake of saturated fat was 30% higher in the ADHD group, but intake of all other nutrients was not different. Surprisingly, no evidence of elevated oxidative stress was found based on analysis of blood and urine samples. Indeed, serum ferritin, magnesium, and ascorbate concentrations were higher in the ADHD group, but iron, zinc, and vitamin B6 were not different. Our brief survey of biochemical and nutritional parameters did not give us any insight into the etiology of lower omega-3 fatty acids, but considering the consistency of the observation in multiple ADHD populations continued research in this field is encouraged.

Sperm fatty acid composition in subfertile men.

Abstract: Introduction The lipid composition of spermatozoa plays an important role for successful fertilization. Patients and methods In the present study, we analyzed the fatty acid (FA) composition of spermatozoa of normozoospermic, asthenozoospermic, oligozoospermic and oligoasthenozoospermic men. Results Spermatozoa from asthenozoospermic ( P P P P P P P P P P P Saturated fatty acids (SFA) were significantly higher in asthenozoospermic ( P P r = 0.53 ), sperm concentration ( r = 0.36 ) and normal sperm morphology ( r = 0.30 ). In addition, there were significant correlations between PUFA with sperm motility ( r = 0.50 ), sperm concentration ( r = 0.35 ), and normal sperm morphology ( r = 0.28 ), and between w6/w3 with sperm motility ( r = - 0.47 ), sperm concentration ( r = - 0.27 ), and normal sperm morphology( r = - 0.24 ). Discussion These suggest that decreased DHA and PUFA, and increased w6/w3 in spermatozoa may be related to infertility in oligo- and/or asthenozoospermic men.

Omega-3 fatty acids, energy substrates, and brain function during aging

Abstract: The maintenance of optimal cognitive function is a central feature of healthy aging. Impairment in brain glucose uptake is common in aging associated cognitive deterioration, but little is known of how this problem arises or whether it can be corrected or bypassed. Several aspects of the challenge to providing the brain with an adequate supply of fuel during aging seem to relate to omega-3 fatty acids. For instance, low intake of omega-3 fatty acids, especially docosahexaenoic acid (DHA), is becoming increasingly associated with several forms of cognitive decline in the elderly, particularly Alzheimer's disease. Brain DHA level seems to be an important regulator of brain glucose uptake, possibly by affecting the activity of some but not all the glucose transporters. DHA synthesis from either α-linolenic acid (ALA) or eicosapentaenoic acid (EPA) is very low in humans begging the question of whether these DHA precursors are likely to be helpful in maintaining cognition during aging. We speculate that ALA and EPA may well have useful supporting roles in maintaining brain function during aging but not by their conversion to DHA. ALA is an efficient ketogenic fatty acid, while EPA promotes fatty acid oxidation. By helping to produce ketone bodies, the effects of ALA and EPA could well be useful in strategies intended to use ketones to bypass problems of impaired glucose access to the brain during aging. Hence, it may be time to consider whether the main omega-3 fatty acids have distinct but complementary roles in brain function.

How fatty acids of different chain length enter and leave cells by free diffusion

Abstract: Opposing views exist as to how unesterified fatty acids (FA) enter and leave cells. It is commonly believed that for short- and medium-chain FA free diffusion suffices whereas it is questioned whether proteins are required to facilitate transport of long-chain fatty acid (LCFA). Furthermore, it is unclear whether these proteins facilitate binding to the plasma membrane, trans-membrane movement, dissociation into the cytosol and/or transport in the cytosol. In this mini-review we approach the controversy from a different point of view by focusing on the membrane permeability constant (P) of FA with different chain length. We compare experimentally derived values of the P of short and medium-chain FA with values of apparent permeability coefficients for LCFA calculated from their dissociation rate constant (k(off)), flip-flop rate constant (k(flip)) and partition coefficient (Kp) in phospholipid bilayers. It was found that Overton's rule is valid as long as k(flip)<

Supplementation with flax oil and vitamin C improves the outcome of Attention Deficit Hyperactivity Disorder (ADHD)

Abstract: Considerable clinical and experimental evidence now supports the idea that deficiencies or imbalances in certain highly unsaturated fatty acids may contribute to a range of common developmental disorders including Attention Deficit Hyperactivity Disorder (ADHD) Few intervention studies with LCPUFA supplementation have reported inconsistent and marginal results This pilot study evaluates the effect of alpha linolenic acid (ALA)-rich nutritional supplementation in the form of flax oil and antioxidant emulsion on blood fatty acids composition and behavior in children with ADHD Post-supplementation levels of RBC membrane fatty acids were significantly higher than pretreatment levels as well as the levels in control There was significant improvement in the symptoms of ADHD reflected by reduction in total hyperactivity scores of ADHD children derived from ADHD rating scale

Long-chain polyunsaturated fatty acids in maternal and infant nutrition

Abstract: Homo sapiens has evolved on a diet rich in alpha-linolenic acid and long chain polyunsaturated fatty acids (LCP). We have, however, gradually changed our diet from about 10,000 years ago and accelerated this change from about 100 to 200 years ago. The many dietary changes, including lower intake of omega3-fatty acids, are related to 'typically Western' diseases. After a brief introduction in essential fatty acids (EFA), LCP and their functions, this contribution discusses our present low status of notably LCPomega3 in the context of our rapidly changing diet within an evolutionary short time frame. It then focuses on the consequences in pregnancy, lactation and neonatal nutrition, as illustrated by some recent data from our group. We discuss the concept of a 'relative' EFA/LCP deficiency in the fetus as the outcome of high transplacental glucose flux. This flux may in the fetus augment de novo synthesis of fatty acids, which not only dilutes transplacentally transported EFA/LCP, but also causes competition of de novo synthesized oleic acid with linoleic acid for delta-6 desaturation. Such conditions were encountered by us in mothers with high body mass indices, diabetes mellitus and preeclampsia. The unifying factor might be compromised glucose homeostasis. In search of the milk arachidonic acid (AA) and docosahexaenoic acid (DHA) contents of our African ancestors, we investigated women in Tanzania with high intakes of freshwater fish as only animal lipid source. These women had milk AA and DHA contents that were well above present recommendations for infant formulae. Both studies stimulate rethinking of 'optimal homeostasis'. Subtle signs of dysbalanced maternal glucose homeostasis may be important and observations from current Western societies may not provide us with an adequate basis for dietary recommendations.

Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.

Abstract: 15-lipoxygenase (15-LOX) belongs to the structurally and functionally related nonheme iron dioxygenases family. It has two isoforms, type-1 (leukocyte type) and type-2 (epidermis type) and converts arachidonic acid to eicosanoids including the anti-cancer 13-HODE. In the current study, we investigate the expression of both isoforms of 15-LOX in human breast cancer ( n = 120 ) and normal mammary tissues ( n = 32 ), using immunohistochemistry and quantitative analysis of the gene transcripts. Both 15-LOX-1 and 15-LOX-2 were found in normal mammary epithelial cells and in vascular endothelial cells. The staining of both 15-LOX-1 and 15-LOX-2 was markedly weaker in breast cancer cells. Using quantitative analysis, it was found that the 15-LOX-1 and 15-LOX-2:CK19 ratios were lower in breast tumour tissues, compared with normal tissues ( P = 0.05 and P = 0.035 , respectively). Although no significant correlation was seen between either isoforms and nodal status and tumour grade, significantly lower ratio of 15-LOX-2:CK19 was seen in late stage breast tumours. Both 15-LOX-2 and 15-LOX-1 were found to be at significantly lower levels in tumours from patients who developed metastasis ( P = 0.0018 for 15-LOX-2 and P = 0.031 for 15-LOX-1, compared with patients who remained disease free), and in patients who died of breast cancer related causes ( P = 0.043 and P = 0.020 vs disease-free group, for 15-LOX-2 and 15-LOX-1, respectively). It was also demonstrated that ER-positive tumours had significantly lower levels of 15-LOX-2, but not 15-LOX-1, compared with ER-negative tumours ( P = 0.031 ). Finally, the study has shown that the 15LOX1:15LOX2 ratio had a strong value in predicting clinical outcome. Patients who developed metastasis, local recurrence and died of breast cancer had significantly lower ratio compared with those who remained disease free ( P = 0.0057 , P = 0.0075 , P = 0.0091 , respectively). In conclusion, the current study reports aberrant expression of both isoforms of 15-LOX, 15-LOX-1 and 15-LOX-2, in human breast cancer. The reduction is correlated with the disease progression of breast cancer and a poor clinical outcome. The study has also reported a link between 15-LOX-2 and oestrogen receptor status in breast tumours. Both isoforms of 15-lipoxygenese have a tumour suppressing role in breast cancer.

Omega-3 fatty acids and perinatal depression: a review of the literature and recommendations for future research.

Abstract: Introduction: Perinatal depression refers to major depression in the context of pregnancy and postpartum. In consideration of its prevalence and consequences, the treatment and prevention of perinatal depression should be important public health priorities. Omega-3 fatty acids are attractive for consideration in perinatal women, due to known health benefits for the mother and baby. Antidepressant medications may pose risks in utero and in breastfeeding. Methods: MEDLINE and manual searches were conducted. Results: Epidemiological and preclinical data support a role of omega-3 fatty acids in perinatal depression. Two studies failed to support a role of omega-3 fatty acids for postpartum depression prophylaxis, although one included a small sample, and the other utilized a low dosage. Two pilot studies suggest good tolerability and potential efficacy in the acute treatment of perinatal depression. Conclusions: Further research studies are warranted to determine the role of omega-3 fatty acids in the treatment of perinatal depression.

Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration

Abstract: Cannabinoid receptors and the endocannabinoids (anandamide (N-arachidonoylethanolamine--AEA) and 2-arachidonoylglycerol (2-AG)), as well as the AEA congener, palmitoylethanolamide (PEA), are involved in ocular physiology. We measured endocannabinoid and PEA levels by isotope-dilution liquid chromatography-mass spectrometric analysis in post-mortem eye tissues of patients with diabetic retinopathy (DR) or age-related macular degeneration (AMD). In eyes with DR, significantly enhanced levels of AEA were found in the retina ( approximately 1.8-fold), ciliary body ( approximately 1.5-fold) and, to a lesser extent, cornea ( approximately 1.3-fold). Surprisingly, 2-AG levels were significantly higher ( approximately 3-fold) only in the iris, whereas PEA levels only slightly increased ( approximately 1.3-fold) in the ciliary body. In eyes with AMD, significantly enhanced levels of AEA were found in the choroid ( approximately 1.3-fold), ciliary body ( approximately 1.4-fold) and cornea ( approximately 1.4-fold), whereas in the retina only a trend towards an increase ( approximately 1.5-fold) was observed. The tissue- and disease-selective nature of the changes observed suggests that the compounds analyzed here may play different roles in the control of eye function under different pathological conditions.

Determination of endogenous tissue inflammation profiles by LC/MS/MS: COX- and LOX-derived bioactive lipids

Abstract: Cyclooxygenase and lipoxygenase arachidonate products, including prostaglandins (PGs), leukotrienes (LTs), and hydroxyeicosatetraenoic acids (HETEs), are known to modulate inflammation within tissues and can serve as important etiologic factors in carcinogenesis. Eicosanoid content in tissues is typically determined either as a single molecular species through antibody-based assays or by high-performance liquid chromatography after addition of an exogenous substrate such as arachidonic acid. Unfortunately, the methods currently in use are either time-consuming or complicated. Here we report a method for simultaneously identifying eicosanoids appearing as endogenous bioactive lipids in in vivo settings using LC/MS/MS. The analyses indicate marked differences in endogenous eicosanoid content between malignant tissue types suggesting a need for selective therapeutic approaches. As a demonstration of the utility of the method, we present data to show that the technique can be used to distinguish eicosapentaenoic acid-derived formation of PGE3 from PGE2 in murine prostate tissue. The method has also been applied to an examination of endogenous eicosanoid metabolism in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral cancer in hamsters demonstrating the inflammatory nature of this type of cancer with elevated levels of both PGE2 and LTB4. In addition, the concentration of the eicosanoid 13-hydroxyoctadecadienoic acid was 67.6% lower in DMBA treated specimens than in control specimens. Thus, our method provides a powerful tool for measuring modulation of eicosanoid metabolites in various preclinical and clinical tissues and may be useful in studies of the endogenous changes in eicosanoid metabolism at various stages of cancer development.

Hydroxy-alkenals from the peroxidation of n-3 and n-6 fatty acids and urinary metabolites.

Abstract: 4-hydroxy-2E-hexenal (4-HHE) and 4-hydroxy-2E-nonenal (4-HNE) have been characterized as prominent by-products of n-3 and n-6 hydroperoxy derivatives of n-3 and n-6 fatty acids, respectively. We also have characterized the homolog 4-hydroxy-2E,6Z-dodecadienal (4-HDDE) as a specific by-product of the 12-lipoxygenase product of arachidonic acid 12-hydroperoxy-eicosatetraenoate (12-HpETE). The three hydroxy-alkenals have been found in human plasma with 4-HHE being the most prominent followed by 4-HNE. They were found increased in tissues submitted to oxidative stress, according to the fatty acid characteristic of those tissues, e.g., 4-HNE and 4-HDDE in blood platelets and 4-HHE in the retina. We have shown they covalently bind to the primary amine moiety of ethanolamine phospholipids (PE), especially the plasmalogen subclass, with the highest hydrophobic alkenal (4-HDDE) being the most reactive. Their carboxylic acid metabolites, 4-hydroxy-2E-hexenoic acid (4-HHA), 4-hydroxy-2E-nonenoic acid (4-HNA) and 4-hydroxy-2E,6Z-dodecadienoic acid (4-HDDA), respectively, were found in human urine and measured in higher amounts in situations in which oxidative stress has been reported such as aging and diabetes. As reported above with their hydroxy-alkenals precursors, 4-HHA proved to be the most prominent followed by 4-HNA. Altogether, the three hydroxy-alkenals, either in their free form or bound to membrane PE, may be considered as specific markers of lipid peroxidation able to discriminate between n-3 and n-6 fatty acids. This is corroborated by the measurement of their urinary carboxylic acid metabolites.

Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids.

Abstract: The aetiology of primary open-angle glaucoma (POAG), which is the commonest cause of non-remediable blindness and visual impairment, is not well understood. Nevertheless, increased intraocular pressure, and vascular factors such as ocular blood flow deficits are thought to be risk factors. There is evidence of decreased optic nerve blood velocity and increased red blood cell aggregability in POAG. These factors are influenced by fatty acids. We have investigated if glaucoma patients have abnormal blood fatty acid composition. Patients with POAG (n=10) and their healthy siblings (n=8) were enrolled. Compared with their healthy siblings, the glaucoma patients had reduced eicosapentaenoic (EPA, P<0.01), and docosahexaenoic (DHA, P<0.05) fatty acids and total omega3 long-chain polyunsaturated fatty acids (LCPUFA) (P<0.05) in red cell choline phosphoglycerides (CPG); decreased EPA (P<0.05) in ethanolamine phosphoglycerides (EPG); lower EPA (P<0.05) and total omega3 LCPUFA (P<0.05) in serine phosphoglycerides (SPG). Similarly, they had reduced EPA, DHA and total omega3 LCPUFA in plasma CPG (P<0.005) and triglycerides (P<0.05). These findings may be significant, since EPA and DHA could modulate impaired systemic microcirculation and ocular blood flow and optic neuropathy, which are the main physiological changes associated with glaucoma.

Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology and treatment of recurrent neuropsychiatric illness.

Abstract: The phosphoinositide (PI)–protein kinase C (PKC) signal transduction pathway is initiated by pre- and postsynaptic G α q-coupled receptors, and regulates several clinically relevant neurochemical events, including neurotransmitter release efficacy, monoamine receptor function and trafficking, monoamine transporter function and trafficking, axonal myelination, and gene expression. Mounting evidence for PI–PKC signaling hyperactivity in the peripheral (platelets) and central (premortem and postmortem brain) tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, coupled with evidence that PI–PKC signal transduction is down-regulated in rat brain following chronic, but not acute, treatment with antipsychotic, mood-stabilizer, and antidepressant medications, suggest that PI–PKC hyperactivity is central to an underlying pathophysiology. Evidence that membrane omega-3 fatty acids act as endogenous antagonists of the PI–PKC signal transduction pathway, coupled with evidence that omega-3 fatty acid deficiency is observed in peripheral and central tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, support the hypothesis that omega-3 fatty acid deficiency may contribute to elevated PI–PKC activity in these illnesses. The data reviewed in this paper outline a potential molecular mechanism by which omega-3 fatty acids could contribute to the pathophysiology and treatment of recurrent neuropsychiatric illness.

Eugenol--the active principle from cloves inhibits 5-lipoxygenase activity and leukotriene-C4 in human PMNL cells.

Abstract: Polymorphonuclear leukocytes (PMNL) play an important role in the modulation of inflammatory conditions in humans. PMNL cells recruited at the site of inflammation, release inflammatory mediators such as leukotrienes, proteolytic enzymes and reactive oxygen species. Among these, leukotrienes are implicated in pathophysiology of allergic and inflammatory disorders like asthma, allergic rhinitis, arthritis, inflammatory bowel disease and psoriasis. 5-Lipoxygenase (5-LO) is the key enzyme in biosynthetic pathway of leukotrienes. Our earlier studies showed that spice phenolic active principles significantly inhibit 5-LO enzyme in human PMNLs. In this study we have further characterized the inhibitory mechanism of eugenol, the active principle of spice-clove on 5-LO enzyme and also its effect on leukotriene C4 (LTC4). Substrate dependent enzyme kinetics showed that the inhibitory effect of eugenol on 5-LO was of a non-competitive nature. Further, eugenol was found to significantly inhibit the formation of LTC4 in calcium ionophore A23187 and arachidonic acid (AA) stimulated PMNL cells. These data clearly suggest that eugenol inhibits 5-LO by non-competitive mechanism and also inhibits formation of LTC4 in human PMNL cells and thus may have beneficial role in modulating 5-LO pathway in human PMNL cells.

Fatty acid compositions of red blood cell phospholipids in children with autism.

Abstract: We compared the compositions of fatty acids including n-3, n-6 polyunsaturated fatty acids, trans- and cis-monounsaturated fatty acids, and saturated fatty acids in the red blood cell membranes of 40 children with autism (20 with early onset autism and 20 with developmental regression) and age-matched, 20 typically developing controls and 20 subjects with non-autistic developmental disabilities. The main findings include increased levels of eicosenoic acid (20:1n9) and erucic acid (22:1n9) in autistic subjects with developmental regression when compared with typically developing controls. In addition, an increase in 20:2n6 and a decrease in 16:1n7t were observed in children with clinical regression compared to those with early onset autism. Our results do not provide strong evidence for the hypothesis that abnormal fatty acid metabolism plays a role in the pathogenesis of autism spectrum disorder, although they suggest some metabolic or dietary abnormalities in the regressive form of autism.

The bioavailability and pharmacodynamics of different concentrations of omega-3 acid ethyl esters

Abstract: Omega-3 fatty acids have a long history of use as dietary supplements and more recently for therapeutic applications as prescription pharmaceuticals. Achieving a high concentration is critical for developing convenient, practical therapeutic formulations. The objective of the study was to explore the uptake and effects of different concentrations of omega-3 acid ethyl esters. Three different omega-3 concentrations were investigated in a clinical study with 101 subjects. All participants were dosed for 14 days with 5.1g per day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters provided in three concentrations: 62.5%, 80% and 85% of total fatty acids. Key endpoints of the study were serum phospholipids and standard fasting lipid panels at day 14. Although administered the same quantity of omega-3 fatty acids, the patients taking the more concentrated formulations had higher levels of EPA/DHA in serum phospholipids and greater reductions in serum triglyceride and VLDL cholesterol levels. Total and non-HDL cholesterol were significantly reduced from baseline with all three formulations. In conclusion the concentration of omega-3 fatty acids of the formulations studied had independent effects on the uptake and effect outcomes during short-term administration. Very high concentrations of omega-3 acid ethyl esters (80%) appear to have higher uptake and are more potent for reducing triglycerides (TGs) and VLDL-cholesterol than formulations with lower concentrations.

Fatty acid composition of liver, adipose tissue, spleen, and heart of mice fed diets containing t10, c12-, and c9, t11-conjugated linoleic acid.

Abstract: Conjugated linoleic acid (CLA) isomers have unique effects on tissue lipids. Here we investigated the influence of individual CLA isomers on the lipid weight and fatty acid composition of lipid metabolizing (i.e. liver and retroperitoneal adipose) and lipid sensitive (i.e. spleen and heart) tissues. Female mice (8 week old; n=6/group) were fed either a control or one of the two CLA isomer supplemented (0.5%) diets for 8 weeks. The cis-9, trans-11-CLA diet reduced the 18:1n-9 wt% by 20-50% in liver, adipose tissue, and spleen, reduced the spleen n-3 polyunsaturated fatty acid (PUFA) by 90%, and increased the n-6 PUFA wt% by 20-50% in all tissues except heart. The trans-10, cis-12-CLA reduced both the n-6 and n-3 PUFA wt% in liver (>50%), reduced the heart n-3 PUFA wt% by 25%, and increased the wt% of spleen n-3 PUFA by 700%. The functional consequences of such changes in tissue fatty acid composition need to be investigated.

N-3 fatty acids in the Mediterranean diet.

Abstract: Fats in the diet of countries in the Mediterranean basin are typically represented by olive oil, but the high consumptions of vegetables and to some extent also of fish result in appreciable intakes of n-3 fatty acids. In fact, various plant foods are relatively rich in the 18 carbon n-3 fatty acid, alpha linolenic acid, ALA, while the generally moderate consumption of fish, except for certain communities living close to the sea, contributes to the intake of the long-chain n-3. Although the amounts of fats in ALA-containing plant foods are low, the relatively high concentrations of this fatty acid and the large size of the portions consumed allow to reach appreciable doses of ALA, an n-3 fatty acid that has been shown to exert favourable effects on various relevant factors in cardiovascular protection. In addition, consumption of relatively small amounts of certain typical dry fruit components of the diet such as walnuts, provides a sizable supply of ALA that is also rather efficiently converted to the ALA derivative eicosapentaenoic acid (EPA). Additional rather typical wild food components of the diet in certain countries, i.e. snails and frogs, are also appreciable sources of ALA. It appears thus that the consumption of typical Mediterranean foods provides relevant intakes of n-3 fatty acids, especially ALA, that appears to be efficiently absorbed and also transformed at least to the long-chain derivative EPA.

Aberrant expression of 5-lipoxygenase-activating protein (5-LOXAP) has prognostic and survival significance in patients with breast cancer

Abstract: 5-lipoxygenase (5-LOX)-activating protein, 5-LOXAP also known as LOX5AP or FLAP, is a protein that works closely with 5-LOX in regulating the metabolism of arachidonate. Some of the eicosanoid products of 5-LOX/5-LOXAP are known to play active roles in the function of cancer cells, including breast cancer cells. The current study investigated the expression of 5-LOXAP in clinical breast cancer and the prognostic impact of 5-LOXAP and 5-LOX in patients with breast cancer. A cohort of breast tumour tissues (n = 122) with normal background tissues (n = 32) were investigated. 5-LOXAP and 5-LOX transcripts were determined using RT-PCR and quantitative RT-PCR. Levels of the transcripts were analysed against clinical and pathological information. Breast tumour tissues had significantly higher levels of 5-LOX transcript compared with normal tissues (P = 0.015). The transcript was seen at significantly higher levels in node positive tumours than that in node negative tumours (P = 0.02). The prognostic significance was assessed using both a prognostic index and clinical outcome. Value of 5-LOXAP was first demonstrated when using the Nottingham Prognostic Index (NPI) as an indicator, in that patients with predicted poor prognosis had significantly higher levels of 5-LOXAP than patients with good prognosis (P = 0.0407). Furthermore, patients who died of breast cancer-related causes had significant higher levels of 5-LOXAP than those patients who remained disease free, following a median 10-year followup. A survival analysis has shown that high levels of 5-LOXAP were significantly correlated with overall survival (mean survival 109.6 month vs. 139.4 months, in tumour from patients with high and low levels of 5-LOXAP, P = 0.05). The same disadvantage of high levels of 5-LOXAP was also seen with disease-free survival (105.2 months vs. 135.6 months, P = 0.017). Analysis of 5-LOXAP together with 5-LOX transcript did not enhance the significance of the survival. However, when 5-LOXAP was considered together with 12-LOX, it improved the predictive power for both overall and disease-free survival (109.0 month vs. 143.1 months, P = 0.0156 for overall survival and 98.3 months vs. 141.3 months for disease-free survival, P = 0.0022). In conclusion, 5-LOXAP expression was aberrant in human breast cancer, particularly in aggressive tumours. Furthermore, 5-LOXAP had a significant prognostic value in patients with breast cancer. This identifies 5-LOXAP as a potential therapeutic target in breast cancer.

Differential effect of saturated, monounsaturated, and polyunsaturated fatty acids on alloxan-induced diabetes mellitus

Abstract: Earlier, we reported that oils rich in omega-3 eicosapentaenoic acid and docosahexaenoic acid and omega-6 gamma-linolenic acid and arachidonic acid prevented the development of alloxan-induced diabetes mellitus in experimental animals. Here we report the results of our studies with pure saturated stearic acid (SA), monounsaturated oleic acid (OA) and omega-6 arachidonic acid (AA) on alloxan-induced diabetes mellitus in Wistar male rats. Prior oral supplementation with AA prevented alloxan-induced diabetes mellitus, whereas both SA and OA were ineffective. Cyclo-oxygenase (COX) and lipoxygenase (LO) inhibitors did not block this protective action of AA against alloxan-induced diabetes, suggesting that both prostaglandins and leukotrienes are not involved, and that AA by itself is effective. Furthermore, AA restored the anti-oxidant status to normal range in various tissues. These results suggest that AA protects pancreatic beta cells against alloxan-induced diabetes in experimental animals by attenuating oxidant stress.

Prostaglandin E2 (PGE2) increases the number of rat bone marrow osteogenic stromal cells (BMSC) via binding the EP4 receptor, activating sphingosine kinase and inhibiting caspase activity

Abstract: Prostaglandin E(2) (PGE(2)) is bone-anabolic, i.e. stimulates bone formation and increases bone mass. In this study, we explored possible intracellular mechanisms of its increase of osteogenic cells in rat bone marrow. Adherent rat bone marrow cells were counted after 12-48 h or cultured for 21 days and mineralized nodules were counted. Also, apoptosis of marrow cells was measured after in vivo PGE(2) injection. PGE(2) (100 nM) increased 2-3 fold the number of adherent BMSC, an effect which was mediated via binding the EP(4) receptor since it was mimicked by forskolin and 11-deoxy-prostaglandin E(1) (PGE(1)) and was blocked by DDA and L-161982 (EP(4) antagonist). PGE(2) stimulated sphingosine kinase (SPK) activity since its effects were blocked by DMS (SPK inhibitor) and mimicked by SPP (SPK product). PGE(2) reduced the activity of caspase-3 and -8 in BMSC and their inhibitors increased BMSC number and nodule formation. In vivo, PGE(2) prevented the increase in the apoptosis of bone marrow cells caused by indomethacin. We propose that PGE(2) exerts an anti-apoptotic effect on BMSC, thereby increasing their number and subsequent osteoblastic differentiation. Such an effect could explain how PGE(2) stimulates bone formation in vivo.

Oxygenation of ω-3 fatty acids by human cytochrome P450 4F3B: Effect on 20-hydroxyeicosatetraenoic acid production

Abstract: Cytochrome P450 (CYP) omega-oxidases convert arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a lipid mediator that modulates vascular tone. We observed that a microsomal preparation containing recombinant human CYP4F3B, which converts AA to 20-HETE, converted eicosapentaenoic acid (EPA) to 20-OH-EPA. Likewise, docosahexaenoic acid (DHA) was converted to 22-OH-DHA, indicating that human CYP4F3B also can oxidize 22-carbon omega-3 fatty acids. Consistent with these findings, addition of 0.5-5 microM EPA, DHA or omega-3 docosapentaenoic acid (DPA) to incubations containing 0.5 microM [3H]AA inhibited [3H]20-HETE production by 15-65%. [3H]20-OH-EPA was rapidly taken up by COS-7 cells, and almost all of the incorporated radioactivity remained as unmodified 20-OH-EPA. The 20-OH-EPA stimulated luciferase activity in COS-7 cells that express peroxisome proliferator-activated receptor alpha, indicating that this EPA metabolite may function as a lipid mediator. These findings suggest that some functional effects of omega-3 fatty acid supplementation may be due to inhibition of 20-HETE formation or the conversion of EPA to the corresponding omega-oxidized product.

Omega 6 to omega 3 fatty acid imbalance early in life leads to persistent reductions in DHA levels in glycerophospholipids in rat hypothalamus even after long-term omega 3 fatty acid repletion $

Abstract: Failure to provide omega 3 fatty acids in the perinatal period results in alterations in nerve growth factor levels, dopamine production and permanent elevations in blood pressure. The present study investigated whether changes in brain (i.e., hypothalamus) glycerophospholipid fatty acid profiles induced by a diet rich in omega 6 fatty acids and very low in alpha-linolenic acid (ALA) during pregnancy and the perinatal period could be reversed by subsequent feeding of a diet containing ALA. Female rats (6 per group) were mated and fed either a low ALA diet or a control diet containing ALA throughout pregnancy and until weaning of the pups at 3 weeks. At weaning, the pups (20 per group) remained on the diet of their mothers until 9 weeks, when half the pups were switched onto the other diet, thus generating four groups of animals. At 33 weeks, pups were killed, the hypothalamus dissected from the male rats and analysed for glycerophospholipid fatty acids. In the animals fed the diet with very little ALA and then re-fed the control diet containing high levels of ALA for 24 weeks, the DHA levels were still significantly less than the control values in PE, PS and PI fractions, by 9%, 18% and 34%, respectively. In this group, but not in the other dietary groups, ALA was detected in all glycerophospholipid classes at 0.2-1.7% of the total fatty acids. The results suggest that omega 6-3 PUFA imbalance early in life leads to irreversible changes in hypothalamic composition. The increased ALA and reduced DHA proportions in the animals re-fed ALA in later life are consistent with a dysfunction or down-regulation of the conversion of ALA to 18:4n-3 by the delta-6 desaturase.

Versatile roles of docosahexaenoic acid in the prenatal brain: from pro- and anti-oxidant features to regulation of gene expression.

Abstract: Docosahexaenoic acid (DHA) is the most ubiquitous polyunsaturated fatty acid (FA) in brain tissue. It is selectively esterified to amino phospholipids (PL) and therefore it is highly prevalent at the cytofacial site of the plasma membrane where it may specifically participate in intracellular events. A highly selective DHA accumulation prior to birth is the result of maternal supply via the placenta through a bio-magnification process. Supplements of DHA via the intra-amniotic route to the fetal rat increase brain DHA levels and also confer neuroprotection to fetuses subjected to global ischemic stress. The protective effect has been attributed to an enhanced free radical scavenging capacity of DHA. Dietary deprivation of linolenic acid (LNA) during the perinatal life on the other hand, resulted in losses of DHA from cerebral PLs [M. Schiefermeier, E. Yavin, n-3 deficient and DHA-enriched diets during critical periods of the developing prenatal rat brain, J. Lipid Res. 43 (2002) 124–131]. LNA deprivation also caused changes in a number of gene markers the identification of which was attained by a labor-intensive suppression subtractive hybridization protocol using mRNA from 2-week-old postnatal brains [E. Yakubov, P. Dinerman, F. Kuperstein, S. Saban, E. Yavin, Improved representation of gene markers on microarray by PCR-select subtracted cDNA targets, Mol. Brain Res. 137 (2005) 110–118]. Most notable was a remarkable elevation of dopamine (DA) receptor (D1 and D2) genes as evaluated by quantitative RT-PCR, SDS-PAGE gel electrophoresis and immunochemical staining [F. Kuperstein, E. Yakubov, P. Dinerman, S. Gil, R. Eylam, N. Salem Jr., E. Yavin, Overexpression of dopamine receptor genes and their products in the postnatal rat brain following maternal n-3 FA dietary deficiency, J. Neurochem. 95 (2005) 1550–1562]. Over-expression of DA receptors has been attributed to a compensatory mechanism resulting from impairment in DA neurotransmitter production, storage and processing. In conclusion, DHA is a versatile molecule with a wide range of actions spanning from participation in cellular oxidative processes and intracellular signaling to modulatory roles in gene expression and growth regulation.

Intravenous lipid emulsions to deliver omega 3 fatty acids

Abstract: A rapid supply of n-3 polyunsaturated fatty acids (PUFA) may be indicated in some acute conditions because of the ability of n-3 PUFA to decrease inflammatory responses and cell sensitivity to various stimuli, and to improve endothelial dysfunction. To achieve these objectives, n-3 PUFA content needs to be quickly raised in cell membranes of key organs. Intravenous fish oil (FO) emulsions are available but their slow hydrolysis limits their infusion rate. Mixtures containing both FO triglycerides and medium chain triglycerides may overcome this problem. These new preparations are rapidly cleared from plasma and efficiently deliver n-3 PUFA to several tissues, largely via direct particle uptake. Recent data suggest that n-3 PUFA incorporation in phospholipids promptly modulates important cell functions. This review also focuses on a novel approach to rapidly supply n-3 PUFA to targeted organs which may offer interesting perspectives in the management of acute illnesses.