Administration Of Arachidonic Acid Research Articles

Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

Arachidonic acid enhances hepatocyte bile acid uptake and alleviates cholestatic liver disease by upregulating OATP1 expression.

Cholestatic liver disease is caused by disorders of bile synthesis, secretion, and excretion. Over the long term, progressive liver cell damage from the disease evolves into liver fibrosis and cirrhosis, ultimately leading to liver failure and even cancer. Notably, cholestatic liver disease has a complex pathogenesis that remains relatively unclear. In this study, we generated two mouse models of cholestatic liver disease using a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and α-naphthyl isothiocyanate (ANIT) gavage. Quantitative proteomics using liquid chromatography-tandem mass spectrometry showed that arachidonic acid metabolism was a common pathway in both models. Additionally, serum arachidonic acid concentrations were lower in both models than in the control group. Arachidonic acid supplementation in the diet of DDC model mice significantly reduced the levels of serum markers of cholestasis (alanine aminotransferase, aspartate transaminase, alkaline phosphatase, total bile acid, and total bilirubin) and decreased the degree of bile duct hyperplasia and cholestasis. To elucidate the mechanisms by which arachidonic acid improved bile stasis, we analyzed gene expression after arachidonic acid administration and found that Oatp1 was upregulated in the liver tissue of cholestatic mice. Arachidonic acid also increased Oatp1 expression in AML12 cells, which promoted bile acid uptake. Conclusively, our research showed that arachidonic acid mitigates cholestatic liver disease by upregulating Oatp1, promoting bile acid uptake by hepatocytes and participating in intestinal-hepatic circulation. Overall, these results suggest that supplementing foods with arachidonic acid in the daily diet may be an effective treatment strategy for cholestatic liver disease.

Infection, Inflammation, and Immunity in Sepsis.

Sepsis is triggered by microbial infection, injury, or even major surgery. Both innate and adaptive immune systems are involved in its pathogenesis. Cytoplasmic presence of DNA or RNA of the invading organisms or damaged nuclear material (in the form of micronucleus in the cytoplasm) in the host cell need to be eliminated by various nucleases; failure to do so leads to the triggering of inflammation by the cellular cGAS-STING system, which induces the release of IL-6, TNF-α, and IFNs. These cytokines activate phospholipase A2 (PLA2), leading to the release of polyunsaturated fatty acids (PUFAs), gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), which form precursors to various pro- and anti-inflammatory eicosanoids. On the other hand, corticosteroids inhibit PLA2 activity and, thus, suppress the release of GLA, AA, EPA, and DHA. PUFAs and their metabolites have a negative regulatory action on the cGAS-STING pathway and, thus, suppress the inflammatory process and initiate inflammation resolution. Pro-inflammatory cytokines and corticosteroids (corticosteroids > IL-6, TNF-α) suppress desaturases, which results in decreased formation of GLA, AA, and other PUFAs from the dietary essential fatty acids (EFAs). A deficiency of GLA, AA, EPA, and DHA results in decreased production of anti-inflammatory eicosanoids and failure to suppress the cGAS-STING system. This results in the continuation of the inflammatory process. Thus, altered concentrations of PUFAs and their metabolites, and failure to suppress the cGAS-STING system at an appropriate time, leads to the onset of sepsis. Similar abnormalities are also seen in radiation-induced inflammation. These results imply that timely administration of GLA, AA, EPA, and DHA, in combination with corticosteroids and anti-IL-6 and anti-TNF-α antibodies, may be of benefit in mitigating radiation-induced damage and sepsis.

Abstract 424: Arachidonic Acid Synergizes With Aspirin In Cardioprotection Following Acute Myocardial Infarction

