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John W. Newman - One of the best experts on this subject based on the ideXlab platform.
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effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low density lipoproteins in isolated perfused rat livers
Physiological Reports, 2021Co-Authors: Rachel E Walker, John W. Newman, Olga V Savinova, Theresa L Pedersen, Gregory C ShearerAbstract:Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis, and thrombosis. Very low-density lipoproteins (VLDL) contain Oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL Oxylipins. A compartmental model of deuterium-labeled linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL Oxylipins on fatty acid incorporation rates. LPS decreased the total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several Oxylipins by a similar amount (13-HOTrE, 35% [4%,55%], -1.3 nM; 9(10)-EpODE, 29% [3%,49%], -2.0 nM; 15(16)-EpODE, 29% [2%,49%], -1.6 nM; AA-derived diols, 32% [5%,52%], -2.4 nM; 19(20)-DiHDPA, 31% [7%,50%], -1.0 nM). However, the EPA-derived epoxide, 17(18)-EpETE, was decreased by 75% [49%,88%], (-0.52 nM) with LPS, double the suppression of other Oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)-EpDPE, by 99% [35%,193%], (2.0 nM). Final VLDL-oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport.
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MS-based targeted metabolomics of eicosanoids and other Oxylipins: Analytical variability and interlaboratory comparison of esterified oxylipin profile
2020Co-Authors: Céline Dalle, Annika I. Ostermann, Malwina Mainka, Jessica Dalloux-chioccioli, Michael Rothe, John W. Newman, Cécile Gladine, Nils Helge SchebbAbstract:Introduction Oxylipins are potent lipid mediators involved in numerous physiological and pathological processes and their quantitative profiling has gained a lot of attention [1]. To maximize the utility of the oxylipin profiling in clinical research it is now crucial (i) to assess its analytical variability; (ii) to determine its comparability between laboratories and (iii) to identify putative critical Oxylipins. These three main challenges are addressed within the EU JPI HDHL*-Oxygenate project. Technological and methodological innovation To address the challenges stated above, a SOP was established by a reference laboratory for the MSbased targeted metabolomics of total Oxylipins (free + esterified, ~160 Oxylipins) in human plasma [2]. The intra- and inter-day variabilities of each oxylipin were assessed. Then, the SOP was transferred to 4 independent laboratories together with mixtures of internal standards, calibrants and 7 different pools of plasma to determine the comparability of oxylipin profiles between labs. Results and impact The cumulated intra-/inter-day variabilities revealed that 68 % of Oxylipins (>LLOQ) have a CV
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ms based targeted metabolomics of eicosanoids and other Oxylipins analytical and inter individual variabilities
Free Radical Biology and Medicine, 2019Co-Authors: Cécile Gladine, Annika I. Ostermann, John W. Newman, Nils Helge SchebbAbstract:Abstract Oxylipins, including the well-known eicosanoids, are potent lipid mediators involved in numerous physiological and pathological processes. Therefore, their quantitative profiling has gained a lot of attention during the last years notably in the active field of health biomarker discovery. Oxylipins include hundreds of structurally and stereochemically distinct lipid species which today are most commonly analyzed by (ultra) high performance liquid chromatography-mass spectrometry based ((U)HPLC-MS) methods. To maximize the utility of oxylipin profiling in clinical research, it is crucial to understand and assess the factors contributing to the analytical and biological variability of oxylipin profiles in humans. In this review, these factors and their impacts are summarized and discussed, providing a framework for recommendations expected to enhance the interlaboratory comparability and biological interpretation of oxylipin profiling in clinical research.
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abnormal lipoprotein Oxylipins in metabolic syndrome and partial correction by omega 3 fatty acids
Prostaglandins Leukotrienes and Essential Fatty Acids, 2018Co-Authors: Theresa L Pedersen, Gregory C Shearer, William S Harris, Kamil Borkowski, Susan L Puumala, John W. NewmanAbstract:Metabolic syndrome (MetSyn) is characterized by chronic inflammation which mediates the associated high risk for cardiovascular and other diseases. Oxylipins are a superclass of lipid mediators with potent bioactivities in inflammation, vascular biology, and more. While their role as locally produced agents is appreciated, most Oxylipins in plasma are found in lipoproteins suggesting defective regulation of inflammation could be mediated by the elevated VLDL and low HDL levels characteristic of MetSyn. Our objective was to compare the oxylipin composition of VLDL, LDL, and HDL in 14 optimally healthy individuals and 31 MetSyn patients, and then to determine the effects of treating MetSyn subjects with 4g/day of prescription omega-3 fatty acids (P-OM3) on lipoprotein oxylipin profiles. We compared oxylipin compositions of healthy (14) and MetSyn (31) subjects followed by randomization and assignment to 4g/d P-OM3 for 16 weeks using LC/MS/MS. Compared to healthy subjects, MetSyn is characterized by abnormalities of (1) pro-inflammatory, arachidonate-derived Oxylipins from the lipoxygenase pathway in HDL; and (2) Oxylipins mostly not derived from arachidonate in VLDL. P-OM3 treatment corrected many components of these abnormalities, reducing the burden of inflammatory mediators within peripherally circulating lipoproteins that could interfere with, or enhance, local effectors of inflammatory stress. We conclude that MetSyn is associated with a disruption of lipoprotein oxylipin patterns consistent with greater inflammatory stress, and the partial correction of these dysoxylipinemias by treatment with omega-3 fatty acids could explain some of their beneficial effects.
