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Advances in Pharmacology (San Diego,... 2010Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid that are produced by the vascular endothelium in responses to various stimuli such... (Review)
Review
Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid that are produced by the vascular endothelium in responses to various stimuli such as the agonists acetylcholine (ACH) or bradykinin or by shear stress which activates phospholipase A(2) to release arachidonic acid. EETs are important regulators of vascular tone and homeostasis. In the modulation of vascular tone, EETs function as endothelium-derived hyperpolarizing factors (EDHFs). In models of vascular inflammation, EETs attenuate inflammatory signaling pathways in both the endothelium and vascular smooth muscle. Likewise, EETs regulate blood vessel formation or angiogenesis by mechanisms that are still not completely understood. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs) and this metabolism limits many of the biological actions of EETs. The recent development of inhibitors of sEH provides an emerging target for pharmacological manipulation of EETs. Additionally, EETs may initiate their biological effects by interacting with a cell surface protein that is a G protein-coupled receptor (GPCR). Since GPCRs represent a common target of most drugs, further characterization of the EET receptor and synthesis of specific EET agonists and antagonist can be used to exploit many of the beneficial effects of EETs in vascular diseases, such as hypertension and atherosclerosis. This review will focus on the current understanding of the contribution of EETs to the regulation of vascular tone, inflammation, and angiogenesis. Furthermore, the therapeutic potential of targeting the EET pathway in vascular disease will be highlighted.
Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Eicosanoids; Endothelium, Vascular; Humans
PubMed: 21081214
DOI: 10.1016/B978-0-12-385061-4.00002-7 -
Prostaglandins, Leukotrienes, and... Feb 2024Enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA) in extremely preterm infants has shown beneficial effects on retinopathy of prematurity... (Randomized Controlled Trial)
Randomized Controlled Trial
Enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA) in extremely preterm infants has shown beneficial effects on retinopathy of prematurity and pulmonary outcome whereas exclusive DHA supplementation has been associated with increased pulmonary morbidity. This secondary analysis evaluates pulmonary outcome in 204 extremely preterm infants, randomized to receive AA (100 mg/kg/day) and DHA (50 mg/kg/day) enterally from birth until term age or standard care. Pulmonary morbidity was primarily assessed based on severity of bronchopulmonary dysplasia (BPD). Serum levels of AA and DHA during the first 28 days were analysed in relation to BPD. Supplementation with AA:DHA was not associated with increased BPD severity, adjusted OR 1.48 (95 % CI 0.85-2.61), nor with increased need for respiratory support at post menstrual age 36 weeks or duration of oxygen supplementation. Every 1 % increase in AA was associated with a reduction of BPD severity, adjusted OR 0.73 (95 % CI 0.58-0.92). In conclusion, in this study, with limited statistical power, enteral supplementation with AA:DHA was not associated with an increased risk of pulmonary morbidity, but higher levels of AA were associated with less severe BPD. Whether AA or the combination of AA and DHA have beneficial roles in the immature lung needs further research.
Topics: Humans; Docosahexaenoic Acids; Arachidonic Acid; Infant, Extremely Premature; Infant, Newborn; Female; Bronchopulmonary Dysplasia; Male; Dietary Supplements; Enteral Nutrition; Lung; Treatment Outcome
PubMed: 38377640
DOI: 10.1016/j.plefa.2024.102613 -
Anatomical Record (Hoboken, N.J. : 2007) Jul 2022Effective therapeutics are not available for acute lung injury (ALI) and acute respiratory distress syndrome. Modified Xiaoqinglong decoction (M-XQL) is reported to...
Modified Xiaoqinglong decoction alleviates lipopolysaccharide-induced acute lung injury in mice by regulating arachidonic acid metabolism and exerting anti-apoptotic and anti-inflammatory effects.
Effective therapeutics are not available for acute lung injury (ALI) and acute respiratory distress syndrome. Modified Xiaoqinglong decoction (M-XQL) is reported to effectively treat pneumonia, but the underlying mechanisms are unclear. In this study, the therapeutic effect and mechanism of M-XQL were examined using a lipopolysaccharide (LPS)-induced ALI mouse model. The effects of M-XQL on lung injury, inflammatory responses, and cell apoptosis were analyzed. Additionally, high-throughput sequencing was performed to evaluate the therapeutic mechanism of M-XQL. Pretreatment with M-XQL significantly and dose-dependently mitigated the pathological changes and upregulation of pulmonary, nitric oxide content and cell apoptosis and serum tumor necrosis factor-alpha contents in the LPS-induced ALI mouse model. RNA sequencing analysis revealed that the expression of several arachidonic acid metabolism-associated genes in the LPS + high-dose M-XQL group differed from that in the LPS group. In particular, the Cbr2, Cyp4f18, and Cyp2e1 levels were upregulated, whereas the Alox12, Ptges, and Ptges2 levels were downregulated in the LPS + high-dose M-XQL group. These results suggest that M-XQL exerts therapeutic effects in ALI mice by regulating arachidonic acid metabolism and exerting anti-apoptotic and anti-inflammatory effects. Thus, M-XQL is a potential agent for the clinical treatment of ALI.
Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Lipopolysaccharides; Lung; Mice
PubMed: 34708578
DOI: 10.1002/ar.24822 -
BMC Biotechnology Aug 2017Arachidonic acid (ARA, C20:4, n-6), which belongs to the omega-6 series of polyunsaturated fatty acids and has a variety of biological activities, is commercially...
BACKGROUND
Arachidonic acid (ARA, C20:4, n-6), which belongs to the omega-6 series of polyunsaturated fatty acids and has a variety of biological activities, is commercially produced in Mortierella alpina. Dissolved oxygen or oxygen utilization efficiency is a critical factor for Mortierella alpina growth and arachidonic acid production in large-scale fermentation. Overexpression of the Vitreoscilla hemoglobin gene is thought to significantly increase the oxygen utilization efficiency of the cells.
RESULTS
An optimized Vitreoscilla hemoglobin (VHb) gene was introduced into Mortierella alpina via Agrobacterium tumefaciens-mediated transformation. Compared with the parent strain, the VHb-expressing strain, termed VHb-20, grew faster under both limiting and non-limiting oxygen conditions and exhibited dramatic changes in cell morphology. Furthermore, VHb-20 produced 4- and 8-fold higher total lipid and ARA yields than those of the wild-type strain under a microaerobic environment. Furthermore, ARA production of VHb-20 was also 1.6-fold higher than that of the wild type under normal conditions. The results demonstrated that DO utilization was significantly increased by expressing the VHb gene in Mortierella alpina.
CONCLUSIONS
The expression of VHb enhances ARA and lipid production under both lower and normal dissolved oxygen conditions. This study provides a novel strategy and an engineered strain for the cost-efficient production of ARA.
Topics: Arachidonic Acid; Bacterial Proteins; Bioreactors; Fatty Acids; Fermentation; Industrial Microbiology; Lipid Metabolism; Mortierella; Recombinant Proteins; Truncated Hemoglobins
PubMed: 28854910
DOI: 10.1186/s12896-017-0388-8 -
PloS One 2013Retinoic acid (RA) has paradoxical effects on cancer cells: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic...
Retinoic acid (RA) has paradoxical effects on cancer cells: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic acid (AA) release occurs in response to RA treatment and, therefore, AA and its downstream metabolites may be involved in cell survival signalling. To test this, we inhibited phospholipase A2-mediated AA release, cyclooxygenases and lipoxygenases with small-molecule inhibitors to determine if this would sensitise cells to cell death after RA treatment. The data suggest that, in response to RA, phospholipase A2-mediated release of AA and subsequent metabolism by lipoxygenases is important for cell survival. Evidence from gene expression reporter assays and PPARδ knockdown suggests that lipoxygenase metabolites activate PPARδ. The involvement of PPARδ in cell survival is supported by results of experiments with the PPARδ inhibitor GSK0660 and siRNA-mediated knockdown. Quantitative reverse transcriptase PCR studies demonstrated that inhibition of 5-lipoxygenase after RA treatment resulted in a strong up-regulation of mRNA for PPARδ2, a putative inhibitory PPARδ isoform. Over-expression of PPARδ2 using a tetracycline-inducible system in neuroblastoma cells reduced proliferation and induced cell death. These data provide evidence linking lipoxygenases and PPARδ in a cell survival-signalling mechanism and suggest new drug-development targets for malignant and hyper-proliferative diseases.
Topics: Arachidonate 5-Lipoxygenase; Arachidonic Acid; Cell Death; Cell Line, Tumor; Cell Survival; Enzyme Activation; Gene Expression; Humans; Isoenzymes; Neuroblastoma; PPAR delta; Signal Transduction
PubMed: 23874790
DOI: 10.1371/journal.pone.0068859 -
PloS One 2016To evaluate the potential relationship between benign prostatic hyperplasia (BPH) and the arachidonic acid (AA) metabolome, a UHPLC-MS/MS method has been developed and...
Quantification of Arachidonic Acid and Its Metabolites in Rat Tissues by UHPLC-MS/MS: Application for the Identification of Potential Biomarkers of Benign Prostatic Hyperplasia.
To evaluate the potential relationship between benign prostatic hyperplasia (BPH) and the arachidonic acid (AA) metabolome, a UHPLC-MS/MS method has been developed and validated for simultaneous determination of AA and its cyclooxygenase(COX) and lipoxygenase(LOX) pathway metabolites (15-HETE, 12-HETE, TXA2, 5-HETE, AA, PGI2, PGF2α, 8-HETE, PGD2, PGE2 and LTB4) in rat tissues. The analytes were extracted from tissue samples with a protein precipitation procedure and then separated on a Shim-pack XR-ODSC18 column with 0.05% formic acid in water (pH adjusted with dilute ammonia) and methanol:acetonitrile (20:80, v/v). Detection was performed on a UHPLC-MS/MS system with electrospray negative ionization (ESI) and a multiple reaction-monitoring mode. The lower limits of quantification (LLOQ) were 0.25-50 ng/mL for all of the analytes in the prostate, seminal, bladder, liver and kidney tissues. The absolute recoveries of the analytes from all of the tissues were more than 50%. By means of the method developed, the AA metabolites in tissue samples from Sham and BPH group rats were determined. The eleven biomarkers in the BPH group prostate, seminal, bladder, liver and kidney tissues were significantly higher than those of the sham group, indicating that BPH fortified the inducible expression of COX and LOX, as well as increased the production of AA and eicosanoids. The method described here offers a useful tool for the evaluation of complex regulatory eicosanoids responses in vivo.
Topics: Animals; Arachidonic Acid; Biomarkers; Calibration; Chromatography, High Pressure Liquid; Eicosanoids; Kidney; Liver; Male; Prostate; Prostatic Hyperplasia; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry; Urinary Bladder
PubMed: 27893755
DOI: 10.1371/journal.pone.0166777 -
International Journal of Molecular... Jul 2023Pharmaceuticals including antibiotics are among the hazardous micropollutants (HMP) of the environment. Incomplete degradation of the HMP leads to their persistence in...
Pharmaceuticals including antibiotics are among the hazardous micropollutants (HMP) of the environment. Incomplete degradation of the HMP leads to their persistence in water bodies causing a plethora of deleterious effects. Conventional wastewater treatment cannot remove HMP completely and a promising alternative comprises biotechnologies based on microalgae. The use of immobilized microalgae in environmental biotechnology is advantageous since immobilized cultures allow the recycling of the microalgal cells, support higher cell densities, and boost tolerance of microalgae to stresses including HMP. Here, we report on a comparative study of HMP (exemplified by the antibiotic ceftriaxone, CTA) removal by suspended and chitosan-immobilized cells of sp. IPPAS C-2047 in flasks and in a column bioreactor. The removal of CTA added in the concentration of 20 mg/L was as high as 65% (in the flasks) or 85% (in the bioreactor). The adsorption on the carrier and abiotic oxidation were the main processes contributing 65-70% to the total CTA removal, while both suspended and immobilized cells took up 25-30% of CTA. Neither the immobilization nor CTA affected the accumulation of arachidonic acid (ARA) by sp. during bioreactor tests but the subsequent nitrogen deprivation increased ARA accumulation 2.5 and 1.7 times in the suspended and chitosan-immobilized microalgae, respectively. The study of the sp. microbiome revealed that the immobilization of chitosan rather than the CTA exposure was the main factor displacing the taxonomic composition of the microbiome. The possibility and limitations of the use of chitosan-immobilized sp. IPPAS C-2047 for HMP removal coupled with the production of valuable long-chain polyunsaturated fatty acids is discussed.
Topics: Arachidonic Acid; Ceftriaxone; Chitosan; Chlorophyta; Fatty Acids; Microbiota; Microalgae; Biomass
PubMed: 37446166
DOI: 10.3390/ijms241310988 -
Journal of the American Society of... Oct 2017Thirty-five years ago, a third pathway for the metabolism of arachidonic acid by cytochrome P450 enzymes emerged. Subsequent work revealed that... (Review)
Review
Thirty-five years ago, a third pathway for the metabolism of arachidonic acid by cytochrome P450 enzymes emerged. Subsequent work revealed that 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids formed by these pathways have essential roles in the regulation of renal tubular and vascular function. Sequence variants in the genes that produce 20-hydroxyeicosatetraenoic acid are associated with hypertension in humans, whereas the evidence supporting a role for variants in the genes that alter levels of epoxyeicosatrienoic acids is less convincing. Studies in animal models suggest that changes in the production of cytochrome P450 eicosanoids alter BP. However, the mechanisms involved remain controversial, especially for 20-hydroxyeicosatetraenoic acid, which has both vasoconstrictive and natriuretic actions. Epoxyeicosatrienoic acids are vasodilators with anti-inflammatory properties that oppose the development of hypertension and CKD; 20-hydroxyeicosatetraenoic acid levels are elevated after renal ischemia and may protect against injury. Levels of this eicosanoid are also elevated in polycystic kidney disease and may contribute to cyst formation. Our review summarizes the emerging evidence that cytochrome P450 eicosanoids have a role in the pathogenesis of hypertension, polycystic kidney disease, AKI, and CKD.