Introduction: Membrane-released arachidonic acid (AA) is metabolized via cyclooxygenase pathway to form prostanoids, including thromboxane, prostacyclin and prostaglandin E2. Aspirin suppresses platelet synthesis of thromboxane, rendering its first-line use for anti-thrombosis in patients with acute myocardial ischemia. We report that endogenous PGE2 protects against myocardial ischemia-reperfusion (MI/R) injury (Nat Commun. 2019;10(1):1888). The impact of AA administration while suppressing thromboxane on MI/R injury is unknown. Methods and Results: C57BL/6J mice were treated intravenously with vehicle, AA, aspirin, or their combination and then subjected to 30min coronary artery ligation and 24hr reperfusion. Cardiac function was assessed by ultrasonography and infraction size quantified by TTC staining. Cardiac microcirculation was assessed by laser doppler flow and vasomotor reactivity determined with isolated coronary arteries. Single treatment with AA at an optimized dose of 0.1mg/Kg, or combined with aspirin at a dose of 10mg/Kg that allowed sufficient suppressing of platelet activation over 24hr, decreased infarct size and improved heart function. Impressively, combination of AA with aspirin provided additional cardioprotection compared with either single treatment. While aspirin, not AA, ameliorated microvascular obstruction following MI/R injury, co-administration of AA and aspirin further increased coronary microcirculatory blood perfusion with improved vascular permeability compared with aspirin alone. MI/R impaired endothelium-dependent dilatation of coronary arteries, and the dual treatment, not AA or ASA alone, increased coronary artery relaxation. Cardiac infiltrated neutrophils and platelet-neutrophil aggregates were also reduced by the combination treatment, consistent with a suppressed leukocyte-ECs adhesion as assessed in vitro. Conclusions: AA and aspirin synergistically protect against MI/R injury and this is attributable to suppressed neutrophil inflammation and improved microvascular obstruction. AA might be used as an adjunct therapy to aspirin in patients with acute myocardial infarction.

Identification of the cyclooxygenase (COX) gene and its role in ovarian development and ovulation of the oriental river prawn Macrobrachium nipponense

Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins (PGs), which are involved in ovarian development and ovulation in crustaceans. In this study, complementary DNA (cDNA) of COX in Macrobrachium nipponense (MnCOX) was identified, and its function in ovarian development and ovulation was investigated by quantitative real-time PCR (qPCR), fluorescence in situ hybridization (FISH), RNA interference (RNAi) and arachidonic acid (AA), dexamethasone (DEX) and DEX+ prostaglandin E2 (PGE2) administration. The results showed that the complete cDNA of MnCOX is 3238 bp, including an 1848 bp open reading frame (ORF) that encodes 615 amino acids. The MnCOX protein conservatively possesses a membrane-binding domain, an epidermal growth factor-like (EGF-like) domain, an animal haem peroxide domain, three N-glycosylation sites and seven essential catalytic residues. The richest MnCOX transcript of nine tissues was found in the gill, followed by the ovary and intestine. In six ovarian development stages, the MnCOX transcript was the richest in the stage Ⅴ ovary. FISH showed that the MnCOX transcript was present in the cytoplasm of oocytes. MnCOX knockdown led to decreases in PGE2 content, expression levels of the vitellogenin (Vg) and vitellogenin receptor (Vgr) genes and the gonadsomatic index (GSI) of prawns. Moreover, oocyte development was delayed, and the oviposition rate and the number of eggs ovulated were reduced after MnCOX knockdown. AA administration increased the expression of MnCOX, PGE2 content and the oviposition rate of prawns. However, DEX administration decreased the expression of MnCOX, PGE2 content, oviposition rate, and the number of eggs ovulated by prawns. The addition of PGE2 to DEX injection rescued the negative effect of DEX on the ovulation of M. nipponense. This investigation illustrates that MnCOX plays an important role in regulating ovarian development and ovulation in M. nipponense by affecting the synthesis of PGs.