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plasma fatty acids Oxylipins and risk of myocardial infarction the singapore chinese health study
Journal of Lipid Research, 2016Co-Authors: Ye Sun, John W. Newman, Jinling Fang, Choon Nam Ong, Hiromi W L Koh, Hyungwon Choi, Woonpuay Koh, Jianmin Yuan, Rob M Van DamAbstract:We aimed to examine the prospective association between plasma FAs, Oxylipins, and risk of acute myocardial infarction (AMI) in a Singapore Chinese population. A nested case-control study with 744 incident AMI cases and 744 matched controls aged 47-83 years was conducted within the Singapore Chinese Health Study. Nineteen plasma FAs and 12 Oxylipins were quantified using MS. These were grouped into 12 FA clusters and 5 oxylipin clusters using hierarchical clustering, and their associations with AMI risk were assessed. Long-chain n-3 FAs [odds ratio (OR) = 0.67 per SD increase, 95% confidence interval (CI): 0.53-0.84, P < 0.001] and stearic acid (OR = 0.65, 95% CI: 0.44-0.97, P = 0.03) were inversely associated with AMI risk, whereas arachidonic acid (AA) was positively associated with AMI risk (OR = 1.25, 95% CI: 1.03-1.52, P = 0.02) in the multivariable model with adjustment for other FAs. Further adjustment for Oxylipins did not substantially change these associations. An inverse association was observed between AA-derived oxylipin, thromboxane (TX)B2, and AMI risk (OR = 0.81, 95% CI: 0.71-0.93, P = 0.003). Circulating long-chain n-3 FAs and stearic acid were associated with a lower and AA was associated with a higher AMI risk in this Chinese population. The association between the oxylipin TXB2 and AMI requires further research.
Nils Helge Schebb - One of the best experts on this subject based on the ideXlab platform.
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Stability of Oxylipins during plasma generation and long-term storage.
Talanta, 2020Co-Authors: Elisabeth Koch, Céline Dalle, Annika I. Ostermann, Laura Kutzner, Malwina Mainka, Cécile Gladine, Katharina M. Rund, Laura-fabienne Froehlich, Justine Bertrand-michel, Nils Helge SchebbAbstract:Abstract Oxidized unsaturated fatty acids – i.e. eicosanoids and other Oxylipins – are lipid mediators involved in the regulation of numerous physiological functions such as inflammation, blood coagulation, vascular tone and endothelial permeability. They have raised strong interest in clinical lipidomics in order to understand their role in health and diseases and their use as biomarkers. However, before the clinical translation, it is crucial to validate the analytical reliability of Oxylipins. This notably requires to assess the putative artificial formation or degradation of Oxylipins by (unsuitable) blood handling during plasma generation, storage and sample preparation. Using a liquid chromatography-mass spectrometry method covering 133 Oxylipins we comprehensively analyzed the total (free + esterified) oxylipin profile in plasma and investigated the influence of i) addition of additives during sample preparation, ii) different storage times and temperatures during the transitory stage of plasma generation and iii) long-term storage of plasma samples at −80 °C. Addition of radical scavenger butylated hydroxytoluene reduced the apparent concentrations of hydroxy-PUFA and thus should be added to the samples at the beginning of sample preparation. The concentrations of all oxylipin classes remained stable (within analytical variance of 20%) during the transitory stage of plasma generation up to 24 h at 4 °C or 4 h at 20 °C before centrifugation of EDTA-whole blood and up to 5 days at −20 °C after plasma separation. The variations in oxylipin concentrations did not correlate with storage time, storage temperature or stage of plasma generation. A significant increase of potentially lipoxygenase derived hydroxy-PUFA compared to immediate processing was only detected when samples were stored for longer times before centrifugation, plasma separation as well as freezing of plasma revealing residual enzymatic activity. Autoxidative rather than enzymatic processes led to a slightly increased concentration of 9-HETE when plasma samples were stored at −80 °C for 15 months. Overall, we demonstrate that total plasma Oxylipins are robust regarding delays during plasma generation and long-term storage at −80 °C supporting the application of oxylipin profiling in clinical research.
