Role Of Arachidonic Acid Research Articles

Molecular Basis of Different Flow-Induced Responses of Small Intra- and Extracranial Cerebral Arteries: Role of Arachidonic Acid and Nitric Oxide Pathways

Background / Objectives. Previous studies showed that increases in intraluminal flow elicit primarily dilations in isolated rat extracranial basilar arteries (BA), whereas constrictions in the intracranial middle cerebral arteries (MCA) (Koller A, Toth P. J Vasc. Res. 2012, PMID: 22739136). These responses are most likely due to the absence or presence of physical constraints (rigid cranium). Thus, we hypothesized that the underlying molecular pathways are also different, corresponding to the functional vasomotor responses. Material and Methods. Protein and gene expression of key AA-pathway enzymes and receptors, such as cyclooxygenase (COX1 and COX2) and thromboxane A2 receptor (TxA2R), and vasodilator enzymes, such as prostacyclin synthase (PGIS) were measured in isolated BA and MCA from male rats (3 months old, n=18). Results. By western blotting protein expression of vasoconstrictor metabolites COX1/2, Cyp4A and receptor TBXA2R were significantly higher whereas expression of dilator PGIS was significantly lower in MCA than in BA. Using qPCR we found that expression of genes coding vasoconstrictor enzymes COX1/2, Cyp4A and receptor TBXA2R was significantly higher, whereas gene coding dilator PGIS was significantly lower in intracranial compared to extracranial arteries. In addition, RNAseq analysis demonstrated that expression of multiple genes coding vasoconstrictor molecules is higher in intracranial compared to extracranial arteries. Conclusions. These findings provide mechanistic basis for the observed different functional, vasomotor responses of BA and MCA to increases in flow, by showing the different expression of enzymes (COX1/2, Cyp) producing constrictor prostanoids (such as 20-HETE), receptors (TxA2R) and dilator prostanoid (PGIS). In addition, these findings reinforce the importance of regional differences in the regulation of cerebral arterial resistance, thereby providing appropriate blood flow to the brain, and at the same time, autoregulation of cerebral blood flow. Ministry of Innovation and Technology (MIT) of Hungary-NRDI TKP2020-NKA-17, TKP2021-EGA-37, and National Research, Development, and Innovation Offce (NKFIH) OTKA K 132596 K_19, and Hungarian Academy of Sciences, Post-Covid 2021-34, and HUN-REN-SU: 02068 of Hungary. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evidence of Active-Forgetting Mechanisms? Blocking Arachidonic Acid Release May Slow Forgetting of Sensitization in Aplysia.

Long-term sensitization in Aplysia is accompanied by a persistent up-regulation of mRNA encoding the peptide neurotransmitter Phe-Met-Arg-Phe-amide (FMRFa), a neuromodulator that opposes the expression of sensitization through activation of the arachidonic acid second-messenger pathway. We completed a preregistered test of the hypothesis that FMRFa plays a critical role in the forgetting of sensitization. Aplysia received long-term sensitization training and were then given whole-body injections of vehicle (N = 27), FMRFa (N = 26), or 4-bromophenacylbromide (4-BPB; N = 31), a phospholipase inhibitor that prevents the release of arachidonic acid. FMRFa produced no changes in forgetting. 4-BPB decreased forgetting measured 6 d after training [d s = 0.55 95% CI(0.01, 1.09)], though the estimated effect size is uncertain. Our results provide preliminary evidence that forgetting of sensitization may be a regulated, active process in Aplysia, but could also indicate a role for arachidonic acid in stabilizing the induction of sensitization.

Dietary Implications of Polyunsaturated Fatty Acids during Pregnancy and in Neonates.

Certain limitations exist for animals to modify fatty acid changes. Besides the role of arachidonic acid (AA), docosahexaenoic acid (DHA) and other 20-carbon long-chain polyunsaturated fatty acids (LCPUFAs) for the synthesis of inflammatory mediators as eicosanoids, different LCPUFAs have many other effects, including their abilities to regulate gene expression and downstream events. LCPUFAs are susceptible to autoxidation, which is prevented by the action of antioxidants in the form of enzymes like superoxide dismutases, catalases and peroxidases, as well as antioxidant compounds that protect against oxidation or repair the damage caused. Under normal conditions, the fetus needs both essential fatty acids (EFAs) and LCPUFAs, which are obtained from its mother by placental transfer. In early pregnancy, dietary derived fatty acids are accumulated in maternal adipose tissue. However, during late pregnancy, corresponding to the period of the highest fetal growth, maternal adipose tissue becomes catabolic and LCPUFAs are released into the circulation by adipose lipolytic activity. The released LCPUFAs are taken up by maternal liver to be esterified and released back to the circulation as triacylglycerides (TAGs) in very-low-density lipoprotein (VLDL) that become available to the placenta to be transferred to the fetus in the form of non-esterified fatty acids (NEFAs). An enhanced adipose tissue lipolysis is maintained around parturition and esterified LCPUFAs are diverted to mammary glands thanks to an increased activity of lipoprotein lipase for milk production. Throughout this process, LCPUFAs become available to the newborn during suckling. The important role of both DHA and AA for the development of the nervous system and for growth has motivated their dietary supplement during different postnatal stages. This has been especially important in preterm infants both because under normal conditions, the fetus acquires most of these fatty acids during late pregnancy, and because the immaturity of the enzyme systems for the synthesis of AA and DHA from their respective EFAs.

Membrane Lipid Derivatives: Roles of Arachidonic Acid and Its Metabolites in Pancreatic Physiology and Pathophysiology.

One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular types of the body by a family of enzymes termed phospholipases: phospholipase A2, phospholipase C and phospholipase D. Phospholipase A2 is considered the most important enzyme type for the release of arachidonic acid. The latter is subsequently subjected to metabolization via different enzymes. Three enzymatic pathways, involving the enzymes cyclooxygenase, lipoxygenase and cytochrome P450, transform the lipid derivative into several bioactive compounds. Arachidonic acid itself plays a role as an intracellular signaling molecule. Additionally, its derivatives play critical roles in cell physiology and, moreover, are involved in the development of disease. Its metabolites comprise, predominantly, prostaglandins, thromboxanes, leukotrienes and hydroxyeicosatetraenoic acids. Their involvement in cellular responses leading to inflammation and/or cancer development is subject to intense study. This manuscript reviews the findings on the involvement of the membrane lipid derivative arachidonic acid and its metabolites in the development of pancreatitis, diabetes and/or pancreatic cancer.

Effects of Arachidonic Acid and Its Metabolites on Functional Beta-Cell Mass.

Arachidonic acid (AA) is a polyunsaturated 20-carbon fatty acid present in phospholipids in the plasma membrane. The three primary pathways by which AA is metabolized are mediated by cyclooxygenase (COX) enzymes, lipoxygenase (LOX) enzymes, and cytochrome P450 (CYP) enzymes. These three pathways produce eicosanoids, lipid signaling molecules that play roles in biological processes such as inflammation, pain, and immune function. Eicosanoids have been demonstrated to play a role in inflammatory, renal, and cardiovascular diseases as well type 1 and type 2 diabetes. Alterations in AA release or AA concentrations have been shown to affect insulin secretion from the pancreatic beta cell, leading to interest in the role of AA and its metabolites in the regulation of beta-cell function and maintenance of beta-cell mass. In this review, we discuss the metabolism of AA by COX, LOX, and CYP, the roles of these enzymes and their metabolites in beta-cell mass and function, and the possibility of targeting these pathways as novel therapies for treating diabetes.

Role of Arachidonic Acid and Its Metabolites in the Biological and Clinical Manifestations of Idiopathic Nephrotic Syndrome.