Syntaxin interacts with arachidonic acid to prevent diabetes mellitus

Syntaxin regulates pancreatic β cell mass and participates in insulin secretion by regulating insulin exocytosis. In addition, syntaxin 4 reduces IFNγ and TNF-α signaling via NF-ĸB in islet β-cells that facilitates plasma glucose sensing and appropriate insulin secretion. Arachidonic acid (AA) has potent anti-inflammatory actions and prevents the cytotoxic actions of alloxan and streptozotocin (STZ) against pancreatic β cells and thus, prevents the development of type 1 diabetes mellitus (induced by alloxan and STZ) and by virtue of its anti-inflammatory actions protects against the development of type 2 diabetes mellitus (DM) induced by STZ in experimental animals that are models of type 1 and type 2 DM in humans. AA has been shown to interact with syntaxin and thus, potentiate exocytosis. AA enhances cell membrane fluidity, increases the expression of GLUT and insulin receptors, and brings about its anti-inflammatory actions at least in part by enhancing the formation of its metabolite lipoxin A4 (LXA4). Prostaglandin E2 (PGE2), the pro-inflammatory metabolite of AA, activates ventromedial hypothalamus (VMH) neurons of the hypothalamus and inhibits insulin secretion leading to reduced glucose tolerance and decreases insulin sensitivity in the skeletal muscle and liver. This adverse action of PGE2 on insulin release and action can be attributed to its (PGE2) pro-inflammatory action and inhibitory action on vagal tone (vagus nerve and its principal neurotransmitter acetylcholine has potent anti-inflammatory actions). High fat diet fed animals have hypothalamic inflammation due to chronic elevation of PGE2. Patients with type 2 DM show low plasma concentrations of AA and LXA4 and elevated levels of PGE2. Administration of AA enhances LXA4 formation without altering or reducing PGE2 levels and thus, tilts the balance more towards anti-inflammatory events. These results suggest that administration of AA is useful in the prevention and management of DM by enhancing the action of syntaxin, increasing cell membrane fluidity, and reducing VMH inflammation. Docosahexaenoic acid (DHA) has actions like AA: it increases cell membrane fluidity; has anti-inflammatory actions by enhancing the formation of its anti-inflammatory metabolites resolvins, protectins and maresins; interacts with syntaxin and enhance exocytosis in general and of insulin. But the DHA content of cell membrane is lower compared to AA and its content in brain is significant. Hence, it is likely DHA is important in neurotransmitters secretion and regulating hypothalamic inflammation. It is likely that a combination of AA and DHA can prevent DM.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Traumatic brain injury patients with platelet inhibition receiving platelet transfusion demonstrate decreased need for neurosurgical intervention and decreased mortality.

Platelet dysfunction is known to occur in patients with traumatic brain injury (TBI), and the correction of platelet dysfunction may prevent hemorrhagic progression in TBI. Thromboelastography with platelet mapping (TEG-PM; Haemonetics) evaluates the degree of platelet function inhibition through the adenosine diphosphate (ADP) and arachidonic acid (AA) pathways. We hypothesized that ADP and AA inhibition would improve with the transfusion of platelets in patients with TBI. A retrospective review was conducted at a Level I trauma center of all patients presenting with TBI from December 2019 to December 2020. Per a practice management guideline, a platelet mapping assay was obtained on all patients with TBI upon admission. If ADP or AA was found to be inhibited (>60%), the patient was transfused 1 unit of platelets and a repeat platelet mapping assay was ordered. Demographic data, laboratory values, and outcomes were analyzed. Over the 13-month study period, 453 patients with TBI underwent TEG-PM with a protocol adherence rate of 66.5% resulting in a total of 147 patients who received platelets for ADP and/or AA inhibition; of those, 107 underwent repeat TEG-PM after platelets were administered. With the administration of platelets, ADP (p < 0.0001), AA (p < 0.0001), and MA (p = 0.0002) all significantly improved. Of 330 patients with TBI not taking antiplatelet medications, 50.9% showed inhibition in ADP and/or AA. If AA or ADP inhibition was noted on admission, mortality was increased (p = 0.0108). If ADP improved with platelet administration, the need for neurosurgical intervention was noted to decrease (p = 0.0182). Patients with TBI and platelet inhibition may benefit from the administration of platelets to correct platelet dysfunction. Thromboelastography with platelet mapping may be implemented in the initial workup of patients presenting with TBI to assess platelet dysfunction and provide prognostic information, which may guide treatment. Therapeutic / Care Management, level III.

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.

Bioactive Lipids-Based Approach to Aging Associated Diseases/Disorders

Abstract Objectives To investigate the role of bioactive lipids (BAL) in ageing associated disorders such as obesity, type 2 diabetes mellitus, hypertension, coronary heart disease, immune dysfunction and cancer. Methods We recruited known patients of type 2 diabetes mellitus, hypertension, coronary heart disease, diabetic nephropathy and cancer and collected their blood samples for the study. In these samples the concentrations of various BAL such as linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid and other lipids in their phospholipid fraction was measured. The role of these BAL in these diseases was also studied in animal models of diabetes mellitus and cancer. To evaluate the mechanism of action of BAL, in animal models of type 2 diabetes mellitus and cancer, the expression of NF-kB, IKB, COX-1, COX-2 and LOX and plasma levels of IL-6, TNF, nitric oxide and lipid peroxides was also studied. Results Plasma levels of arachidonic acid in the phospholipid fraction was found to be low in all the patients recruited in the study. In some of these patients plasma levels of gamma-linolenic acid, eicosapentaenic acid and docosahexaenoic acid were also found to be altered. But, of all the lipids estimated, arachidonic acid was found to be consistently low in those with obesity, type 2 diabetes mellitus, hypertension, coronary heart disease and cancer. In animal models of type 2 diabetes mellitus, hypertension and cancer, administration of arachidonic acid produced significant amelioration of these conditions suggesting a critical role for this lipid in these diseases. Further studies revealed that arachidonic acid suppresses inflammation and enhanced the formation of lipoxin A4 (LXA4), which is a potent anti-inflammatory compound. A significant suppression of pro-inflammatory genes and restoration of anti-oxidant status to normal. Conclusions Based on the results of the present study, ageing associated diseases such as obesity, type 2 diabetes mellitus, hypertension, coronary heart disease, and cancer are inflammatory conditions with low circulating concentrations of arachidonic acid and lipoxin A4. These results imply that appropriate administration of arachidonic acid and lipoxin A4 could be of benefit in ageing and ageing associated diseases. Funding Sources Nil.

