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Archivum Immunologiae Et Therapiae... 2007Arachidonic acid (AA), a second-messenger molecule released from membrane phospholipids by phospholipase A(2) in activated cells, is a stimulator of neutrophil... (Review)
Review
Arachidonic acid (AA), a second-messenger molecule released from membrane phospholipids by phospholipase A(2) in activated cells, is a stimulator of neutrophil responses, including the oxygen-dependent respiratory burst. The polyunsaturated fatty acid is also the precursor of biologically active eicosanoids. There are several mechanisms by which AA stimulates the respiratory burst. These include the direct binding of AA to S100 proteins which regulate the assembly of the NADPH oxidase as well as the activation of key signaling molecules which control the respiratory burst. Arachidonic acid also stimulates it own release from membrane phospholipids and this contributes to optimal respiratory burst activity. Thus, increased levels of AA at sites of inflammation will influence the magnitude and course of the inflammatory response, not only by directly affecting the function of infiltrating neutrophils and other leukocytes, but also through its metabolites generated by lipoxygenases and cyclooxygenases.
Topics: Arachidonic Acid; Esterification; Fatty Acids; Gene Expression Regulation, Enzymologic; Humans; Models, Biological; NADPH Oxidases; Neutrophils; Phospholipases A; Signal Transduction; Superoxides
PubMed: 17417690
DOI: 10.1007/s00005-007-0014-x -
Lipids in Health and Disease Feb 2014Arachidonic acid (ARA) is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E₂...
Dietary supplementation of arachidonic acid increases arachidonic acid and lipoxin A₄ contents in colon, but does not affect severity or prostaglandin E₂ content in murine colitis model.
BACKGROUND
Arachidonic acid (ARA) is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E₂ (PGE₂) and lipoxin A₄ (LXA₄). The effects of dietary ARA on colon maintenance are unclear because PGE₂ has both mucosal protective and proinflammatory effects, and LXA₄ has an anti-inflammatory role. Our objective is to clarify the effects of dietary ARA on an experimental murine colitis model.
METHODS
C57BL/6 mice were fed three types of ARA diet (0.075%, 0.15% or 0.305% ARA in diet), DHA diet (0.315% DHA) or control diet for 6 weeks, and were then administered dextran sodium sulphate (DSS) for 7 days to induce colitis. We evaluated colitis severity, fatty acid and lipid mediator contents in colonic tissue, and the expression of genes related to lipid mediator formation.
RESULTS
ARA composition of colon phospholipids was significantly elevated in an ARA dose-dependent manner. ARA, as well as DHA, did not affect colitis severity (body weight loss, colon shortening, diarrhea and hemoccult phenomena) and histological features. PGE₂ contents in the colon were unchanged by dietary ARA, while LXA₄ contents increased in an ARA dose-dependent manner. Gene expression of cyclooxygenase (COX)-1 and COX-2 was unchanged, while that of 12/15-lipoxgenase (LOX) was significantly increased by dietary ARA. ARA composition did not correlate with neither colon length nor PGE₂ contents, but significantly correlated with LXA₄ content.
CONCLUSION
These results suggest that dietary ARA increases ARA and LXA₄ contents in colon, but that it has no effect on severity and PGE₂ content in a DSS-induced murine colitis model.
Topics: Administration, Oral; Animals; Arachidonic Acid; Colitis; Colon; Dextran Sulfate; Dietary Supplements; Dinoprostone; Docosahexaenoic Acids; Female; Gene Expression; Lipoxins; Mice; Mice, Inbred C57BL; Phospholipids; Severity of Illness Index; Tissue Distribution
PubMed: 24507383
DOI: 10.1186/1476-511X-13-30 -
Fukushima Journal of Medical Science Jun 2016Using the perforated patch voltage clamp, we investigated swelling-activated ionic channels (SACs) in rat urinary bladder smooth muscle cells. Hypo-osmotic (60%) bath...
Using the perforated patch voltage clamp, we investigated swelling-activated ionic channels (SACs) in rat urinary bladder smooth muscle cells. Hypo-osmotic (60%) bath solution increased a membrane current which was inhibited by the SAC inhibitor, gadolinium. The reversal potential of the hypotonicity-induced current shifted in the positive direction by increasing external K(+) concentration. The hypotonicity-induced current was inhibited by extracellular acidic pH, phorbol ester and forskolin. These pharmacological properties are identical to those of arachidonic acid-induced current present in these cells, suggesting the presence of TREK-1, a four-transmembrane two pore domain K(+) channel. Using RT-PCR we screened rat bladder smooth muscles and cerebellum for expression of TREK-1, TREK-2 and TRAAK mRNAs. Only TREK-1 mRNA was expressed in the bladder, while all three were expressed in the cerebellum. We conclude that a mechanosensitive K(+) channel is present in rat bladder myocytes, which is activated by arachidonic acid and most likely is TREK-1. This K(+) channel may have an important role in the regulation of bladder smooth muscle tone during urine storage.
Topics: Animals; Arachidonic Acid; Colforsin; Hydrogen-Ion Concentration; Male; Membrane Potentials; Muscle, Smooth; Potassium Channels, Tandem Pore Domain; Rats; Rats, Sprague-Dawley; Tetradecanoylphorbol Acetate; Urinary Bladder
PubMed: 26911303
DOI: 10.5387/fms.2015-20 -
The American Journal of Clinical... Jun 2007Concentrations of the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) in human breast milk are... (Meta-Analysis)
Meta-Analysis
Concentrations of the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) in human breast milk are important indicators of infant formula DHA and AA concentrations, and recent evidence suggests that neural maturation of breastfed infants is linked to breast-milk LCPUFA concentrations. We report a descriptive meta-analysis that considered 106 studies of human breast milk culled to include only studies that used modern analysis methods capable of making accurate estimates of fatty acid (FA) profiles and criteria related to the completeness of reporting. The final analysis included 65 studies of 2474 women. The mean (+/-SD) concentration of DHA in breast milk (by wt) is 0.32 +/- 0.22% (range: 0.06-1.4%) and that of AA is 0.47 +/- 0.13% (range: 0.24-1.0%), which indicates that the DHA concentration in breast milk is lower than and more variable than that of AA. The highest DHA concentrations were primarily in coastal populations and were associated with marine food consumption. The correlation between breast-milk DHA and AA concentrations was significant but low (r = 0.25, P = 0.02), which indicates that the mean ratio of DHA to AA in regional breast milk varies widely. This comprehensive analysis of breast-milk DHA and AA indicates a broad range of these nutrients worldwide and serves as a guide for infant feeding.
Topics: Arachidonic Acid; Docosahexaenoic Acids; Female; Humans; Milk, Human
PubMed: 17556680
DOI: 10.1093/ajcn/85.6.1457 -
TheScientificWorldJournal Sep 2007Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A... (Review)
Review
Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and w-3 polyunsaturated fatty acids (PUFA)-derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS-based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.
Topics: Animals; Arachidonic Acid; Chromatography, Liquid; Fatty Acids, Omega-3; Homeostasis; Humans; Inflammation; Receptors, Cell Surface; Tandem Mass Spectrometry
PubMed: 17767360
DOI: 10.1100/tsw.2007.188 -
Bioresource Technology Mar 2017Arachidonic acid (ARA) is one of the most abundant polyunsaturated fatty acids (PUFAs) in the mammalian brain. Many enzymatically- and nonenzymatically-produced...
Arachidonic acid (ARA) is one of the most abundant polyunsaturated fatty acids (PUFAs) in the mammalian brain. Many enzymatically- and nonenzymatically-produced metabolic products have important and potent pharmacological properties. However, uniformly isotope labeled forms of ARA are not commercially available for studying the metabolic fates of ARA. This study describes a simple and efficient protocol for the biosynthesis of U-C-ARA from U-C-glucose, and U-C-ARA from U-C-glucose by Mortierella alpina. The protocols yield approximately 100nmol quantities of U-C-ARA with an isotopic purity of 95% from a 500μl batch volume, and approximately 2μCi quantities of U-C-ARA with an apparent specific activity in excess of 1200Ci/mol from a 250μl batch volume.
Topics: Arachidonic Acid; Carbon Isotopes; Carbon Radioisotopes; Glucose; Isotope Labeling; Mortierella
PubMed: 28013130
DOI: 10.1016/j.biortech.2016.12.050 -
Prostaglandins Dec 1997The isoprostanes are a new class of natural products produced in vivo by a non-enzymatic free-radical-induced peroxidation of polyunsaturated fatty acid. In the case of... (Review)
Review
The isoprostanes are a new class of natural products produced in vivo by a non-enzymatic free-radical-induced peroxidation of polyunsaturated fatty acid. In the case of arachidonic acid, for example, four classes of isoprostanes can be produced. Because of the specific structural features distinguishing them from other free-radical-generated products, e.g., HETEs, etc., the isoprostanes can provide an exclusive and selective index for the oxidant component of several inflammatory and degenerative diseases. The possible mechanisms of formation of the individual isoprostanes is discussed in detail. Class III products, such as 8-iso-PGF2 alpha and 8-iso-PGE2 have been shown to be vasoconstrictors and modulate platelet function. Several synthetic representatives from the four classes of arachidonic-acid-derived isoprostanes have already been prepared by total synthesis. These synthetic standards have been used for the identification and quantitation of these isoprostanes in biological fluids using gas chromatography/mass spectrometry methodology.
