The Antihypertensive Effect of Quercetin in Young Spontaneously Hypertensive Rats; Role of Arachidonic Acid Metabolism.

Hypertension affects almost 50% of the adult American population. Metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the blood pressure-lowering potential of quercetin (QR), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered QR in drinking water at concentrations of 10, 30, and 60 mg/L. Blood pressure was monitored at seven-day intervals. After a total of seven weeks of treatment, rats were killed and kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Medium- and high-dose QR resisted the rise in blood pressure observed in the untreated SHR and significantly inhibited the activity of the CYP4A enzyme in renal cortical microsomes. The activity of the sEH enzyme in renal cortical cytosols was significantly inhibited only by the high QR dose. Our data not only demonstrate the antihypertensive effect of QR, but also provide a novel mechanism for its underlying cardioprotective properties.

Emergence of omega-3 fatty acids in biomedical research.

Shortly after the discovery that linoleic acid was an essential fatty acid in 1930, α-linolenic acid also was reported to prevent the fatty acid deficiency syndrome in animals. However, several prominent laboratories could not confirm the findings with α-linolenic acid, and as a result there was a loss of interest in omega-3 fatty acids in lipid research. Even the findings that a prostaglandin can be synthesized from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is necessary for optimum retinal function generated only limited interest in omega-3 fatty acids. The breakthrough came in the 1970s when Dyerberg and Bang reported that the low incidence of atherosclerotic coronary disease in Greenland Eskimos was due to the high marine lipid content of their diet. They subsequently found that EPA, which was increased in Eskimo plasma, inhibited platelet aggregation, and they concluded that the low incidence of coronary artery disease was due to the anti-thrombotic effect of EPA. This stimulated widespread interest and research in EPA and DHA, leading to the present view that, like their omega-6 counterparts, omega-3 fatty acids have important physiological functions and are essential fatty acids.

Neonatal fatty acid status and cardiometabolic health at 9years.

BACKGROUND: Long chain polyunsaturated fatty acid (LCPUFA) status is associated with risk of cardiovascular diseases in adulthood. We previously demonstrated no effect of LCPUFA supplementation after birth on BP and anthropometrics. Little is known about the association between fatty acid status at birth and cardiometabolic health at older ages. AIM: To evaluate associations between docosahexaenoic acid (DHA) and arachidonic acid (AA) levels in the umbilical cord and blood pressure (BP) and anthropometrics at 9years. STUDY DESIGN: Observational follow-up study. Multivariable analyses were carried out to adjust for potential confounders. SUBJECTS: 229 children who took part in a randomized controlled trial (RCT) on the effects of LCPUFA formula supplementation. OUTCOME MEASURES: BP was chosen as primary outcome; heart rate and anthropometrics as secondary outcomes. RESULTS: AA levels in the wall of the umbilical vein and artery were negatively associated with diastolic BP (B: vein -0.831, 95% CI: -1.578; -0.083, p=0.030; artery: -0.605, 95% CI: -1.200; -0.010, p=0.046). AA was not associated with systolic BP; DHA not with diastolic nor systolic BP. The AA:DHA ratio in the umbilical vein was negatively associated with diastolic BP (B: -1.738, 95% CI: -3.141; -0.335, p=0.015). Heart rate and anthropometrics were not associated with neonatal LCPUFA status. CONCLUSIONS: Higher AA levels and a higher AA:DHA ratio at birth are associated with lower diastolic BP at age 9. This suggests that the effect of LCPUFAs at early age is different from that in adults, where DHA is regarded anti-adipogenic and AA as adipogenic.

Evidence for the essentiality of arachidonic and docosahexaenoic acid in the postnatal maternal and infant diet for the development of the infant's immune system early in life.

Long-chain polyunsaturated fatty acids (LCPUFA), especially the balance between arachidonic (AA) and docosahexaenoic (DHA) acids are known to have important immunomodulatory roles during the postnatal period when the immune system is rapidly developing. AA and DHA are required in infant formula in many countries but are optional in North America. The rationale for adding these LCPUFA to full-term formula is based on their presence in breast milk and randomized controlled studies that suggest improved cognitive function in preterm infants, but results are more variable in full-term infants. Recently, the European Food Safety Authority has proposed, based on a lack of functional evidence, that AA is not required in infant formula for full-term infants during the first year of life but DHA should remain mandatory. The purpose of this review is to review the evidence from epidemiological and intervention studies regarding the essentiality of AA and DHA in the postnatal infant and maternal diet (breast-feeding) for the immune system development early in life. Although studies support the essentiality of DHA for the immune system development, more research is needed to rule out the essentiality of AA. Nevertheless, intervention studies have demonstrated improvement in many markers of immune function in infants fed formula supplemented with AA and DHA compared with unsupplemented formula, which appears to consistently result in beneficial health outcomes including reduction in the risk of developing allergic and atopic disease early in life.

Current information and Asian perspectives on long-chain polyunsaturated fatty acids in pregnancy, lactation, and infancy: systematic review and practice recommendations from an early nutrition academy workshop.

The Early Nutrition Academy supported a systematic review of human studies on the roles of pre- and postnatal long-chain polyunsaturated fatty acids (LC-PUFA) published from 2008 to 2013 and an expert workshop that reviewed the information and developed recommendations, considering particularly Asian populations. An increased supply of n-3 LC-PUFA during pregnancy reduces the risk of preterm birth before 34 weeks of gestation. Pregnant women should achieve an additional supply ≥200 mg docosahexaenic acid (DHA)/day, usually achieving a total intake ≥300 mg DHA/day. Higher intakes (600-800 mg DHA/day) may provide greater protection against early preterm birth. Some studies indicate beneficial effects of pre- and postnatal DHA supply on child neurodevelopment and allergy risk. Breast-feeding is the best choice for infants. Breast-feeding women should get ≥200 mg DHA/day to achieve a human milk DHA content of ∼0.3% fatty acids. Infant formula for term infants should contain DHA and arachidonic acid (AA) to provide 100 mg DHA/day and 140 mg AA/day. A supply of 100 mg DHA/day should continue during the second half of infancy. We do not provide quantitative advice on AA levels in follow-on formula fed after the introduction of complimentary feeding due to a lack of sufficient data and considerable variation in the AA amounts provided by complimentary foods. Reasonable intakes for very-low-birth weight infants are 18-60 mg/kg/day DHA and 18-45 mg/kg/day AA, while higher intakes (55-60 mg/kg/day DHA, ∼1% fatty acids; 35-45 mg/kg/day AA, ∼0.6-0.75%) appear preferable. Research on the requirements and effects of LC-PUFA during pregnancy, lactation, and early childhood should continue. © 2014 S. Karger AG, Basel.

Arachidonic acid and lipoxin A4 as possible endogenous anti-diabetic molecules.

In both type 1 and type 2 diabetes mellitus, increased production of pro-inflammatory cytokines and reactive oxygen species (ROS) occurs that induce apoptosis of ß cells and cause peripheral insulin resistance respectively though the degree of their increased production is higher in type 1 and less in type 2 diabetes mellitus. Despite this, the exact mechanism(s) that lead to increased production of pro-inflammatory cytokines: interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and ROS is not known. Studies showed that plasma concentrations of arachidonic acid (AA) and lipoxin A4 (LXA4) are low in alloxan-induced type 1 diabetes mellitus in experimental animals and patients with type 2 diabetes mellitus. Prior administration of AA, eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively) and transgenic animals that produce increased amounts of EPA and DHA acids were protected from chemical-induced diabetes mellitus that was associated with enhanced formation of LXA4 and resolvins, while protectin D1 ameliorated peripheral insulin resistance. AA, LXA4, resolvins and protectins inhibit IL-6 and TNF-α production and suppress ROS generation. Thus, AA and lipoxins, resolvins and protectins may function as endogenous anti-diabetic molecules implying that their administration could be useful in the prevention and management of both types of diabetes mellitus.

Arachidonic acid supplementation enhances in vitro skeletal muscle cell growth via a COX-2-dependent pathway.

Arachidonic acid (AA) is the metabolic precursor to a diverse range of downstream bioactive lipid mediators. A positive or negative influence of individual eicosanoid species [e.g., prostaglandins (PGs), leukotrienes, and hydroxyeicosatetraenoic acids] has been implicated in skeletal muscle cell growth and development. The collective role of AA-derived metabolites in physiological states of skeletal muscle growth/atrophy remains unclear. The present study aimed to determine the direct effect of free AA supplementation and subsequent eicosanoid biosynthesis on skeletal myocyte growth in vitro. C2C12 (mouse) skeletal myocytes induced to differentiate with supplemental AA exhibited dose-dependent increases in the size, myonuclear content, and protein accretion of developing myotubes, independent of changes in cell density or the rate/extent of myogenic differentiation. Nonselective (indomethacin) or cyclooxygenase 2 (COX-2)-selective (NS-398) nonsteroidal anti-inflammatory drugs blunted basal myogenesis, an effect that was amplified in the presence of supplemental free AA substrate. The stimulatory effects of AA persisted in preexisting myotubes via a COX-2-dependent (NS-389-sensitive) pathway, specifically implying dependency on downstream PG biosynthesis. AA-stimulated growth was associated with markedly increased secretion of PGF(2α) and PGE(2); however, incubation of myocytes with PG-rich conditioned medium failed to mimic the effects of direct AA supplementation. In vitro AA supplementation stimulates PG release and skeletal muscle cell hypertrophy via a COX-2-dependent pathway.

Role of long-chain polyunsaturated fatty acids in the first year of life.

The 2 most abundant long-chain polyunsaturated fatty acids (LCPUFAs) in the brain are docosahexaenoic acid (DHA) and arachidonic acid (ARA), where they have a functional and structural role in infant development. DHA is concentrated in the prefrontal cortex, which is important for association and short-term memory, and in some retinal cells. Concentrations of PUFAs in human breast milk are relatively consistent during the first year of life, and studies have shown that breast-fed infants have a greater mean weight percentage of DHA and a greater proportion of DHA in their red blood cells and brain cortex than formula-fed infants. Furthermore, cortex DHA in breast-fed infants increases with age, probably due to the length of feeding. Maternal supplementation with cod liver oil, which is rich in DHA and eicosapentaenoic acid, improved children's intelligence quotient compared with corn-oil supplementation by 4 years of age. The LCPUFA content of human breast milk is affected by a number of factors, including diet, gestational age, parity, and smoking. Supplementation of formula feed with DHA and ARA results in infant development that is similar to breast-feeding, and may have benefits on blood pressure in later childhood. The beneficial effects of LCPUFA supplementation on visual acuity continue after weaning irrespective of the type of diet. The long-term effects and duration of supplementation of breast- and formula-fed infants requires further investigation.

Regulation of TLR2 expression by prostaglandins in brain glia.

TLR have emerged as important primary sensors for diverse stimuli and are increasingly implicated in various diseases. However, the molecular mechanisms underlying the regulation of the TLR system remain poorly understood. In this study, we report that some PGs may control TLR-mediated inflammatory events through modulation of TLR2 expression in brain immune cells. We first found that 15-deoxy-Delta12,14-PG J(2) (15d-PGJ(2)) markedly altered the expression of TLR2 but not TLR4, TLR1, and TLR9 at the message and protein levels in activated glia. Down-regulation of TLR2 expression and downstream events of TLR2 activation, including phagocytosis by 15d-PGJ(2), were also observed in cells treated with representative TLR2 ligands such as lipoteichoic acid and Pam(3)CSK(4). We further revealed that certain 15d-PGJ(2)-related PGs such as 15d-PGD(2) and PGD(2) also suppressed the ligand-stimulated increase of TLR2 expression, whereas PGE(2) and arachidonic acids did not. Interestingly, TLR2 expression was down-regulated even when such PGs were added at several hours after stimulator treatment. These findings appear to be independent of peroxisome proliferator-activated receptor gamma and D prostanoid receptors (DPs) because potent synthetic peroxisome proliferator-activated receptor gamma agonists, selective DP1 agonist, or DP2 agonist did not mimic the effects of such PGs on TLR2 expression. Taken together, our results suggest that 15d-PGJ(2), 15d-PGD(2), and PGD(2) may play notable roles as modulators of the TLR2-mediated inflammatory events, and provide new insight into the resolution of inflammation in the brain.