Can Bioactive Lipids Inactivate Coronavirus (COVID-19)?

SARS-CoV-2, SARS and MERS are all enveloped viruses that can cause acute respiratory syndrome. Arachidonic acid (AA) and other unsaturated fatty acids (especially eicosapentaenoic acd, EPA and docosahexaenoic acid DHA) are known to inactivate enveloped viruses and inhibit proliferation of various microbial organisms. The pro-inflammatory metabolites of AA and EPA such as prostaglandins, leukotrienes and thromboxanes induce inflammation whereas lipoxins, resolvins, protectins and maresins derived from AA, EPA and DHA not only suppress inflammation but also enhance would healing and augment phagocytosis of macrophages and other immunocytes and decrease microbial load. In view of these actions, it is suggested that AA and other unsaturated fatty acids and their metabolites may serve as endogenous anti-viral compounds and their deficiency may render humans susceptible to SARS-CoV-2, SARS and MERS and other similar viruses’ infections. Hence, oral or intravenous administration of AA and other unsaturated fatty acids may aid in enhancing resistance and recovery from SARS-CoV-2, SARS and MERS infections.

Induction of vitellogenesis, methyl farnesoate synthesis and ecdysteroidogenesis in two edible crabs by arachidonic acid and prostaglandins.

The present study investigated the effect of arachidonic acid (AA) and selected prostaglandins on the regulation of vitellogenesis, ecdysteroidogenesis and methyl farnesoate (MF) synthesis in the freshwater crab Oziotelphusa senex senex and the giant mud crab, Scylla serrata Administration of AA and prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2) significantly increased ovarian index, oocyte diameter and ovarian vitellogenin levels and ecdysteroid and MF levels in the hemolymph of crabs. Secretions of MF and ecdysteroids from in vitro cultured mandibular organs (MO) and Y-organs (YO) isolated from intermolt crabs injected with AA, PGF2α and PGE2 were greater when compared with controls. In contrast, injection of prostaglandin D2 (PGD2) had no effect on vitellogenesis, ecdysteroid and MF levels in circulation. In vitro secretion of MF from MO explants isolated from avitellogenic crabs incubated with AA, PGF2α and PGE2 increased in a time-dependent manner. Conversely, incubation of YOs isolated from avitellogenic crabs with AA, PGF2α and PGE2 had no effect on secretion of ecdsyteroids. These results implicate prostaglandins in the regulation of reproduction by inducing the synthesis of MF and consequent ecdysteroid synthesis in brachyuran crabs, and provide an alternative molecular intervention mechanism to the traditional eyestalk ablation methodology to induce vitellogenesis and ovarian maturation in crustaceans.

Effect of chronic administration of arachidonic acid on the performance of learning and memory in aged rats.

BackgroundArachidonic acid (AA, C20:4, ω-6) is a ω-6 polyunsaturated fatty acid (PUFA) and plays diverse roles in cell signaling. Numerous reports on the effects of ω-3 PUFAs, such as docosahexaenoic acid (DHA, C22:6, ω-3) and eicosapentaenoic acid (EPA, C20:5, ω-3) on learning and memory impairments of rats are available, however, the role of AA on brain cognition is largely unknown.ObjectiveIn this study, our aim was to investigate the effect of oral administration of AA on spatial memory-related learning ability in aged (100 weeks) male rats.DesignOne group was per orally administered 240 mg/kg per day AA oil and the other group was administered the similar volume of control oil. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to evaluate two types of spatial memory-related learning ability displayed by reference memory errors (RMEs) and working memory errors (WMEs). Also, the time required to complete the task was recorded. The levels of lipid peroxide (LPO) and reactive oxygen species (ROS) were measured, as an indicator oxidative stress in the plasma and brain corticohippocampal brain tissues.ResultsThe scores of RMEs and WMEs, which are analogous to long-term and short-term memory, respectively, were not affected, however, the trial time was shorter in the AA-administered rats than that of the controls. AA also significantly increased the degree of oxidative stress both in the plasma and corticohippocampal brain tissues.ConclusionsOur results suggest that though AA deposition in the corticohippocampal tissues of senescent rats caused a faster performance activity, which is reminiscent to hyperactive behavior of animals, the spatial learning ability-related memory of the rats, however, was not improved.