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Clinical blood sampling for oxylipin analysis - effect of storage and pneumatic tube transport of blood on free and total oxylipin profile in human plasma and serum.
The Analyst, 2020Co-Authors: Katharina M. Rund, Fabian Nolte, Julian Doricic, Robert Greite, Sebastian Schott, Ralf Lichtinghagen, Faikah Gueler, Nils Helge SchebbAbstract:Quantitative analysis of Oxylipins in blood samples is of increasing interest in clinical studies. However, storage after sampling and transport of blood might induce artificial changes in the apparent oxylipin profile due to ex vivo formation/degradation by autoxidation or enzymatic activity. In the present study we investigated the stability of free (i.e. non-esterified) and total Oxylipins in EDTA-plasma and serum generated under clinical conditions assessing delays in sample processing and automated transportation: Free cytochrome P450 monooxygenase and 5-lipoxygenase (LOX) formed Oxylipins as well as autoxidation products were marginally affected by storage of whole blood up to 4 h at 4 °C, while total (i.e. the sum of free and esterified) levels of these Oxylipins were stable up to 24 h and following transport. Cyclooxygenase (COX) products (TxB2, 12-HHT) and 12-LOX derived hydroxy-fatty acids were prone to storage and transport induced changes due to platelet activation. Total oxylipin patterns were generally more stable than the concentration of free Oxylipins. In serum, coagulation induced higher levels of COX and 12-LOX products showing a high inter-individual variability. Overall, our results indicate that total EDTA-plasma Oxylipins are the most stable blood oxylipin marker for clinical samples. Here, storage of blood before further processing is acceptable for a period up to 24 hours at 4 °C. However, levels of platelet derived Oxylipins should be interpreted with caution regarding potential ex vivo formation.
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MS-based targeted metabolomics of eicosanoids and other Oxylipins: Analytical variability and interlaboratory comparison of esterified oxylipin profile
2020Co-Authors: Céline Dalle, Annika I. Ostermann, Malwina Mainka, Jessica Dalloux-chioccioli, Michael Rothe, John W. Newman, Cécile Gladine, Nils Helge SchebbAbstract:Introduction Oxylipins are potent lipid mediators involved in numerous physiological and pathological processes and their quantitative profiling has gained a lot of attention [1]. To maximize the utility of the oxylipin profiling in clinical research it is now crucial (i) to assess its analytical variability; (ii) to determine its comparability between laboratories and (iii) to identify putative critical Oxylipins. These three main challenges are addressed within the EU JPI HDHL*-Oxygenate project. Technological and methodological innovation To address the challenges stated above, a SOP was established by a reference laboratory for the MSbased targeted metabolomics of total Oxylipins (free + esterified, ~160 Oxylipins) in human plasma [2]. The intra- and inter-day variabilities of each oxylipin were assessed. Then, the SOP was transferred to 4 independent laboratories together with mixtures of internal standards, calibrants and 7 different pools of plasma to determine the comparability of oxylipin profiles between labs. Results and impact The cumulated intra-/inter-day variabilities revealed that 68 % of Oxylipins (>LLOQ) have a CV
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Stability of Oxylipins during plasma generation and long-term storage
Talanta, 2020Co-Authors: Elisabeth Koch, Céline Dalle, Laura Kutzner, Malwina Mainka, Cécile Gladine, Katharina M. Rund, Annika Ostermann, Laura-fabienne Froehlich, Justine Bertrand-michel, Nils Helge SchebbAbstract:Oxidized unsaturated fatty acids - i.e. eicosanoids and other Oxylipins - are lipid mediators involved in the regulation of numerous physiological functions such as inflammation, blood coagulation, vascular tone and endothelial permeability. They have raised strong interest in clinical lipidomics in order to understand their role in health and diseases and their use as biomarkers. However, before the clinical translation, it is crucial to validate the analytical reliability of Oxylipins. This notably requires to assess the putative artificial formation or degradation of Oxylipins by (unsuitable) blood handling during plasma generation, storage and sample preparation. Using a liquid chromatography-mass spectrometry method covering 133 Oxylipins we comprehensively analyzed the total (free + esterified) oxylipin profile in plasma and investigated the influence of i) addition of additives during sample preparation, ii) different storage times and temperatures during the transitory stage of plasma generation and iii) long-term storage of plasma samples at -80 degrees C. Addition of radical scavenger butylated hydroxytoluene reduced the apparent concentrations of hydroxy-PUFA and thus should be added to the samples at the beginning of sample preparation. The concentrations of all oxylipin classes remained stable (within analytical variance of 20%) during the transitory stage of plasma generation up to 24 h at 4 degrees C or 4 h at 20 degrees C before centrifugation of EDTA-whole blood and up to 5 days at - 20 degrees C after plasma separation. The variations in oxylipin concentrations did not correlate with storage time, storage temperature or stage of plasma generation. A significant increase of potentially lipoxygenase derived hydroxy-PUFA compared to immediate processing was only detected when samples were stored for longer times before centrifugation, plasma separation as well as freezing of plasma revealing residual enzymatic activity. Autoxidative rather than enzymatic processes led to a slightly increased concentration of 9-HETE when plasma samples were stored at - 80 degrees C for 15 months. Overall, we demonstrate that total plasma Oxylipins are robust regarding delays during plasma generation and long-term storage at -80 degrees C supporting the application of oxylipin profiling in clinical research.
