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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 -
Archives of Biochemistry and Biophysics Feb 2024The X-ray crystal structures of soybean lipoxygenase (LOX) and rabbit 15-LOX were reported in the 1990s. Subsequent 3D structures demonstrated a conserved U-like shape... (Review)
Review
The X-ray crystal structures of soybean lipoxygenase (LOX) and rabbit 15-LOX were reported in the 1990s. Subsequent 3D structures demonstrated a conserved U-like shape of the substrate cavities as reviewed here. The 8-LOX:arachidonic acid (AA) complex showed AA bound to the substrate cavity carboxylate-out with C10 at 3.4 Å from the iron metal center. A recent cryo-electron microscopy (EM) analysis of the 12-LOX:AA complex illustrated AA in the same position as in the 8-LOX:AA complex. The 15- and 12-LOX complexes with isoenzyme-specific inhibitors/substrate mimics confirmed the U-fold. 5-LOX oxidizes AA to leukotriene A, the first step in biosynthesis of mediators of asthma. The X-ray structure showed that the entrance to the substrate cavity was closed to AA by Phe and Tyr residues of a partly unfolded α2-helix. Recent X-ray analysis revealed that soaking with inhibitors shifted the short α2-helix to a long and continuous, which opened the substrate cavity. The α2-helix also adopted two conformations in 15-LOX. 12-LOX dimers consisted of one closed and one open subunit with an elongated α2-helix. C-ENDOR-MD computations of the 9-MnLOX:linoleate complex showed carboxylate-out position with C11 placed 3.4 ± 0.1 Å from the catalytic water. 3D structures have provided a solid ground for future research.
Topics: Animals; Rabbits; Lipoxygenases; Binding Sites; Cryoelectron Microscopy; Lipoxygenase; Arachidonate 15-Lipoxygenase; Arachidonic Acid; Arachidonate 12-Lipoxygenase
PubMed: 38145834
DOI: 10.1016/j.abb.2023.109874 -
Biochimica Et Biophysica Acta Feb 2012The development of mass spectrometry-based techniques is opening new insights into the understanding of arachidonic acid (AA) metabolism. AA incorporation, remodeling... (Review)
Review
The development of mass spectrometry-based techniques is opening new insights into the understanding of arachidonic acid (AA) metabolism. AA incorporation, remodeling and release are collectively controlled by acyltransferases, phospholipases and transacylases that exquisitely regulate the distribution of AA between the different glycerophospholipid species and its mobilization during cellular stimulation. Traditionally, studies involving phospholipid AA metabolism were conducted by using radioactive precursors and scintillation counting from thin layer chromatography separations that provided only information about lipid classes. Today, the input of lipidomic approaches offers the possibility of characterizing and quantifying specific molecular species with great accuracy and within a biological context associated to protein and/or gene expression in a temporal frame. This review summarizes recent results applying mass spectrometry-based lipidomic approaches to the identification of AA-containing glycerophospholipids, phospholipid AA remodeling and synthesis of oxygenated metabolites.
Topics: Animals; Arachidonic Acid; Biological Transport; Cells; Humans; Inflammation
PubMed: 22155285
DOI: 10.1016/j.bbalip.2011.11.006 -
Nutrients Apr 2021Arachidonic acid (AA), a major long-chain omega-6 polyunsaturated fatty acid, is associated with ischemic heart disease (IHD) and stroke. We assessed bi-directional...
Associations of Arachidonic Acid Synthesis with Cardiovascular Risk Factors and Relation to Ischemic Heart Disease and Stroke: A Univariable and Multivariable Mendelian Randomization Study.
Arachidonic acid (AA), a major long-chain omega-6 polyunsaturated fatty acid, is associated with ischemic heart disease (IHD) and stroke. We assessed bi-directional associations of AA synthesis reflected by plasma phospholipid AA with CVD risk factors, and identified mediators of associations of AA with IHD and stroke using Mendelian randomization (MR). We used two-sample MR to assess bi-directional associations of AA synthesis with lipids, blood pressure, adiposity, and markers of inflammation and coagulation. We used multivariable MR to assess mediators of associations of AA with IHD and stroke. Genetically predicted AA (% of total fatty acids increase) was positively associated with apolipoprotein B (ApoB, 0.022 standard deviations (SD), 95% confidence interval (CI) 0.010, 0.034), high-density (0.030 SD, 95% CI 0.012, 0.049) and low-density lipoprotein cholesterol (LDL-C, 0.016 SD, 95% CI 0.004, 0.027) and lower triglycerides (-0.031 SD, 95% CI -0.049, -0.012) but not with other traits. Genetically predicted these traits gave no association with AA. The association of AA with IHD was attenuated adjusting for ApoB or LDL-C. Genetically predicted AA was associated with lipids but not other traits. Given ApoB is thought to be the key lipid in IHD, the association of AA with IHD is likely mediated by ApoB.
Topics: Arachidonic Acid; Female; Finland; Heart Disease Risk Factors; Humans; Male; Mendelian Randomization Analysis; Myocardial Ischemia; Stroke; United Kingdom
PubMed: 33924871
DOI: 10.3390/nu13051489 -
Journal of Chromatography. B,... Aug 2014The cytochrome P450 metabolites of arachidonic acid (AA) are mostly present in tissues, such as the liver, as bound to phospholipids, with only a small fraction...
The cytochrome P450 metabolites of arachidonic acid (AA) are mostly present in tissues, such as the liver, as bound to phospholipids, with only a small fraction available as free acids. The purpose of this study was to develop and validate a UHPLC-MS/MS method for quantitation of free liver concentrations of AA and four epoxygenated (5,6-, 8,9-, 11,12-, and 14,15-EET), four dihydroxylated (5,6-, 8,9-, 11,12-, and 14,15-DHET), and two ω/(ω-1) hydroxylated (19- and 20-HETEs) metabolites of AA in rat livers using deuterated internal standards. The analytes were rapidly and efficiently (79-92%) recovered from 100mg of fresh liver into methanol. After evaporation, the reconstituted samples were injected either undiluted (for the simultaneous analysis of the metabolites) into a gradient or diluted (for AA analysis) into an isocratic UHPLC system with run times of 5 and 2 min, respectively. Mass spectrometry was conducted using multiple reaction monitoring in negative mode. The method was linear (r(2)≥ 0.98) in the concentration ranges tested for metabolites (0.19-120 ng/g liver) and AA (7.8-500 μg/g liver). The lower limit of quantitation of the assay was between 0.57 and 5.6 pg injected on column for different AA metabolites. The assay was validated (n=5) based on acceptable intra- and inter-run accuracy and precision values. Additionally, matrix effect was minimal for most analytes. Freeze-thaw of samples drastically increased the free liver concentrations of analytes, presumably due to their release from the membrane storage sites. Therefore, fresh liver samples should be used for analysis. However, the methanolic extracts may be stored at -80°C for at least two weeks without any compromise. The method was successfully used in the measurement of all the analytes in the rats subjected to 60 min of hepatic ischemia (n=6) or sham operation (n=6). Ischemia resulted in significantly higher free concentrations of AA and most of its studied metabolites. The method is precise, accurate, and sensitive for measurement of free liver concentrations of AA and its P450 metabolites in the rat liver.
Topics: Animals; Arachidonic Acid; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Ischemia; Limit of Detection; Liver; Liver Diseases; Male; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry
PubMed: 24134894
DOI: 10.1016/j.jchromb.2013.08.008 -
PloS One 2015Salmons raised in aquaculture farms around the world are increasingly subjected to sub-optimal environmental conditions, such as high water temperatures during summer...