The Red AlgaGracilariopsis chordaand Its Active Constituent Arachidonic Acid Promote Spine Dynamics via Dendritic Filopodia and Potentiate Functional Synaptic Plasticity in Hippocampal Neurons

Exogenous neurotrophins can induce neuronal differentiation, outgrowth, survival, and synaptic function in the central nervous system. In primary cultures of rat hippocampal neurons, an ethanol extract of the red alga Gracilariopsis chorda (GCE) and its active compound arachidonic acid (AA) significantly increased the densities of dendritic filopodia and spines, promoted the expression of presynaptic vesicle protein 2 (SV2) and postsynaptic density protein 95 (PSD-95), induced robust synaptogenesis, and increased the expression of cell division control protein 42 (CDC42) and actin-related protein 2 (ARP2), which are important for actin organization in dendritic protrusions, and facilitated presynaptic plasticity by increasing the size of the synaptic vesicle pool at presynaptic nerve terminals. In addition, oral administration of GCE and AA for 10 days, at concentrations of 1 mg/g and 2.2 μg/g body weight, respectively, significantly protected against scopolamine-induced memory impairment in mice by increasing the latency time in the passive avoidance test. These results provide strong scientific evidence that these natural products can be used as neurotrophic substances and/or dietary supplements for the prevention and treatment of memory-related neurological disorders via the reconstruction of axo-dendrites and its synapses.

Arachidonic acid-induced Ca2+ entry and migration in a neuroendocrine cancer cell line

BackgroundStore-operated Ca2+ entry (SOCE) has been implicated in the migration of some cancer cell lines. The canonical SOCE is defined as the Ca2+ entry that occurs in response to near-maximal depletion of Ca2+ within the endoplasmic reticulum. Alternatively, arachidonic acid (AA) has been shown to induce Ca2+ entry in a store-independent manner through Orai1/Orai3 hetero-multimeric channels. However, the role of this AA-induced Ca2+ entry pathway in cancer cell migration has not been adequately assessed.MethodsThe present study investigated the involvement of AA-induced Ca2+ entry in migration in BON cells, a model gastro-enteropancreatic neuroendocrine tumor (GEPNET) cell line using pharmacological and gene knockdown methods in combination with live cell fluorescence imaging and standard migration assays.ResultsWe showed that both the store-dependent and AA-induced Ca2+ entry modes could be selectively activated and that exogenous administration of AA resulted in Ca2+ entry that was pharmacologically distinct from SOCE. Also, whereas homomeric Orai1-containing channels appeared to largely underlie SOCE, the AA-induced Ca2+ entry channel required the expression of Orai3 as well as Orai1. Moreover, we showed that AA treatment enhanced the migration of BON cells and that this migration could be abrogated by selective inhibition of the AA-induced Ca2+ entry.ConclusionsTaken together, these data revealed that an alternative Orai3-dependent Ca2+ entry pathway is an important signal for GEPNET cell migration.

The acute cardiorespiratory effects of centrally injected arachidonic acid; the mediation of prostaglandin E, D and F2α

Arachidonic acid (AA), which is released from synaptic membrane phospholipid by neuroreceptor-initiated activation of phospholipase A2, is abundant in the brain and works as a neurotransmitter and/or neuromodulator in the central nervous system. Recently we reported that centrally injected AA generated pressor and hyperventilation effects by activating thromboxane A2 (TXA2) signaling pathway. The present study was designed to investigate the mediation of other metabolites of AA such as prostaglandin (PG) D, PGE and PGF2α alongside TXA2 in the AA-evoked cardiorespiratory effects in anaesthetized rats.Intracerebroventricular (i.c.v.) administration of AA caused pressor, bradycardic and hyperventilation responses by increasing pO2 and decreasing pCO2 in adult male anaesthetized Sprague Dawley rats. Pretreatment (i.c.v) with different doses of DP/EP prostanoid receptor antagonist, AH6809 or FP prostanoid receptor antagonist, PGF2α dimethylamine partially blocked the cardiorespiratory and blood gas changes induced by AA.In conclusion, these data plainly report that central PGD, PGE or PGF2α might mediate, at least partly, centrally administered AA-evoked cardiorespiratory and blood gas responses.