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ms based targeted metabolomics of eicosanoids and other Oxylipins analytical and inter individual variabilities
Free Radical Biology and Medicine, 2019Co-Authors: Cécile Gladine, Annika I. Ostermann, John W. Newman, Nils Helge SchebbAbstract:Abstract Oxylipins, including the well-known eicosanoids, are potent lipid mediators involved in numerous physiological and pathological processes. Therefore, their quantitative profiling has gained a lot of attention during the last years notably in the active field of health biomarker discovery. Oxylipins include hundreds of structurally and stereochemically distinct lipid species which today are most commonly analyzed by (ultra) high performance liquid chromatography-mass spectrometry based ((U)HPLC-MS) methods. To maximize the utility of oxylipin profiling in clinical research, it is crucial to understand and assess the factors contributing to the analytical and biological variability of oxylipin profiles in humans. In this review, these factors and their impacts are summarized and discussed, providing a framework for recommendations expected to enhance the interlaboratory comparability and biological interpretation of oxylipin profiling in clinical research.
Gregory C Shearer - One of the best experts on this subject based on the ideXlab platform.
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effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low density lipoproteins in isolated perfused rat livers
Physiological Reports, 2021Co-Authors: Rachel E Walker, John W. Newman, Olga V Savinova, Theresa L Pedersen, Gregory C ShearerAbstract:Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis, and thrombosis. Very low-density lipoproteins (VLDL) contain Oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL Oxylipins. A compartmental model of deuterium-labeled linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL Oxylipins on fatty acid incorporation rates. LPS decreased the total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several Oxylipins by a similar amount (13-HOTrE, 35% [4%,55%], -1.3 nM; 9(10)-EpODE, 29% [3%,49%], -2.0 nM; 15(16)-EpODE, 29% [2%,49%], -1.6 nM; AA-derived diols, 32% [5%,52%], -2.4 nM; 19(20)-DiHDPA, 31% [7%,50%], -1.0 nM). However, the EPA-derived epoxide, 17(18)-EpETE, was decreased by 75% [49%,88%], (-0.52 nM) with LPS, double the suppression of other Oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)-EpDPE, by 99% [35%,193%], (2.0 nM). Final VLDL-oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport.
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abnormal lipoprotein Oxylipins in metabolic syndrome and partial correction by omega 3 fatty acids
Prostaglandins Leukotrienes and Essential Fatty Acids, 2018Co-Authors: Theresa L Pedersen, Gregory C Shearer, William S Harris, Kamil Borkowski, Susan L Puumala, John W. NewmanAbstract:Metabolic syndrome (MetSyn) is characterized by chronic inflammation which mediates the associated high risk for cardiovascular and other diseases. Oxylipins are a superclass of lipid mediators with potent bioactivities in inflammation, vascular biology, and more. While their role as locally produced agents is appreciated, most Oxylipins in plasma are found in lipoproteins suggesting defective regulation of inflammation could be mediated by the elevated VLDL and low HDL levels characteristic of MetSyn. Our objective was to compare the oxylipin composition of VLDL, LDL, and HDL in 14 optimally healthy individuals and 31 MetSyn patients, and then to determine the effects of treating MetSyn subjects with 4g/day of prescription omega-3 fatty acids (P-OM3) on lipoprotein oxylipin profiles. We compared oxylipin compositions of healthy (14) and MetSyn (31) subjects followed by randomization and assignment to 4g/d P-OM3 for 16 weeks using LC/MS/MS. Compared to healthy subjects, MetSyn is characterized by abnormalities of (1) pro-inflammatory, arachidonate-derived Oxylipins from the lipoxygenase pathway in HDL; and (2) Oxylipins mostly not derived from arachidonate in VLDL. P-OM3 treatment corrected many components of these abnormalities, reducing the burden of inflammatory mediators within peripherally circulating lipoproteins that could interfere with, or enhance, local effectors of inflammatory stress. We conclude that MetSyn is associated with a disruption of lipoprotein oxylipin patterns consistent with greater inflammatory stress, and the partial correction of these dysoxylipinemias by treatment with omega-3 fatty acids could explain some of their beneficial effects.