Topics: Animals; Arachidonic Acid; Cytochrome P-450 Enzyme System; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Transplantation
PubMed: 28701518
DOI: 10.1681/ASN.2017030252 -
Platelets 2019The use of arachidonic acid (AA) to stimulate platelets is considered as a specific approach to study aspirin treatment efficacy. However, very high concentrations of AA...
The use of arachidonic acid (AA) to stimulate platelets is considered as a specific approach to study aspirin treatment efficacy. However, very high concentrations of AA are used, and it has been previously reported that AA can induce cell lysis in other settings. Several clinical studies have reported decreased responses to AA in whole blood tests in the presence of clopidogrel. Our aim was to investigate whether unspecific effects contribute to AA-induced aggregation and platelet activation in light transmission aggregometry (LTA) in platelet-rich plasma (PRP), and in assays using whole blood, multiple electrode aggregometry (MEA, Multiplate®), and flow cytometry. We report that cell lysis, especially of red blood cells, does occur at concentrations of AA used in the clinical tests and that ADP is very important for the AA-induced platelet activation responses. In flow cytometry, very limited platelet activation was detected before reaching AA concentrations in the millimolar range, where cell lysis also occurred, making it problematic to develop a reliable flow cytometry assay using AA as reagent. We conclude that cell lysis and ADP release contribute to AA-induced platelet responses, most markedly in whole blood assays. This finding could potentially explain some differences between studies comparing methods using whole blood and PRP and also how clopidogrel treatment could influence AA-induced aggregation results in previously published studies. Our findings highlight some issues with AA as reagent for platelet activation, which also have an impact on how platelet activation assays using AA should be interpreted.
Topics: Arachidonic Acid; Blood Cells; Female; Humans; Male; Platelet Activation; Platelet Function Tests
PubMed: 30580677
DOI: 10.1080/09537104.2018.1557614 -
Journal of Neuroinflammation Jan 2024Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration.... (Review)
Review
BACKGROUND
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering the increasing prevalence among young adults worldwide and the disabling phenotype of the disease, a deeper understanding of the complexity of the disease pathogenesis is needed to ultimately improve diagnosis and personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute to MS pathogenesis. For example, disturbances in LM profiles and especially those derived from the ω-6 PUFA arachidonic acid (AA) have been reported in people with MS (PwMS), where they may contribute to the chronicity of neuroinflammatory processes. Moreover, we have previously shown that certain AA-derived LMs also associated with neurodegenerative processes in PwMS, suggesting that AA-derived LMs are involved in more pathological events than solely neuroinflammation. Yet, to date, a comprehensive overview of the contribution of these LMs to MS-associated pathological processes remains elusive.
MAIN BODY
This review summarizes and critically evaluates the current body of literature on the eicosanoid biosynthetic pathway and its contribution to key pathological hallmarks of MS during different disease stages. Various parts of the eicosanoid pathway are highlighted, namely, the prostanoid, leukotriene, and hydroxyeicosatetraenoic acids (HETEs) biochemical routes that include specific enzymes of the cyclooxygenases (COXs) and lipoxygenases (LOX) families. In addition, cellular sources of LMs and their potential target cells based on receptor expression profiles will be discussed in the context of MS. Finally, we propose novel therapeutic approaches based on eicosanoid pathway and/or receptor modulation to ultimately target chronic neuroinflammation, demyelination and neurodegeneration in MS.
SHORT CONCLUSION
The eicosanoid pathway is intrinsically linked to specific aspects of MS pathogenesis. Therefore, we propose that novel intervention strategies, with the aim of accurately modulating the eicosanoid pathway towards the biosynthesis of beneficial LMs, can potentially contribute to more patient- and MS subtype-specific treatment opportunities to combat MS.
Topics: Young Adult; Humans; Arachidonic Acid; Neuroinflammatory Diseases; Multiple Sclerosis; Eicosanoids; Fatty Acids, Omega-3; Disease Progression
PubMed: 38233951
DOI: 10.1186/s12974-023-02981-w