Nrf2 is crucial for the down-regulation of Cyp7a1 induced by arachidonic acid in Hepg2 cells.

In former research, cyp7a1 expression was decreased but Nrf2 transcription and hepatic arachidonic acid (AA) concentration were increased in high-fat diet fed mice. This study aims to investigate the influence of AA in CYP7A1 expression and the role of Nrf2 in regulating CYP7A1 in the process. HepG2 cells were administered with different concentrations of AA. Nrf2 and CYP7A1 expressions were analyzed by real-time PCR and western blot. Nrf2 silenced and over-expressed cell models were constructed by Nrf2 siRNA and eukaryotic expression vector transient transfections and were used to investigate the role of Nrf2 in regulating CYP7A1 following AA administration. The results showed that Nrf2 was increased dose-dependently but CYP7A1 was decreased dose-dependently in cells treated with increasing concentrations of AA. The expression of CYP7A1 was increased by Nrf2 silence and was decreased by Nrf2 over-expression in HepG2 cells treated with different concentrations of AA. In conclusion, Nrf2 plays a significant role in the down-regulation of CYP7A1 induced by AA in HepG2 cells.

Arachidonic acid attenuates brain damage in a rat model of ischemia/reperfusion by inhibiting inflammatory response and oxidative stress.

The aim of the present study was to study the effects of arachidonic acid (ARA) in a rat brain ischemia/reperfusion model induced by middle cerebral artery occlusion (MCAO). A total of 50 rats were randomly divided into five groups: control group, MCAO group, MCAO + ARA 0.3 g/kg group, MCAO + ARA 1 g/kg group, and MCAO + ARA 3 g/kg group. The MCAO + ARA groups received ARA by intraperitoneal injection daily for 14 consecutive days, while the rats in the control and MCAO groups were given equivalent volume of saline. We detected the Morris water maze test and pathological changes to investigate the ischemia/reperfusion injury. The protein levels of tumor necrosis factor-alpha and interleukin-6 in the hippocampus were detected by enzyme-linked immunosorbent assay kits. In addition, the activities of superoxide dismutase, glutathione peroxidase, and malondialdehyde were assayed in hippocampus homogenates to evaluate the oxidative stress after ischemia/reperfusion. The results indicated that ARA administration decreased biochemical parameters of inflammation and oxidative stress. Morris water maze test and histopathological examination further verified the protective effects of ARA on ischemia/reperfusion injury rats. These findings demonstrated that ARA could protect MCAO-induced brain injury rats by inhibition of inflammation and oxidative stress, suggesting that it may have potential as a therapy for cerebral ischemia/reperfusion injury.

The effects of centrally injected arachidonic acid on respiratory system: Involvement of cyclooxygenase to thromboxane signaling pathway

Arachidonic acid (AA) is a polyunsaturated fatty acid that is present in the phospholipids of the cell membranes of the body and is abundant in the brain. Exogenously administered AA has been shown to affect brain metabolism and to exhibit cardiovascular and neuroendocrine actions. However, little is known regarding its respiratory actions and/or central mechanism of its respiratory effects. Therefore, the present study was designed to investigate the possible effects of centrally injected AA on respiratory system and the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway on AA-induced respiratory effects in anaesthetized rats. Intracerebroventricular (i.c.v.) administration of AA induced dose- and time-dependent increase in tidal volume, respiratory rates and respiratory minute ventilation and also caused an increase in partial oxygen pressure (pO2) and decrease in partial carbon dioxide pressure (pCO2) in male anaesthetized Spraque Dawley rats. I.c.v. pretreatment with ibuprofen, a non-selective COX inhibitor, completely blocked the hyperventilation and blood gases changes induced by AA. In addition, central pretreatment with different doses of furegrelate, a TXA2 synthesis inhibitor, also partially prevented AA-evoked hyperventilation and blood gases effects. These data explicitly show that centrally administered AA induces hyperventilation with increasing pO2 and decreasing pCO2 levels which are mediated by the activation of central COX to TXA2 signaling pathway.

Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats.

Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography–tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney.