The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients' lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.

Long-Chain Polyunsaturated Fatty Acids in the Green Microalga Lobosphaera incisa Contribute to Tolerance to Abiotic Stresses.

Lobosphaera incisa is a green microalga that accumulates high levels of the valuable omega-6 long-chain polyunsaturated fatty acids (LC-PUFA) arachidonic acid (ARA, 20:4n-6) in triacylglycerols (TAG) under nitrogen (N) starvation. LC-PUFA accumulation is a rare trait in photosynthetic microalgae with insufficiently understood physiological significance. In this study, RNAi was attempted, for the first time in L. incisa, to produce knockdown lines for the Δ5 desaturase gene. Two lines, termed modified lines, which were isolated during screening for transgenic events, demonstrated alterations in their LC-PUFA profile, ARA-biosynthesis gene expression and lipid class distribution. In line M5-78, which appeared to carry a mutation in the Δ6 elongase gene, LC-PUFA were substituted by 18:3n-6 in all glycerolipids. Line M2-35, for which the exact genetic background has not been established, displayed a dramatic reduction in 20:4n-6, concomitant with an augmented proportion of 18:1n-9, in particular in the extraplastidial membrane lipids and TAG. The physiological responses of the modified lines to stressful conditions were compared with the wild type and the Δ5 desaturase mutant. In the N-replete cells of modified lines, the frequency of lipid droplets was reduced, while a number of starch grains increased, suggesting altered partitioning of assimilated carbon into reserve products. Furthermore, both lines exhibited reduced ability to accumulate TAG under N deprivation and recover from N starvation. Both lines demonstrated lower photosynthetic pigment contents, impairments in photosynthesis under a range of stressful conditions, and less efficient functioning of photoprotection under optimal conditions. Possible implications of fatty acids modifications in the stress response of L. incisa are addressed.

Dietary omega-3 deficiency exacerbates inflammation and reveals spatial memory deficits in mice exposed to lipopolysaccharide during gestation.

Maternal immune activation (MIA) is a common environmental insult on the developing brain and represents a risk factor for neurodevelopmental disorders. Animal models of in utero inflammation further revealed a causal link between maternal inflammatory activation during pregnancy and behavioural impairment relevant to neurodevelopmental disorders in the offspring. Accumulating evidence point out that proinflammatory cytokines produced both in the maternal and fetal compartments are responsible for social, cognitive and emotional behavioral deficits in the offspring. Polyunsaturated fatty acids (PUFAs) are essential fatty acids with potent immunomodulatory activities. PUFAs and their bioactive derivatives can promote or inhibit many aspects of the immune and inflammatory response. PUFAs of the n-3 series ('n-3 PUFAs', also known as omega-3) exhibit anti-inflammatory/pro-resolution properties and promote immune functions, while PUFAs of the n-6 series ('n-6 PUFAs' or omega-6) favor pro-inflammatory responses. The present study aimed at providing insight into the effects of n-3 PUFAs on the consequences of MIA on brain development. We hypothesized that a reduction in n-3 PUFAs exacerbates both maternal and fetal inflammatory responses to MIA and later-life defects in memory in the offspring. Based on a lipopolysaccharide (LPS) model of MIA (LPS injection at embryonic day 17), we showed that n-3 PUFA deficiency 1) alters fatty acid composition of the fetal and adult offspring brain; 2) exacerbates maternal and fetal inflammatory processes with no significant alteration of microglia phenotype, and 3) induces spatial memory deficits in the adult offspring. We also showed a strong negative correlation between brain content in n-3 PUFA and cytokine production in MIA-exposed fetuses. Overall, our study is the first to address the deleterious effects of n-3 PUFA deficiency on brain lipid composition, inflammation and memory performances in MIA-exposed animals and indicates that it should be considered as a potent environmental risk factor for the apparition of neurodevelopmental disorders.

[What the surgeon needs to know about basic new concepts of inflammation and their therapeutic consequences: sanitation of inflammation is not a passive but rather an active process regulated by lipid mediators]. / Was der Chirurg über grundlegend neue Konzepte zur Entzündung und deren therapeutische Konsequenzen wissen sollte: Die Ausheilung der Entzündung ist kein passiver, sondern ein durch Lipidmediatoren regulierter aktiver Prozess.

The acute inflammatory response as a physiological programme that protects the organism against injurious pathogens is characterised by highly regulated actions of pro- and anti-inflammatory mediators. Intensive investigations during the last decades have led to the identification of these mediators and their complex interplay as well as the design and development of anti-inflammatory therapies. However, the resolution of acute inflammation has long been considered to be a passive process. In consequence, little was known about the mechanisms which guide acute inflammation either to complete resolution, repair of inflamed tissue and restoration of normal function or to a chronic inflammatory process characterised by persistent signs of inflammation, tissue damage and impaired function. Predominantly during the last decade the so-called specialised proresolving mediators (SPM) have been identified. These essential fatty acid-derived mediators - lipoxins, resolvins, protectins, and maresins - terminate the acute inflammatory responses and stimulate their complete resolution. SPM possess both anti-inflammatory and proresolving activities in that they inhibit pro-inflammatory cytokines, limit infiltration of neutrophils, enhance macrophage uptake, and finally stimulate their non-phlogistic activation and clearance of apoptotic neutrophils and microbial particles. It has been demonstrated in multiple animal models of human inflammatory diseases that, e.g., atherosclerosis, diabetes, and inflammatory bowel diseases are caused by a decreased synthesis and/or an impaired signal transduction of the proresolving mediators. Future studies are warranted to clarify whether these proresolving lipid mediators will participate in healing human inflammatory diseases and their complications.

Consequences of essential fatty acids.

Essential fatty acids (EFA) are nutrients that form an amazingly large array of bioactive mediators that act on a large family of selective receptors. Nearly every cell and tissue in the human body expresses at least one of these receptors, allowing EFA-based signaling to influence nearly every aspect of human physiology. In this way, the health consequences of specific gene-environment interactions with these nutrients are more extensive than often recognized. The metabolic transformations have similar competitive dynamics for the n-3 and n-6 homologs when converting dietary EFA from the external environment of foods into the highly unsaturated fatty acid (HUFA) esters that accumulate in the internal environment of cells and tissues. In contrast, the formation and action of bioactive mediators during tissue responses to stimuli tend to selectively create more intense consequences for n-6 than n-3 homologs. Both n-3 and n-6 nutrients have beneficial actions, but many common health disorders are undesired consequences of excessive actions of tissue n-6 HUFA which are preventable. This review considers the possibility of preventing imbalances in dietary n-3 and n-6 nutrients with informed voluntary food choices. That action may prevent the unintended consequences that come from eating imbalanced diets which support excessive chronic actions of n-6 mediators that harm human health. The consequences from preventing n-3 and n-6 nutrient imbalances on a nationwide scale may be very large, and they need careful evaluation and implementation to avoid further harmful consequences for the national economy.

Polyunsaturated fatty acid intake and blood pressure in adolescents.

Evidence that intake of polyunsaturated fatty acids (PUFAs) may modify blood pressure (BP) is generally limited to middle-aged or hypertensive populations. This study examined cross-sectional associations between BP and dietary intake of PUFAs in 814 adolescents aged 13-15 years participating in the Western Australian Pregnancy Cohort (Raine) Study. Fatty acid intakes were assessed using 3-day diet records and resting BP was determined using multiple oscillometric readings. In multivariate regression models, systolic BP was inversely associated with intakes of polyunsaturated (b=-0.436, P<0.01), omega-3 (b=-2.47, P=0.02), omega-6 (b=-0.362, P=0.04) and long chain omega-3 fatty acids (b=-4.37, P=0.04) in boys. Diastolic BP and mean arterial pressure were inversely associated with intakes of long chain omega-3 fatty acids in boys (b=-3.93, P=0.01, b=-4.05, P=0.01, respectively). For specific long-chain omega-3s, significant inverse associations were observed between eicosapentaenoic acid (EPA) and docosahexaenoic acid, such as systolic BP decreasing by 4.7 mm Hg (95% CI -9.3 to -0.1) for a quarter gram increase in EPA, but no significant associations were observed with docosapentaenoic acid. No significant associations were observed in girls, or with the omega-6 to omega-3 ratio. Our results suggest that gender may moderate relationships between fatty acid intake and BP in adolescence.

[N-6 fatty acids and cardiovascular health: dietary intake recommendations]. / Acides gras oméga-6 et maladies cardiovasculaires: recommandations en matière d'apport alimentaire.

Omega-6 polyunsaturated fatty acids (n-6 PUFA) are well known for their critical role in many physiological functions and reduce risks of cardiovascular disease (CVD). However, some argue that excessive consumption of n-6 PUFA may lead to adverse effects on health and therefore recommend reducing dietary n-6 PUFA intake or fixing an upper limit. Epidemiological studies show that n-6 PUFA dietary intake significantly lowers blood LDL-cholesterol levels. In addition, n-6 PUFA intake lower several cardiovascular risk factors such as blood pressure, inflammatory markers, haemostatic parameters and obesity. Data from prospective cohort and interventional studies converge towards a specific protective role of dietary n-6 PUFA intake, in particular linoleic acid, against CVD. In regards to studies examined in this narrative review, recommendation for n-6 PUFA intake above 5%, and ideally about 10% of total energy appears justified for the prevention of ischemic heart disease.

The relationships of nutrients, routes of delivery, and immunocompetence.

Malnutrition has marked consequences on surgical outcomes. Adequate nutrition is important for the proper functioning of all organ systems, particularly the immune system. Determination of the type and amount of nutrient supplementation and the appropriate route of nutrient delivery is essential to bolster the immune system and enhance the host's response to stress. Correct administration of immunonutrients could lead to reductions in patient morbidity following major surgery, trauma, and critical illness.

Developmentally dependent and different roles of fatty acids OMEGA-6 and OMEGA-3.

The developmentally-dependent differences in the biological significances and effects of PUFA-OMEGA-6 (namely of arachidonic acid) and PUFA-OMEGA-3 (namely of docosahexaenoic acid) are discussed. The clinical results as well as developmental experiences are indicating a hypothesis of the evolution that created mutual relationship between those two substances (with immunological basis and following recuperation). The anti-inflammatory actions of PUFA-OMEGA-3 are the most visible (and significant) contrasts as compared with the large affects of namely arachidonic acid and its metabolites.

Importance of a balanced omega 6/omega 3 ratio for the maintenance of health: nutritional recommendations.

The modification of dietary patterns has led to a change in fatty acid consumption, with an increase in the consumption of ω-6 fatty acids and a marked reduction in the consumption of ω-3 fatty acids. This in turn has given rise to an imbalance in the ω-6/ω-3 ratio, which is now very different from the original 1:1 ratio of humans in the past. Given the involvement of ω-6 and ω-3 essential fatty acids in disease processes, the present article examines changes in dietary patterns that have led to the present reduction in the consumption of ω-3 essential fatty acids, and to study the importance of the ω-6/ω-3 balance in maintaining good health. In addition, an assessment is made of the established recommendations for preventing a poor intake of ω-3 essential fatty acids, and the possible options for compensating the lack of these fatty acids in the diet.

Dietary omega-3 and -6 polyunsaturated fatty acids affect the composition and development of sheep granulosa cells, oocytes and embryos.

The evidence that omega-3 (n-3) and -6 (n-6) polyunsaturated fatty acids (PUFAs) have differential effects on ovarian function, oocytes and embryo quality is inconsistent. We report on the effects of n-3 versus n-6 PUFA-enriched diets fed to 36 ewes over a 6-week period, prior to ovarian stimulation and follicular aspiration, on ovarian steroidogenic parameters and embryo quality. Follicle number and size were unaltered by diet, but follicular-fluid progesterone concentrations were greater in n-3 PUFA-fed ewes than in n-6 PUFA-fed ewes. The percentage of saturated FAs (mostly stearic acid) was greater in oocytes than in either granulosa cells or plasma, indicating selective uptake and/or de novo synthesis of saturated FAs at the expense of PUFAs by oocytes. High-density lipoproteins (HDLs) fractionated from sera of these ewes increased granulosa cell proliferation and steroidogenesis relative to the FA-free BSA control during culture, but there was no differential effect of n-3 and n-6 PUFAs on either oestradiol or progesterone production. HDL was ineffective in delivering FAs to embryos during culture, although n-6 PUFA HDL reduced embryo development. All blastocysts, irrespective of the treatment, contained high levels of unsaturated FAs, in particular linoleic acid. Transcripts for HDL and low-density lipoprotein (LDL) receptors (SCARB1 and LDLR) and stearoyl-CoA desaturase (SCD) are reported in sheep embryos. HDL reduced the expression of transcripts for LDLR and SCD relative to the BSA control. The data support a differential effect of n-3 and n-6 PUFAs on ovarian steroidogenesis and pre-implantation development, the latter in the absence of a net uptake of FAs.

Infant feed first year. 1: Feeding practices in the first six months of life.

The World Health Organization recommends exclusive breast-feeding for the first six months of life. Breast milk remains the best source of nutrition for infants and mothers need to be motivated to continue as long as possible. However, when breast milk is not an option, health care professionals should be able to advise parents on the best alternative. Many different formulae are available for infants between 0-6 months. Although the main ingredients are strictly regulated by the European Union, formulae may differ in their protein and fat source, and in the addition of novel ingredients offering different benefits. Whey protein dominant infant formulae empty from the stomach in a similar way to breast milk, which is also high in this protein. Long chain polyunsaturated fatty acids impact on visual attention, cognitive behaviour and the immune system, whereas nucleotides decrease the risk of developing diarrhoea. The addition of specific prebiotics to infant formulae is relatively new, but the impact of these on the development of immunity in early childhood has been well researched. Health care professionals need to take these factors into account when advising parents on a suitable alternative to breast milk.

Acute changes in dietary omega-3 and omega-6 polyunsaturated fatty acids have a pronounced impact on survival following ischemic renal injury and formation of renoprotective docosahexaenoic acid-derived protectin D1.

Exacerbated inflammation plays an important role in the pathogenesis of ischemic renal injury (IRI), which is the major cause of intrinsic acute renal failure. Clinical studies suggest that long-term treatment with omega-3 polyunsaturated fatty acids (PUFA) improves renal function and lowers the risk of death or end-stage renal disease. Docosahexaenoic acid, a principle omega-3 PUFA of fish oils, is of particular interest as it is found in most human tissues and is converted to protectin D1 (PD1), which exhibits antiinflammatory and proresolving bioactions. We set out to investigate the impact of acute dietary modulation of omega-3 or omega-6 PUFA on IRI and renal lipid autacoid circuits, using an established mouse model and liquid chromatography-mass spectroscopy/mass spectroscopy-based lipidomics. Thirty minutes of renal ischemia significantly elevated serum creatinine in the omega-6 diet group while renal function remained normal in the matched omega-3 diet group. Notably, extending ischemia to 45 min caused 100% mortality in the omega-6 group, in sharp contrast to 0% mortality in the omega-3 group. Protection against IRI in the omega-3 group correlated with decreased polymorphonuclear leukocyte recruitment, chemokine and cytokine levels, abrogated formation of lipoxygenase- and cyclooxygenase-derived eicosanoids, and increased renal levels of PD1. Systemic treatment with PD1 reduced kidney polymorphonuclear leukocyte influx and, more importantly, amplified renoprotective heme-oxygenase-1 protein and mRNA expression in injured and uninjured kidneys. These findings suggest therapeutic or dietary amplification of PD1 circuits restrains acute renal injury and that short-term changes in dietary omega-3 and omega-6 PUFA dramatically impacts renal lipid autacoid formation and outcome of IRI.

[Polyunsaturated fatty acids: anticonvulsive effects and underlying mechanisms]. / Acides gras poly-insaturés: propriétés et mécanismes anticonvulsivants.

Omega-3 and omega-6 poly-unsaturated fatty acids (PUFA) are the major families of PUFA that can be found as components of the human diet. After ingestion, both omega-3 and omega-6 PUFA are distributed to every cell in the body where they are involved in a myriad of physiological processes, including regulation of cardiovascular, immune, hormonal, metabolic, neuronal, and visual functions. At the cellular level, these effects are mediated by changes in membrane phospholipids structure, by interference with eicosanoid intracellular signaling, and by regulation of gene expression. The literature suggests the antiepileptic properties of PUFA, although these evidences emerge from basic science rather than from clinical trials. Several hypotheses have been suggested to explain the anticonvulsive effects of PUFA: modification of the membrane fluidity, direct action of PUFA on cell membrane ionic channels and/or receptors, modulation of inflammatory responses. Regarding the published clinical trials, the data are conflicting. It is currently not known whether different doses or different omega-3: omega-6 ratios would be effective.

Asthma, allergy, mood disorders, and nutrition.

BACKGROUND: Growing evidence supports comorbidity of asthma and allergies with mood disorders and various connections between these diseases. It still remains unclear whether this comorbidity is caused by the same pathophysiological factors or whether there are other links between asthma and depression. There is no definite answer to the question of an optimal treatment to deal with both asthma and depression, when they occur simultaneously. Epidemiological and clinical trials on the influence of nutrition on certain diseases suggest the effects of omega3 polyunsaturated fatty acids (PUFAs) in aiding treatment of mood disorders and inflammatory conditions. OBJECTIVE: This is an overview showing the connections between asthma, allergic disease, and mood disorders, and the influence of nutrition on these conditions. Evidence indicates positive correlations between consumption of PUFAs and mood correction. Several analyses show the connection between diet and asthma. They may form a basis for potential recommending omega3 PUFAs as an adjuvant in prevention and treatment of mental disorders, asthma, and allergy.

Fatty acid facts, Part I. Essential fatty acids as treatment for depression, or food for mood?

The epidemic character of depressive disorders has prompted further research into dietary habits that could make an etiological contribution. One clear change in the diet of the population in developed countries has been the replacement of omega-3 polyunsaturated fatty acids by saturated fats and trans-fats as well as by omega-6 polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids are essential fatty acids, and the members of the -3 and -6 series are crucial for human health. In biochemical processes there is a competition between these two series. A higher dietary intake of omega-6 results in the excessive incorporation of these molecules in the cell membrane with numerous pathological consequences, presumably due to the formation of proinflammatory eicosanoids. Members of the omega-3 family and their derivatives modulate the inflammatory action. Essential fatty acids play a major role in brain development and brain functioning. The omega-3 series members docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) provide fluidity to the cell membrane, facilitating certain processes including neurotransmission and ion channel flow. It is thought that omega-3 deficiency during the fetal and postnatal period may have a long-term effect at various levels. Epidemiological studies have demonstrated a positive association between omega-3 deficits and mood disorders. As for treatment, there is convincing evidence that add-on omega-3 fatty acids to standard antidepressant pharmacotherapy results in improved mood. There is no evidence that fatty acid monotherapy has a mood-elevating effect, with a possible exception for childhood depression. There are indications that omega-3 has a prophylactic effect on perinatal depression and has a negative effect on natural killer cell activity and T-lymphocyte function. These observations need further study in view of the popularity of self-medication.