Salmons raised in aquaculture farms around the world are increasingly subjected to sub-optimal environmental conditions, such as high water temperatures during summer seasons. Aerobic scope increases and lipid metabolism changes are known plasticity responses of fish for a better acclimation to high water temperature. The present study aimed at investigating the effect of high water temperature on the regulation of fatty acid metabolism in juvenile Atlantic salmon fed different dietary ARA/EPA ratios (arachidonic acid, 20:4n-6/ eicosapentaenoic acid, 20:5n-3), with particular focus on apparent in vivo enzyme activities and gene expression of lipid metabolism pathways. Three experimental diets were formulated to be identical, except for the ratio EPA/ARA, and fed to triplicate groups of Atlantic salmon (Salmo salar) kept either at 10°C or 20°C. Results showed that fatty acid metabolic utilisation, and likely also their dietary requirements for optimal performance, can be affected by changes in their relative levels and by environmental temperature in Atlantic salmon. Thus, the increase in temperature, independently from dietary treatment, had a significant effect on the β-oxidation of a fatty acid including EPA, as observed by the apparent in vivo enzyme activity and mRNA expression of pparα -transcription factor in lipid metabolism, including β-oxidation genes- and cpt1 -key enzyme responsible for the movement of LC-PUFA from the cytosol into the mitochondria for β-oxidation-, were both increased at the higher water temperature. An interesting interaction was observed in the transcription and in vivo enzyme activity of Δ5fad-time-limiting enzyme in the biosynthesis pathway of EPA and ARA. Such, at lower temperature, the highest mRNA expression and enzyme activity was recorded in fish with limited supply of dietary EPA, whereas at higher temperature these were recorded in fish with limited ARA supply. In consideration that fish at higher water temperature recorded a significantly increased feed intake, these results clearly suggested that at high, sub-optimal water temperature, fish metabolism attempted to increment its overall ARA status -the most bioactive LC-PUFA participating in the inflammatory response- by modulating the metabolic fate of dietary ARA (expressed as % of net intake), reducing its β-oxidation and favouring synthesis and deposition. This correlates also with results from other recent studies showing that both immune- and stress- responses in fish are up regulated in fish held at high temperatures. This is a novel and fundamental information that warrants industry and scientific attention, in consideration of the imminent increase in water temperatures, continuous expansion of aquaculture operations, resources utilisation in aquafeed and much needed seasonal/adaptive nutritional strategies.
Topics: Animals; Arachidonic Acid; Eicosapentaenoic Acid; Salmo salar; Temperature; Water
PubMed: 26599513
DOI: 10.1371/journal.pone.0143622 -
Prostaglandins, Leukotrienes, and... 2007Numerous studies on perinatal long-chain polyunsaturated fatty acid nutrition have clarified the influence of dietary docosahexaenoic acid (DHA) and arachidonic acid... (Review)
Review
Numerous studies on perinatal long-chain polyunsaturated fatty acid nutrition have clarified the influence of dietary docosahexaenoic acid (DHA) and arachidonic acid (ARA) on central nervous system PUFA concentrations. In humans, omnivorous primates, and piglets, DHA and ARA plasma and red blood cells concentrations rise with dietary preformed DHA and ARA. Brain and retina DHA are responsive to diet while ARA is not. DHA is at highest concentration in cells and tissues associated with high energy consumption, consistent with high DHA levels in mitochondria and synaptosomes. DHA is a substrate for docosanoids, signaling compounds of intense current interest. The high concentration in tissues with high rates of oxidative metabolism may be explained by a critical role related to oxidative metabolism.
Topics: Animals; Arachidonic Acid; Central Nervous System; Dietary Fats, Unsaturated; Docosahexaenoic Acids; Fatty Acids; Humans
PubMed: 18023566
DOI: 10.1016/j.plefa.2007.10.016 -
The American Journal of Clinical... Jan 2020Recently adopted regulatory standards on infant and follow-on formula for the European Union stipulate that from February 2020 onwards, all such products marketed in the...
Recently adopted regulatory standards on infant and follow-on formula for the European Union stipulate that from February 2020 onwards, all such products marketed in the European Union must contain 20-50 mg omega-3 DHA (22:6n-3) per 100 kcal, which is equivalent to about 0.5-1% of fatty acids (FAs) and thus higher than typically found in human milk and current infant formula products, without the need to also include ω-6 arachidonic acid (AA; 20:4n-6). This novel concept of infant formula composition has given rise to concern and controversy because there is no accountable evidence on its suitability and safety in healthy infants. Therefore, international experts in the field of infant nutrition were invited to review the state of scientific research on DHA and AA, and to discuss the questions arising from the new European regulatory standards. Based on the available information, we recommend that infant and follow-on formula should provide both DHA and AA. The DHA should equal at least the mean content in human milk globally (0.3% of FAs) but preferably reach 0.5% of FAs. Although optimal AA intake amounts remain to be defined, we strongly recommend that AA should be provided along with DHA. At amounts of DHA in infant formula up to ∼0.64%, AA contents should at least equal the DHA contents. Further well-designed clinical studies should evaluate the optimal intakes of DHA and AA in infants at different ages based on relevant outcomes.
Topics: Arachidonic Acid; Child Development; Child Health; Docosahexaenoic Acids; European Union; Fatty Acids; Food Additives; Humans; Infant; Infant Formula; Pediatrics
PubMed: 31665201
DOI: 10.1093/ajcn/nqz252 -
Cells Jan 2024(1) Background: Inflammatory responses are implicated in embryo implantation, decidualization, pregnancy maintenance and labor. Both embryo implantation and...
(1) Background: Inflammatory responses are implicated in embryo implantation, decidualization, pregnancy maintenance and labor. Both embryo implantation and decidualization are essential to successful pregnancy in rodents and primates. S100A6 is involved in inflammation, tumor development, apoptosis and calcium homeostasis. S100A6 is strongly expressed in mouse decidua, but the underlying mechanisms of how S100A6 regulates implantation and decidualization are poorly defined. (2) Methods: Mouse endometrial stromal and epithelial cells are isolated from day 4 pseudopregnant mouse uteri. Both immunofluorescence and Western blotting are used to analyze the expression and localization of proteins. The molecular mechanism is verified in vitro by Western blotting and the quantitative polymerase chain reaction. (3) Results: From days 4 to 8 of pregnancy, S100A6 is specifically expressed in mouse subluminal stromal cells. Blastocyst-derived lactic acid induces AA secretion by activating the luminal epithelial p-cPLA2. The epithelial AA induces stromal S100A6 expression through the COX2/PGI2/PPAR δ pathway. Progesterone regulates S100A6 expression through the progesterone receptor (PR). S100A6/RAGE signaling can regulate decidualization via EGFR/ERK1/2 in vitro. (4) Conclusions: S100A6, as an inflammatory mediator, is important for mouse implantation and decidualization.
Topics: Pregnancy; Female; Animals; Mice; Decidua; Arachidonic Acid; Uterus; Embryo Implantation; Blastocyst
PubMed: 38334598
DOI: 10.3390/cells13030206 -
Clinical Nutrition (Edinburgh, Scotland) Aug 2007Arachidonic acid, a precursor to a series of inflammatory mediators, may contribute to the development of insulin resistance. We examined the association between adipose...
BACKGROUND & AIMS
Arachidonic acid, a precursor to a series of inflammatory mediators, may contribute to the development of insulin resistance. We examined the association between adipose tissue arachidonic acid and the metabolic syndrome in Costa Rica, a country in which the metabolic syndrome is highly prevalent.
METHODS
The 484 study participants each provided a fasting blood sample and an adipose tissue biopsy that was analyzed for fatty acid composition. Criteria for the metabolic syndrome were those established in the Third Report of the National Cholesterol Education Program Expert Panel. The data were analyzed by multivariate logistic regression.
RESULTS
Subjects with greater adipose tissue arachidonic acid content had an increasing risk of the metabolic syndrome across quintiles: odds ratio (95% confidence interval), 1.00; 1.51 (0.78-2.91); 2.40 (1.26-4.55); 3.50 (1.84-6.66); and 6.01 (3.11-11.61); test for trend, P<0.0001, after adjustment for age, gender and area of residence. Further adjustment for metabolic risk factors, including adipose fatty acids and body mass index, did not significantly modify the result. Adipose tissue arachidonic acid was also independently associated with abdominal obesity, hypertriglyceridemia, elevated fasting glucose, and high blood pressure.
CONCLUSIONS
This study identifies arachidonic acid as an important independent marker of metabolic dysregulation. A better understanding of the role of this fatty acid in the pathogenesis of the metabolic syndrome is warranted.
Topics: Adipose Tissue; Arachidonic Acid; Biomarkers; Confidence Intervals; Costa Rica; Female; Humans; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Odds Ratio; Risk Factors
PubMed: 17507118
DOI: 10.1016/j.clnu.2007.03.004