Studies concerning the role of arachidonic acid (AA) and its metabolites in kidney disease are scarce, and this applies in particular to idiopathic nephrotic syndrome (INS). INS is one of the most frequent glomerular diseases in childhood; it is characterized by T-lymphocyte dysfunction, alterations of pro- and anti-coagulant factor levels, and increased platelet count and aggregation, leading to thrombophilia. AA and its metabolites are involved in several biological processes. Herein, we describe the main fields where they may play a significant role, particularly as it pertains to their effects on the kidney and the mechanisms underlying INS. AA and its metabolites influence cell membrane fluidity and permeability, modulate platelet activity and coagulation, regulate lymphocyte activity and inflammation, preserve the permeability of the glomerular barrier, influence podocyte physiology, and play a role in renal fibrosis. We also provide suggestions regarding dietary measures that are able to prevent an imbalance between arachidonic acid and its parental compound linoleic acid, in order to counteract the inflammatory state which characterizes numerous kidney diseases. On this basis, studies of AA in kidney disease appear as an important field to explore, with possible relevant results at the biological, dietary, and pharmacological level, in the final perspective for AA to modulate INS clinical manifestations.

Transcriptomic profiling of phospholipase A2 and the role of arachidonic acid during Brucella abortus 544 infection in both in vitro and in vivo systems

To date, the antimicrobial activity of arachidonic acid (AA) with regard to pathogenesis of Brucella in macrophages is unknown. We found that AA is highly toxic to B. abortus in a time- and dose-dependent manner. Transcription profiling of different groups of phospholipases A2 (PLA2) was examined, ten PLA2 were detected including cPLA2-IV-A, cPLA2-IV-B, iPLA2-VI, sPLA2-I-B, sPLA2-II-C, sPLA2-II-D, sPLA2-II-E, sPLA2-V, sPLA2-X, sPLA2-XII-A. Phagocytic signaling investigation indicated that AA treatment attenuated p38α activity in infected culture macrophages possibly leading to inhibition of Brucella internalization. Post-treatment with the fatty acid did not influence bacterial intracellular multiplication or alter production of antimicrobial effectors like ROS and NO in RAW 264.7 cells. On the other hand, AA administration significantly reduced bacterial load and modestly inhibited pro-inflammatory cytokine secretion including TNF, IFN-γ and IL-6 in mice plasma. To our knowledge, we are the first to suggest that B. abortus invasion to RAW 264.7 macrophages is impaired by AA.

Spleen Oxylipin and Polyunsaturated Fatty Acid Profiles are Altered by Dietary Source of Polyunsaturated Fatty Acid and by Sex.

As the largest secondary lymphoid organ, the spleen plays an important role in immune responses. The role of arachidonic acid (ARA) and its 20-carbon eicosanoids in modulating immune function has long been of interest. However, recent advances have enabled the identification of numerous other n-6 and n-3 polyunsaturated fatty acid (PUFA)-derived oxylipins. Here, we investigate the effects of diet and sex on the spleen nonesterified oxylipin profiles and phospholipid and neutral lipid PUFA composition in Sprague-Dawley rats supplemented with oils rich in α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or linoleic acid. Dietary ALA, EPA, and DHA resulted in lower levels of ARA and ARA oxylipins. Oxylipins derived from other n-6 PUFA were also reduced despite no or opposite effect on their PUFA levels. Each diet also resulted in higher levels of oxylipins almost exclusively derived from the supplemented PUFA, despite PUFA in the same biosynthetic pathway also often being increased. Further, while oxylipin differences often reflected changes to phospholipid PUFA, there were instances where they corresponded more closely to changes in neutral lipid PUFA. With respect to sex effects, >50% of lipoxygenase ARA-derived oxylipins were higher in males in at least one diet group, while multiple DHA oxylipins were lower in males only in rats provided the DHA diet. This fundamental description of oxylipin composition in the spleen, including the influence of diet and sex and the relationship to PUFA composition, will help inform future studies examining the functions of these oxylipins under physiological and pathological conditions.

Laminar shear stress modulates endothelial luminal surface stiffness in a tissue-specific manner.

Endothelial cells form vascular beds in all organs and are exposed to a range of mechanical forces that regulate cellular phenotype. We sought to determine the role of endothelial luminal surface stiffness in tissue-specific mechanotransduction of laminar shear stress in microvascular mouse cells and the role of arachidonic acid in mediating this response. Microvascular mouse endothelial cells were subjected to laminar shear stress at 4 dynes/cm2 for 12hours in parallel plate flow chambers that enabled real-time optical microscopy and atomic force microscopy measurements of cell stiffness. Lung endothelial cells aligned parallel to flow, while cardiac endothelial cells did not. This rapid alignment was accompanied by increased cell stiffness. The addition of arachidonic acid to cardiac endothelial cells increased alignment and stiffness in response to shear stress. Inhibition of arachidonic acid in lung endothelial cells and embryonic stem cell-derived endothelial cells prevented cellular alignment and decreased cell stiffness. Our findings suggest that increased endothelial luminal surface stiffness in microvascular cells may facilitate mechanotransduction and alignment in response to laminar shear stress. Furthermore, the arachidonic acid pathway may mediate this tissue-specific process. An improved understanding of this response will aid in the treatment of organ-specific vascular disease.

Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis

ObjectiveWhen molecular drivers of healthy adipogenesis are perturbed, this can cause hepatic steatosis. The role of arachidonic acid (AA) and its downstream enzymatic cascades, such as cyclooxygenase, in adipogenesis is well established. The exact contribution of the P450 epoxygenase pathway, however, remains to be established. Enzymes belonging to this pathway are mainly encoded by the CYP2J locus which shows extensive allelic expansion in mice. Here we aimed to establish the role of endogenous epoxygenase during adipogenesis under homeostatic and metabolic stress conditions. MethodsWe took advantage of the simpler genetic architecture of the Cyp2j locus in the rat and used a Cyp2j4 (orthologue of human CYP2J2) knockout rat in two models of metabolic dysfunction: physiological aging and cafeteria diet (CAF). The phenotyping of Cyp2j4−/− rats under CAF was integrated with proteomics (LC-MS/MS) and lipidomics (LC-MS) analyses in the liver and the adipose tissue. ResultsWe report that Cyp2j4 deletion causes adipocyte dysfunction under metabolic challenges. This is characterized by (i) down-regulation of white adipose tissue (WAT) PPARγ and C/EBPα, (ii) adipocyte hypertrophy, (iii) extracellular matrix remodeling, and (iv) alternative usage of AA pathway. Specifically, in Cyp2j4−/− rats treated with a cafeteria diet, the dysfunctional adipogenesis is accompanied by exacerbated weight gain, hepatic lipid accumulation, and dysregulated gluconeogenesis. ConclusionThese results suggest that AA epoxygenases are essential regulators of healthy adipogenesis. Our results uncover their synergistic role in fine-tuning AA pathway in obesity-mediated hepatic steatosis.

Role of Arachidonic Acid in Promoting Hair Growth.

BackgroundArachidonic acid (AA) is an omega-6 polyunsaturated fatty acid present in all mammalian cell membranes, and involved in the regulation of many cellular processes, including cell survival, angiogenesis, and mitogenesis. The dermal papilla, composed of specialized fibroblasts located in the bulb of the hair follicle, contributes to the control of hair growth and the hair cycle.ObjectiveThis study investigated the effect of AA on hair growth by using in vivo and in vitro models.MethodsThe effect of AA on human dermal papilla cells (hDPCs) and hair shaft elongation was evaluated by MTT assay and hair follicle organ culture, respectively. The expression of various growth and survival factors in hDPCs were investigated by western blot or immunohistochemistry. The ability of AA to induce and prolong anagen phase in C57BL/6 mice was analyzed.ResultsAA was found to enhance the viability of hDPCs and promote the expression of several factors responsible for hair growth, including fibroblast growth factor-7 (FGF-7) and FGF-10. Western blotting identified the role of AA in the phosphorylation of various transcription factors (ERK, CREB, and AKT) and increased expression of Bcl-2 in hDPCs. In addition, AA significantly promoted hair shaft elongation, with increased proliferation of matrix keratinocytes, during ex vivo hair follicle culture. It was also found to promote hair growth by induction and prolongation of anagen phase in telogen-stage C57BL/6 mice.ConclusionThis study concludes that AA plays a role in promoting hair growth by increasing the expression of growth factors in hDPCs and enhancing follicle proliferation and survival.

Metabolism of arachidonic acid by the cytochrome P450 enzyme in patients with chronic Keshan disease and dilated cardiomyopathy

Keshan disease (KD) is an endemic cardiomyopathy. The etiology of KD is selenium deficiency; however, it is not the only one and there is no effective approach to preventing and curing this disease. The aim of the present study was to explore the differences in the role of arachidonic acid (AA) by the cytochrome P450 enzyme between chronic KD (CKD), dilated cardiomyopathy (DCM) and control patients. Reverse transcription-quantitative polymerase chain reaction was used to detect the CYP1A1 and CYP2C19 gene expression levels in 6 CKD patients, 6 DCM and 6 healthy controls. An enzyme-linked immunosorbent assay kit was applied to detect serum protein expression of CYP1A1 and CYP2C19, AA and epoxyeicosatrienoic acids (EETs), and 20-hydroxyeicosatetraenoic acids (20-HETE) in 67 CKD patients, 28 DCM, and 58 controls. The present results showed that the expression levels of CYP1A1 and CYP2C19 genes were significantly upregulated compared with the control group (P<0.01). The expression level of the CYP1A1 protein in the CKD (49.55±35.11 pg/ml) and DCM (46.68 ±13.01 pg/ml) groups were enhanced compared with the control group (44.33±16.76 pg/ml) (P<0.01). The production of the CYP2C19 protein in the CKD (57.52±28.22 pg/ml) and DCM (56.36±11.26 pg/ml) groups was enhanced compared with the control group (51.43±10.76 pg/ml). The concentrations of AA in the CKD (126.27±47.91 ng/ml) and DCM (133.24±58.67 ng/ml) groups were also significantly increased compared to the control (78.16±23.90 ng/ml) (P<0.001). The concentration of 20-HETE in the CKD (198.34±17.22 ng/ml) and DCM (194.46±20.35 ng/ml) groups were also significantly increased compared to the control (130.10±16.10 ng/ml) (P<0.001). The only difference between CKD and DCM was for the expression of the CYP1A1 gene and protein. The maximum concentration of EETs was in the control group (44.37±6.14 pg/ml), and the other two groups were lower than the control group (P<0.001). These findings indicated that AA-derived CYP450 metabolites may have a critical role in the pathogenesis of KD and DCM. Upregulation of the CYP2C19 gene and frequent protein expression may be a protective compensation reaction, while CYP1A1 may aggravate myocardial injury.

Immunopathogenesis of HIV infection in cocaine users: role of arachidonic acid.

Arachidonic acid (AA) is known to be increased in HIV infected patients and illicit drug users are linked with severity of viral replication, disease progression, and impaired immune functions. Studies have shown that cocaine accelerates HIV infection and disease progression mediated by immune cells. Dendritic cells (DC) are the first line of antigen presentation and defense against immune dysfunction. However, the role of cocaine use in HIV associated acceleration of AA secretion and its metabolites on immature dendritic cells (IDC) has not been elucidated yet. The aim of this study is to elucidate the mechanism of AA metabolites cyclooxygenase-2 (COX-2), prostaglandin E2 synthetase (PGE2), thromboxane A2 receptor (TBXA2R), cyclopentenone prostaglandins (CyPG), such as 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), 14-3-3 ζ/δ and 5-lipoxygenase (5-LOX) mediated induction of IDC immune dysfunctions in cocaine using HIV positive patients. The plasma levels of AA, PGE2, 15d-PGJ2, 14-3-3 ζ/δ and IDC intracellular COX-2 and 5-LOX expression were assessed in cocaine users, HIV positive patients, HIV positive cocaine users and normal subjects. Results showed that plasma concentration levels of AA, PGE2 and COX-2, TBXA2R and 5-LOX in IDCs of HIV positive cocaine users were significantly higher whereas 15d-PGJ2 and 14-3-3 ζ/δ were significantly reduced compared to either HIV positive subjects or cocaine users alone. This report demonstrates that AA metabolites are capable of mediating the accelerative effects of cocaine on HIV infection and disease progression.

Arachidonate-Regulated Ca2+ Influx in Human Airway Smooth Muscle

Plasma membrane Ca(2+) influx, especially store-operated Ca(2+) entry triggered by sarcoplasmic reticulum (SR) Ca(2+) release, is a key component of intracellular calcium concentration ([Ca(2+)]i) regulation in airway smooth muscle (ASM). Agonist-induced Ca(2+) oscillations in ASM that involve both influx and SR mechanisms have been previously demonstrated. In nonexcitable cells, [Ca(2+)]i oscillations involve Ca(2+) influx via arachidonic acid (AA) -stimulated channels, which show similarities to store-operated Ca(2+) entry, although their molecular identity remains undetermined. Little is known about AA-regulated Ca(2+) channels or their regulation in ASM. In enzymatically dissociated human ASM cells loaded with the Ca(2+) indicator, fura-2, AA (1-10 μM) triggered [Ca(2+)]i oscillations that were inhibited by removal of extracellular Ca(2+). Other fatty acids, such as the diacylglycerol analog, 1-oleoyl-2-acetyl-SN-glycerol, oleic acid, and palmitic acid (10 μM each), failed to elicit similar [Ca(2+)]i responses. Preincubation with LaCl3 (1 μM or 1 mM) inhibited AA-induced oscillations. Inhibition of receptor-operated channels (SKF96,365 [10 μM]), lipoxygenase (zileuton [10 μM]), or cyclooxygenase (indomethacin [10 μM]) did not affect oscillation parameters. Inhibition of SR Ca(2+) release (ryanodine [10 μM] or inositol 1,4,5-trisphosphate receptor inhibitor, xestospongin C [1 μM]) decreased [Ca(2+)]i oscillation frequency and amplitude. Small interfering RNA against caveolin-1, stromal interaction molecule 1, or Orai3 (20 nM each) reduced the frequency and amplitude of AA-induced [Ca(2+)]i oscillations. In ASM cells derived from individuals with asthma, AA increased oscillation amplitude, but not frequency. These results are highly suggestive of a novel AA-mediated Ca(2+)-regulatory mechanism in human ASM, reminiscent of agonist-induced oscillations. Given the role of AA in ASM intracellular signaling, especially with inflammation, AA-regulated Ca(2+) channels could potentially contribute to increased [Ca(2+)]i in diseases such asthma.

The role of arachidonic acid in the regulation of nitric oxide synthase isoforms by HIV gp120 protein in astroglial cells

HIV-associated neurocognitive disorder (HAND) is a common cognitive impairment in AIDS that affects 15 to 50% of adults infected with human immunodeficiency virus (HIV). Excessive amounts of nitric oxide (NO), as produced by inducible NO synthase (iNOS) upon exposure of activated microglia and astrocytes to cytokines and/or viral proteins (e.g., HIV tat and gp120), are assumed to contribute to neuronal abnormalities in HAND. Evidence exists supporting the notion that iNOS induction takes place after an early decline in physiological NO levels (i.e., NO released by constitutive NOS). Here, we demonstrate that HIV-1 gp120 is able to inhibit neuronal NOS through a cytosolic phospholipase A2 (cPLA2)-dependent arachidonic acid (AA) production, this response being critical for allowing activation of the transcriptional factor NF-κB and subsequent iNOS and interleukin-1β transcription in astroglial cells. In this context, AA seems to act as an upstream proinflammatory effector. In view of the pathogenic role of cPLA2 in HAND, a deeper insight into the molecular and cellular mechanisms of its modulation may be helpful in finding new drugs to manage cognitive impairment in HIV-1 patients.

Involvement of PLA2, COX and LOX inRhinella arenarumoocyte maturation

In Rhinella arenarum, progesterone is the physiological nuclear maturation inducer that interacts with the oocyte surface and starts a cascade of events that leads to germinal vesicle breakdown (GVBD). Polyunsaturated fatty acids and their metabolites produced through cyclooxygenase (COX) and lipoxygenase (LOX) pathways play an important role in reproductive processes. In amphibians, to date, the role of arachidonic acid (AA) metabolites in progesterone (P4)-induced oocyte maturation has not been clarified. In this work we studied the participation of three enzymes involved in AA metabolism - phospholipase A2 (PLA2), COX and LOX in Rhinella arenarum oocyte maturation. PLA2 activation induced maturation in Rhinella arenarum oocytes in a dose-dependent manner. Oocytes when treated with 0.08 μM melittin showed the highest response (78 ± 6% GVBD). In follicles, PLA2 activation did not significantly induce maturation at the assayed doses (12 ± 3% GVBD). PLA2 inhibition with quinacrine prevented melittin-induced GVBD in a dose-dependent manner, however PLA2 inactivation did not affect P4-induced maturation. This finding suggests that PLA2 is not the only phospholipase involved in P4-induced maturation in this species. P4-induced oocyte maturation was inhibited by the COX inhibitors indomethacin and rofecoxib (65 ± 3% and 63 ± 3% GVBD, respectively), although COX activity was never blocked by their addition. Follicles showed a similar response following the addition of these inhibitors. Participation of LOX metabolites in maturation seems to be correlated with seasonal variation in ovarian response to P4. During the February to June period (low P4 response), LOX inhibition by nordihydroguaiaretic acid or lysine clonixinate increased maturation by up to 70%. In contrast, during the July to January period (high P4 response), LOX inhibition had no effect on hormone-induced maturation.

Editorial [The Role of Arachidonic Acid in the Neuronal Development in Relation to Psychiatric Disorders

Editorial [The Role of Arachidonic Acid in the Neuronal Development in Relation to Psychiatric Disorders

Editorial [The Role of Arachidonic Acid in the Neuronal Development in Relation to Psychiatric Disorders

Editorial [The Role of Arachidonic Acid in the Neuronal Development in Relation to Psychiatric Disorders

Role of Intramitochondrial Arachidonic Acid and Acyl-CoA Synthetase 4 in Angiotensin II-Regulated Aldosterone Synthesis in NCI-H295R Adrenocortical Cell Line

Although the role of arachidonic acid (AA) in angiotensin II (ANG II)- and potassium-stimulated steroid production in zona glomerulosa cells is well documented, the mechanism responsible for AA release is not fully described. In this study we evaluated the mechanism involved in the release of intramitochondrial AA and its role in the regulation of aldosterone synthesis by ANG II in glomerulosa cells. We show that ANG II and potassium induce the expression of acyl-coenzyme A (CoA) thioesterase 2 and acyl-CoA synthetase 4, two enzymes involved in intramitochondrial AA generation/export system well characterized in other steroidogenic systems. We demonstrate that mitochondrial ATP is required for AA generation/export system, steroid production, and steroidogenic acute regulatory protein induction. We also demonstrate the role of protein tyrosine phosphatases regulating acyl-CoA synthetase 4 and steroidogenic acute regulatory protein induction, and hence ANG II-stimulated aldosterone synthesis.

Teleost fish larvae adapt to dietary arachidonic acid supply through modulation of the expression of lipid metabolism and stress response genes

Dietary fatty acid supply can affect stress response in fish during early development. Although knowledge on the mechanisms involved in fatty acid regulation of stress tolerance is scarce, it has often been hypothesised that eicosanoid profiles can influence cortisol production. Genomic cortisol actions are mediated by cytosolic receptors which may respond to cellular fatty acid signalling. An experiment was designed to test the effects of feeding gilthead sea-bream larvae with four microdiets, containing graded arachidonic acid (ARA) levels (0·4, 0·8, 1·5 and 3·0%), on the expression of genes involved in stress response (steroidogenic acute regulatory protein, glucocorticoid receptor and phosphoenolpyruvate carboxykinase), lipid and, particularly, eicosanoid metabolism (hormone-sensitive lipase, PPARα, phospholipase A2, cyclo-oxygenase-2 and 5-lipoxygenase), as determined by real-time quantitative PCR. Fish fatty acid phenotypes reflected dietary fatty acid profiles. Growth performance, survival after acute stress and similar whole-body basal cortisol levels suggested that sea-bream larvae could tolerate a wide range of dietary ARA levels. Transcription of all genes analysed was significantly reduced at dietary ARA levels above 0·4%. Nonetheless, despite practical suppression of phospholipase A2 transcription, higher leukotriene B4 levels were detected in larvae fed 3·0% ARA, whereas a similar trend was observed regarding PGE2 production. The present study demonstrates that adaptation to a wide range of dietary ARA levels in gilthead sea-bream larvae involves the modulation of the expression of genes related to eicosanoid synthesis, lipid metabolism and stress response. The roles of ARA, other polyunsaturates and eicosanoids as signals in this process are discussed.