Pivotal role of arachidonic acid in the regulation of neuronal nitric oxide synthase activity and inducible nitric oxide synthase expression in activated astrocytes.

Astrocytes respond to agents leading to progressively greater increases in the intracellular concentration of Ca(2+) ([Ca(2+)](i)) with a linear release of arachidonic acid (ARA), due to activation of cytosolic phospholipase A(2), and with a bell-shaped curve of nitric oxide (NO) release, due to Ca(2+)-dependent activation/inhibition of neuronal NO synthase (nNOS). Inhibition of nNOS is mediated by a signaling driven by ARA, either extensively released at high [Ca(2+)](i) or supplemented to the cultures at nanomolar levels. Proinflammatory factors, as bacterial lipopolysaccharide/interferon-gamma, cause rapid ARA-dependent nNOS inhibition, critical for the delayed expression of nuclear factor-kappaB (NF-kappaB)-dependent genes as inducible NOS. We therefore propose that the onset of the neuroinflammatory response is strictly regulated by the relative amounts of NO and ARA produced by their constitutive enzymes. In particular, the inflammatory product ARA initiates the inflammatory response via inhibition of nNOS, thereby allowing NF-kappaB activation. Astrocytes contribute to the regulation of this process by producing both constitutive NO and ARA, as well as by expressing NF-kappaB-dependent genes.

Arachidonic acid as a retrograde signal controlling growth and dynamics of retinotectal arbors.

In the developing visual system, correlated presynaptic activity between neighboring retinal ganglion cells (RGC) stabilizes retinotopic synapses via a postsynaptic NMDAR (N-methyl-D-aspartate receptor)-dependent mechanism. Blocking NMDARs makes individual axonal arbors larger, which underlies an unsharpened map, and also increases branch turnover, as if a stabilizing factor from the postsynaptic partner is no longer released. Arachidonic acid (AA), a candidate retrograde stabilizing factor, is released by cytoplasmic phospholipase A2 (cPLA2) after Ca(2+) entry through activated NMDARs, and can activate presynaptic protein kinase C to phosphorylate various substrates such as GAP43 to regulate cytoskeletal dynamics. To test the role of cPLA2 in the retinotectal system of developing zebrafish, we first used PED6, a fluorescent reporter of cPLA2 activity, to show that 1-3 min of strobe flashes activated tectal cPLA2 by an NMDAR-dependent mechanism. Second, we imaged the dynamic growth of retinal arbors during both local inhibition of tectal cPLA2 by a pharmacological inhibitor, arachidonic tri-fluoromethylketone, and its suppression by antisense oligonucleotides (both injected intraventricularly). Both methods produced larger arbors and faster branch dynamics as occurs with blocking NMDARs. In contrast, intraocular suppression of retinal cPLA2 with large doses of antisense oligos produced none of the effects of tectal cPLA2 inhibition. Finally, if AA is the retrograde messenger, the application of exogenous AA to the tectum should reverse the increased branch turnover caused by blocking either NMDARs or cPLA2. In both cases, intraventricular injection of AA stabilized the overall branch dynamics, bringing rates down below the normal values. The results suggest that AA generated postsynaptically by cPLA2 downstream of Ca(2+) entry through NMDARs acts as a retrograde signal to regulate the dynamic growth of retinal arbors.

Roles of long-chain polyunsaturated fatty acids in the term infant: developmental benefits.

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are two long-chain polyunsaturated fatty acids (LCPUFAs) found naturally in human milk. DHA and ARA have been receiving increased attention from health care professionals and the public. Research suggests that DHA intake and status have a significant impact on visual and cognitive development in breastfed infants. For formula-fed infants, studies have shown mixed results from DHA or DHA plus ARA supplementation. There are several important differences among LCPUFA studies with term infants that may contribute to the differing results, including levels of LCPUFA added to the formula, variations in test methods, ages of infants evaluated, and sources of LCPUFA. Nevertheless, several expert groups recommend that infant formulas be supplemented with DHA and ARA. Recommendations for term infants for DHA and ARA range from 0.2 percent to 0.4 percent and from 0.35 percent to 0.7 percent of the fatty acids, respectively.