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effect of omega 3 fatty acid ethyl esters on the oxylipin composition of lipoproteins in hypertriglyceridemic statin treated subjects
PLOS ONE, 2014Co-Authors: John W. Newman, Theresa L Pedersen, William S Harris, Verdayne R Brandenburg, Gregory C ShearerAbstract:Background: Oxylipins mediate inflammation, vascular tension, and more. Their presence in lipoproteins could explain why lipoproteins mediate nearly identical activities. Methods: To determine how Oxylipins are distributed in the lipoproteins of hypertriglyceridemic subjects, and whether omega-3 fatty acids alter them in a manner consistent with improved cardiovascular health, we recruited 15 dyslipidemic subjects whose levels of low density lipoprotein cholesterol (LDL-C) were at goal but who remained hypertriglyceridemic (200–499 mg/dL). They were treated them with the indicated dose of 4 g/d omega-3 acid ethyl esters (P-OM3) for 8 weeks. Measured Oxylipins included mid-chain alcohols (HETEs, HEPEs and HDoHEs), ketones (KETEs), epoxides (as EpETrEs, EpETEs, and EpDPEs). Results: At baseline, arachidonate-Oxylipins (HETEs, KETEs, and EpETrEs) were most abundant in plasma with the greatest fraction of total abundance (mean |95% CI|) being carried in high density lipoproteins (HDL); 42% |31, 57| followed by very low density lipoproteins (VLDL); 27% |20, 36|; and LDL 21% |16, 28|. EPA- and DHA-derived Oxylipins constituted less than 11% of total. HDL carried alcohols and epoxides but VLDL was also rich in ketones. Treatment decreased AA-derived Oxylipins across lipoprotein classes (223% |233, 212|, p=0.0003), and expanded EPA2(322% |241, 422|, p,0.0001) and DHA-derived Oxylipins (123% |80, 176|, p,0.0001). Conclusions: Each lipoprotein class carries a unique oxylipin complement. P-OM3 treatment alters the oxylipin content of all classes, reducing pro-inflammatory and increasing anti-inflammatory species, consistent with the improved inflammatory and vascular status associated with the treatment. Trial Registration: ClinicalTrials.gov NCT00959842
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detection of omega 3 Oxylipins in human plasma and response to treatment with omega 3 acid ethyl esters
Journal of Lipid Research, 2010Co-Authors: Gregory C Shearer, John W. Newman, Theresa L Pedersen, William S HarrisAbstract:The long-chain omega-3 fatty acids (n-3 FA) eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) have beneficial health effects, but the molecular mediators of these effects are not well characterized. Oxygenated n-3 FAs (Oxylipins) may be an important class of mediators. Members of this chemical class include epoxides, alcohols, diols, and ketones, many of which have bioactivity in vitro. Neither the presence of n-3 Oxylipins in human plasma nor the effect of n-3 FA ingestion on their levels has been documented. We measured plasma Oxylipins derived from both the n-3 and n-6 FA classes in healthy volunteers (n = 10) before and after 4 weeks of treatment with prescription n-3 FA ethyl esters (4 g/day). At baseline, EPA and DHA Oxylipins were detected in low (1–50 nM) range, with alcohols > epoxides ≥ diols. Treatment increased n-3 oxylipin levels 2- to 5-fold and reduced selected n-6 Oxylipins by ∼20%. This is the first documentation that endogenous n-3 oxylipin levels can be modulated by n-3 FA treatment in humans. The extent to which the beneficial cardiovascular effects of n-3 FAs are mediated by increased n-3 and/or reduced n-6 oxylipin levels remains to be explored.
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Impact of circulating esterified eicosanoids and other Oxylipins on endothelial function
Current Atherosclerosis Reports, 2009Co-Authors: Gregory C Shearer, John W. NewmanAbstract:Eicosanoids, including epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and other Oxylipins derived from polyunsaturated fatty acids, have emerging roles in endothelial inflammation and subsequent atherosclerosis. Unlike eicosanoids in the prostanoid series, they are known to be esterified in cell lipids such as phospholipids and triglycerides; however, our understanding of these reservoirs is in its infancy. This review focuses on recent work identifying circulating Oxylipins, primarily esterified with lipoprotein lipids, and their effects on markers of endothelial dysfunction. These Oxylipins are known to be released by at least one lipase (lipoprotein lipase) and to mediate increased expression of inflammatory markers in endothelial cells, which coincides with the known roles of lipoproteins in endothelial dysfunction. The implications of the lipolytic release of lipoproteinbound Oxylipins for the inflammatory response, challenges to analysis of this oxylipin compartment, and the potential importance of non-arachidonatederived Oxylipins are discussed.
Bruce D Hammock - One of the best experts on this subject based on the ideXlab platform.