Topics: Animals; Arachidonic Acid; Free Radicals; Humans; Oxygen; Prostaglandins; Stereoisomerism; Terminology as Topic
PubMed: 9533180
DOI: 10.1016/s0090-6980(97)00183-4 -
Cancer Science Jun 2013Omega-6 (n-6) arachidonic acid (AA) and its pro-inflammatory metabolites, including prostaglandin E2 (PGE(2)), are known to promote tumorigenesis. Delta-6 desaturase...
Omega-6 (n-6) arachidonic acid (AA) and its pro-inflammatory metabolites, including prostaglandin E2 (PGE(2)), are known to promote tumorigenesis. Delta-6 desaturase (D6D) is the rate-limiting enzyme for converting n-6 linoleic acid (LA) to AA. Our objective was to determine if AA synthesis, specifically D6D activity, and PGE(2) levels are increased in cancerous breast tissue, and whether these variables differ between estrogen receptor positive (ER+) and negative (ER-) breast cancers. Gas chromatography was performed on surgical breast tissue samples collected from 69 women with breast cancer. Fifty-four had ER+ breast cancer, and 15 had ER- breast cancer. Liquid chromatography-mass spectrometry was used to determine PGE(2) levels. Lipid analysis revealed higher levels of LA metabolites (C18:3 n-6, C20:3 n-6, and AA) in cancerous tissue than in adjacent noncancerous tissue (P < 0.01). The ratio of LA metabolites to LA, a measure of D6D activity, was increased in cancerous tissue, suggesting greater conversion of LA to AA (P < 0.001), and was higher in ER- than in ER+ patients, indicating genotype-related trends. Similarly, PGE(2) levels were increased in cancerous tissue, particularly in ER- patients. The results showed that the endogenous AA synthetic pathway, D6D activity, and PGE(2) levels are increased in breast tumors, particularly those of the ER- genotype. These findings suggest that the AA synthetic pathway and the D6D enzyme in particular may be involved in the pathogenesis of breast cancer. The development of drugs and nutritional interventions to alter this pathway may provide new strategies for breast cancer prevention and treatment.
Topics: Arachidonic Acid; Breast Neoplasms; Chromatography, Gas; Chromatography, Liquid; Female; Humans; Linoleoyl-CoA Desaturase; Mass Spectrometry; Receptors, Estrogen
PubMed: 23414387
DOI: 10.1111/cas.12129 -
Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma.Journal of Experimental & Clinical... Nov 2021Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum...
UNLABELLED
Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed.
METHODS
Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells.
RESULTS
We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug.
CONCLUSIONS
AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.
Topics: Antineoplastic Agents; Arachidonic Acid; Female; Humans; Male; Mass Spectrometry; Mesothelioma, Malignant; Stress, Physiological
PubMed: 34727953
DOI: 10.1186/s13046-021-02118-y -
Journal of Neuroinflammation Jan 2020Arachidonic acid-derived prostaglandins not only contribute to the development of inflammation as intercellular pro-inflammatory mediators, but also promote the... (Review)
Review
Arachidonic acid-derived prostaglandins not only contribute to the development of inflammation as intercellular pro-inflammatory mediators, but also promote the excitability of the peripheral somatosensory system, contributing to pain exacerbation. Peripheral tissues undergo many forms of diseases that are frequently accompanied by inflammation. The somatosensory nerves innervating the inflamed areas experience heightened excitability and generate and transmit pain signals. Extensive studies have been carried out to elucidate how prostaglandins play their roles for such signaling at the cellular and molecular levels. Here, we briefly summarize the roles of arachidonic acid-derived prostaglandins, focusing on four prostaglandins and one thromboxane, particularly in terms of their actions on afferent nociceptors. We discuss the biosynthesis of the prostaglandins, their specific action sites, the pathological alteration of the expression levels of related proteins, the neuronal outcomes of receptor stimulation, their correlation with behavioral nociception, and the pharmacological efficacy of their regulators. This overview will help to a better understanding of the pathological roles that prostaglandins play in the somatosensory system and to a finding of critical molecular contributors to normalizing pain.
Topics: Animals; Arachidonic Acid; Humans; Nociception; Pain; Prostaglandins
PubMed: 31969159
DOI: 10.1186/s12974-020-1703-1