[Primary role and extraction of arachidonic acid].

Arachidonic acid (AA), which is one of the essential fatty acids in the human body, plays an important physiological, pharmacological and health role. This paper discusses the general characteristics of arachidonic acid, physiological, pharmacological effects and health roles. There are also a comparison of arachidonic acid extraction methods and domestic developments and problems existed. At last, it is prospected the trend of its development.

Beta-carotene and arachidonic acid induced DNA methylation and the regulation of pro-chemotactic activity of endothelial cells and its progenitors.

DNA methylation is one of the important mechanisms regulating gene expression. Since beta-carotene (BC) was shown to have pro-chemotactic activity and stimulates expression of pro-angiogenic genes, this study was undertaken to define the possible changes in DNA methylation in endothelial cell and its progenitors in the presence of BC. The culture medium for human umbilical vein endothelial cells (HUVEC) and endothelial progenitor cells (EPC) was supplemented with BC (1 - 10 microM) with the presence of arachidonic acid (AA) (3 microM). Global DNA methylation tended to be lower in both endothelial cell lines, after incubation with BC and AA. HUVEC incubated with AA demonstrated the lowest DNA methylation. The decrease of DNA methylation in EPC, induced by BC, was concentration-dependent. The microarray study revealed, that the angiogenesis and homing-related genes were mostly influenced by BC and AA in investigated cells. Our results indicate that BC and AA-induced DNA hypomethylation in EPC and HUVEC, might be a mechanism which may alter gene expression in endothelial cells what in certain conditions may be connected with the suggested pro-malignant effect of this compounds.

Arachidonic acid preserves hippocampal neuron membrane fluidity in senescent rats.

Previous studies indicate that long-term dietary supplementation with arachidonic acid (AA) in 20-month-old rats (OA) effectively restores performance in a memory task and the induction of long-term potentiation in the hippocampus to the level of young control animals (YC). The present study examined protein mobility using the live cell imaging technique "Fluorescent Recovery After Photobleaching (FRAP)" in YC, old control (OC) and OA neurons in hippocampal slice preparations. Three measures; mobile fraction (M(f)), diffusion constant (D) and time constant (tau), were estimated among YC, OC and OA. Each of these parameters was significantly different between OC and YC, suggesting that membrane fluidity is lower in OC than in YC. In contrast, D and tau were comparable in OA and YC, indicating that hippocampal neuronal membranes supplemented with AA were more fluid than those in OC, whereas the fraction of diffusible protein in the bleached region remained smaller than in YC. Long-term administration of AA to senescent rats might help to preserve membrane fluidity and maintain hippocampal plasticity.

Bioactive lipids in schizophrenia.

Bioactive lipids, in particular arachidonic acid (AA), are vital for monoaminergic neurotransmission, brain development and synaptic plasticity. Phospholipases A2 (PLA2) are key-enzymes in AA metabolism and are activated during monoaminergic neurotransmission. Reduced membrane AA levels, and an altered activity of PLA2 have been found in peripheral membranes of drug-naïve patients with schizophrenia with some conflicting results in more chronic patient populations. Furthermore, in vivo brain phosphorus-31 magnetic resonance spectroscopy suggests reduced lipid membrane precursors (phosphomonoesters) and increased membrane breakdown products (phosphodiesters) in drug-naïve or early treated first-episode schizophrenia patients compared to age-matched controls or chronic populations and these changes were correlated with peripheral red blood cell membrane AA levels. We postulate that processes modulating membrane lipid metabolism are associated with psychotic illnesses and might partially explain the mechanism of action of antipsychotic agents, as well as experimental agents such as purified ethyl-eicosapentaenoic acid (E-EPA). Recent supplementation trials suggest that E-EPA is a modestly effective augmentation treatment resulting in reduced doses of antipsychotic medication in acutely ill patients with schizophrenia (but not in residual-type schizophrenia). This review investigates the role of bioactive lipids in schizophrenia and its treatment, as well as its potential use in prevention.