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Vascular Lipidomic Profiling of Potential Endogenous Fatty Acid PPAR Ligands Reveals the Coronary Artery as Major Producer of CYP450-Derived Epoxy Fatty Acids
Cells, 2020Co-Authors: Matthew L. Edin, Bruce D Hammock, Darryl C. Zeldin, Fred B. Lih, Scott Thomson, David Bishop-baileyAbstract:A number of Oxylipins have been described as endogenous PPAR ligands. The very short biological half-lives of Oxylipins suggest roles as autocrine or paracrine signaling molecules. While coronary arterial atherosclerosis is the root of myocardial infarction, aortic atherosclerotic plaque formation is a common readout of in vivo atherosclerosis studies in mice. Improved understanding of the compartmentalized sources of oxylipin PPAR ligands will increase our knowledge of the roles of PPAR signaling in diverse vascular tissues. Here, we performed a targeted lipidomic analysis of ex vivo-generated Oxylipins from porcine aorta, coronary artery, pulmonary artery and perivascular adipose. Cyclooxygenase (COX)-derived prostanoids were the most abundant detectable oxylipin from all tissues. By contrast, the coronary artery produced significantly higher levels of Oxylipins from CYP450 pathways than other tissues. The TLR4 ligand LPS induced prostanoid formation in all vascular tissue tested. The 11-HETE, 15-HETE, and 9-HODE were also induced by LPS from the aorta and pulmonary artery but not coronary artery. Epoxy fatty acid (EpFA) formation was largely unaffected by LPS. The pig CYP2J homologue CYP2J34 was expressed in porcine vascular tissue and primary coronary artery smooth muscle cells (pCASMCs) in culture. Treatment of pCASMCs with LPS induced a robust profile of pro-inflammatory target genes: TNFα, ICAM-1, VCAM-1, MCP-1 and CD40L. The soluble epoxide hydrolase inhibitor TPPU, which prevents the breakdown of endogenous CYP-derived EpFAs, significantly suppressed LPS-induced inflammatory target genes. In conclusion, PPAR-activating Oxylipins are produced and regulated in a vascular site-specific manner. The CYP450 pathway is highly active in the coronary artery and capable of providing anti-inflammatory Oxylipins that prevent processes of inflammatory vascular disease progression.
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dimethyl sulfoxide decreases levels of oxylipin diols in mouse liver
Frontiers in Pharmacology, 2019Co-Authors: Poonamjot Deol, Bruce D Hammock, Jun Yang, Christophe Morisseau, Frances M SladekAbstract:Dimethylsulfoxide (DMSO) is widely used as a solvent and cryopreservative in laboratories and considered to have many beneficial health effects in humans. Oxylipins are a class of biologically active metabolites of polyunsaturated fatty acids (PUFAs) that have been linked to a number of diseases. In this study, we investigated the effect of DMSO on oxylipin levels in mouse liver. Liver tissue from male mice (C57Bl6/N) that were either untreated or injected with 1% DMSO at 18 weeks of age was analyzed for oxylipin levels using ultrahigh performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). A decrease in oxylipin diols from linoleic acid (LA, C18:2n6), alpha-linolenic acid (ALA, C18:3n3) and docosahexeanoic acid (DHA, C22:6n3) was observed two hours after injection with DMSO. In contrast, DMSO had no effect on the epoxide precursors or other Oxylipins including those derived from arachidonic acid (C20:4n6) or eicosapentaenoic acid (EPA, C20:5n3). It also did not significantly affect the diol:epoxide ratio, suggesting a pathway distinct from, and potentially complementary to, soluble epoxide hydrolase inhibitors (sEHI). Since Oxylipins have been associated with a wide array of pathological conditions, from arthritis pain to obesity, our results suggest one potential mechanism underlying the apparent beneficial health effects of DMSO. They also indicate that caution should be used in the interpretation of results using DMSO as a vehicle in animal experiments.
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intimal smooth muscle cells are a source but not a sensor of anti inflammatory cyp450 derived Oxylipins
Biochemical and Biophysical Research Communications, 2015Co-Authors: Scott Thomson, Bruce D Hammock, Matthew L. Edin, Darryl C. Zeldin, Fred B. Lih, Michael Davies, Muhammad M Yaqoob, Derek W Gilroy, David BishopbaileyAbstract:Vascular pathologies are associated with changes in the presence and expression of morphologically distinct vascular smooth muscle cells. In particular, in complex human vascular lesions and models of disease in pigs and rodents, an intimal smooth muscle cell (iSMC) which exhibits a stable epithelioid or rhomboid phenotype in culture is often found to be present in high numbers, and may represent the reemergence of a distinct developmental vascular smooth muscle cell phenotype. The CYP450-oxylipin - soluble epoxide hydrolase (sEH) pathway is currently of great interest in targeting for cardiovascular disease. sEH inhibitors limit the development of hypertension, diabetes, atherosclerosis and aneurysm formation in animal models. We have investigated the expression of CYP450-oxylipin-sEH pathway enzymes and their metabolites in paired intimal (iSMC) and medial (mSMC) cells isolated from rat aorta. iSMC basally released significantly larger amounts of epoxy-oxylipin CYP450 products from eicosapentaenoic acid > docosahexaenoic acid > arachidonic acid > linoleic acid, and expressed higher levels of CYP2C12, CYP2B1, but not CYP2J mRNA compared to mSMC. When stimulated with the pro-inflammatory TLR4 ligand LPS, epoxy-oxylipin production did not change greatly in iSMC. In contrast, LPS induced epoxy-oxylipin products in mSMC and induced CYP2J4. iSMC and mSMC express sEH which metabolizes primary epoxy-Oxylipins to their dihydroxy-counterparts. The sEH inhibitors TPPU or AUDA inhibited LPS-induced NFκB activation and iNOS induction in mSMC, but had no effect on NFκB nuclear localization or inducible nitric oxide synthase in iSMC; effects which were recapitulated in part by addition of authentic epoxy-Oxylipins. iSMCs are a rich source but not a sensor of anti-inflammatory epoxy-Oxylipins. Complex lesions that contain high levels of iSMCs may be more resistant to the protective effects of sEH inhibitors.
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increase of epa derived hydroxy epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long chain omega 3 pufa
Prostaglandins & Other Lipid Mediators, 2014Co-Authors: Jan Philipp Schuchardt, Bruce D Hammock, Andreas Hahn, Ina Willenberg, Jun Yang, Inga Schneider, Nils Helge SchebbAbstract:a b s t r a c t Introduction: Several supplementation studies with long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) describe an increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acids in blood, while changes in levels of other LC n-3 and n-6 PUFA-derived Oxylipins were minor. In order to investigate the kinetics of changes in oxylipin levels in response to LC n-3 PUFA ingestion, we conducted a single dose treatment study with healthy subjects. Subjects and methods: In the present kinetic study, we compared patterns of hydroxy, epoxy and dihydroxy fatty acids in plasma of 6 healthy men before and after 6, 8, 24, and 48 h of fish oil (1008 mg EPA and 672 mg DHA) ingestion. Levels of EPA- as well as other LC PUFA-derived hydroxy, epoxy and dihydroxy fatty acids were analyzed in plasma by LC-MS. Additionally, levels of these Oxylipins were compared with their parent PUFA levels in plasma phospholipids. Results: All EPA-derived oxylipin levels were significantly increased 6 h after LC n-3 PUFA ingestion and gradually drop thereafter reaching the baseline levels about 48 h after treatment. The relative increase in EPA plasma phospholipid levels highly correlated with the increase of plasma EPA-derived oxylipin levels at different time points. In contrast, plasma levels of arachidonic acid- and DHA-derived Oxylipins as well as parent PUFA levels in plasma phospholipids were hardly changed. Discussion and conclusions: Our findings demonstrate that a single dose of LC n-3 PUFAs can rapidly induce a shift in the EPA oxylipin profile of healthy subjects within a few hours. Taking the high biological activity of the EPA-derived epoxy fatty acids into account, even short-term treatment with LC n-3 PUFAs may cause systemic effects, which warrant further investigation.
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modulation of blood oxylipin levels by long chain omega 3 fatty acid supplementation in hyper and normolipidemic men
Prostaglandins Leukotrienes and Essential Fatty Acids, 2014Co-Authors: Jan Philipp Schuchardt, Bruce D Hammock, Andreas Hahn, Simone Schmidt, Gaby Kressel, Ina Willenberg, Nils Helge SchebbAbstract:Abstract Introduction Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) such as EPA and DHA have been shown to possess beneficial health effects, and it is believed that many of their effects are mediated by their oxygenated products (Oxylipins). Recently, we have shown that serum levels of several hydroxy, epoxy, and dihydroxy FAs are dependent on the individual status of the parent FAs in a cohort of normo- and hyperlipidemic subjects. So far, the effect of an increased dietary LC n-3 PUFA intake on hydroxy, epoxy, and dihydroxy FA levels has not been investigated in subjects with mild combined hyperlipidemia. Subjects and methods In the present study, we compared oxylipin patterns of 10 hyperlipidemic (cholesterol >200mg/dl; triglyceride >150mg/ml) and 10 normolipidemic men in response to twelve weeks of LC n-3 PUFA intake (1.14g DHA and 1.56g EPA). Levels of 44 free hydroxy, epoxy and dihydroxy FAs were analyzed in serum by LC-MS. Additionally, oxylipin levels were compared with their parent PUFA levels in erythrocyte membranes; a biomarker for the individual PUFA status. Results Differences in the oxylipin pattern between normo- and hyperlipidemic subjects were minor before and after treatment. In all subjects, levels of EPA-derived Oxylipins (170–4800pM) were considerably elevated after LC n-3 PUFA intake (150–1400%), the increase of DHA-derived Oxylipins (360–3900pM) was less pronounced (30–130%). The relative change of EPA in erythrocyte membranes is strongly correlated (r≥0.5; p Discussion and conclusions The dietary LC PUFA composition has a direct influence on the endogenous oxylipin profile, including several highly biological active EPA- and DHA-derived lipid mediators. The shift in oxylipin pattern appears to be dependent on the initial LC PUFA status particularly for EPA. The finding that also levels of other Oxylipins derived from ALA, LA or AA are modified by LC n-3 PUFA intake might suggest that at least some of the effects of EPA and DHA could be mediated by a shift in the entire oxylipin profile.
Theresa L Pedersen - One of the best experts on this subject based on the ideXlab platform.
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effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low density lipoproteins in isolated perfused rat livers
Physiological Reports, 2021Co-Authors: Rachel E Walker, John W. Newman, Olga V Savinova, Theresa L Pedersen, Gregory C ShearerAbstract:Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis, and thrombosis. Very low-density lipoproteins (VLDL) contain Oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL Oxylipins. A compartmental model of deuterium-labeled linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL Oxylipins on fatty acid incorporation rates. LPS decreased the total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several Oxylipins by a similar amount (13-HOTrE, 35% [4%,55%], -1.3 nM; 9(10)-EpODE, 29% [3%,49%], -2.0 nM; 15(16)-EpODE, 29% [2%,49%], -1.6 nM; AA-derived diols, 32% [5%,52%], -2.4 nM; 19(20)-DiHDPA, 31% [7%,50%], -1.0 nM). However, the EPA-derived epoxide, 17(18)-EpETE, was decreased by 75% [49%,88%], (-0.52 nM) with LPS, double the suppression of other Oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)-EpDPE, by 99% [35%,193%], (2.0 nM). Final VLDL-oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport.
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abnormal lipoprotein Oxylipins in metabolic syndrome and partial correction by omega 3 fatty acids
Prostaglandins Leukotrienes and Essential Fatty Acids, 2018Co-Authors: Theresa L Pedersen, Gregory C Shearer, William S Harris, Kamil Borkowski, Susan L Puumala, John W. NewmanAbstract:Metabolic syndrome (MetSyn) is characterized by chronic inflammation which mediates the associated high risk for cardiovascular and other diseases. Oxylipins are a superclass of lipid mediators with potent bioactivities in inflammation, vascular biology, and more. While their role as locally produced agents is appreciated, most Oxylipins in plasma are found in lipoproteins suggesting defective regulation of inflammation could be mediated by the elevated VLDL and low HDL levels characteristic of MetSyn. Our objective was to compare the oxylipin composition of VLDL, LDL, and HDL in 14 optimally healthy individuals and 31 MetSyn patients, and then to determine the effects of treating MetSyn subjects with 4g/day of prescription omega-3 fatty acids (P-OM3) on lipoprotein oxylipin profiles. We compared oxylipin compositions of healthy (14) and MetSyn (31) subjects followed by randomization and assignment to 4g/d P-OM3 for 16 weeks using LC/MS/MS. Compared to healthy subjects, MetSyn is characterized by abnormalities of (1) pro-inflammatory, arachidonate-derived Oxylipins from the lipoxygenase pathway in HDL; and (2) Oxylipins mostly not derived from arachidonate in VLDL. P-OM3 treatment corrected many components of these abnormalities, reducing the burden of inflammatory mediators within peripherally circulating lipoproteins that could interfere with, or enhance, local effectors of inflammatory stress. We conclude that MetSyn is associated with a disruption of lipoprotein oxylipin patterns consistent with greater inflammatory stress, and the partial correction of these dysoxylipinemias by treatment with omega-3 fatty acids could explain some of their beneficial effects.
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effect of omega 3 fatty acid ethyl esters on the oxylipin composition of lipoproteins in hypertriglyceridemic statin treated subjects
PLOS ONE, 2014Co-Authors: John W. Newman, Theresa L Pedersen, William S Harris, Verdayne R Brandenburg, Gregory C ShearerAbstract:Background: Oxylipins mediate inflammation, vascular tension, and more. Their presence in lipoproteins could explain why lipoproteins mediate nearly identical activities. Methods: To determine how Oxylipins are distributed in the lipoproteins of hypertriglyceridemic subjects, and whether omega-3 fatty acids alter them in a manner consistent with improved cardiovascular health, we recruited 15 dyslipidemic subjects whose levels of low density lipoprotein cholesterol (LDL-C) were at goal but who remained hypertriglyceridemic (200–499 mg/dL). They were treated them with the indicated dose of 4 g/d omega-3 acid ethyl esters (P-OM3) for 8 weeks. Measured Oxylipins included mid-chain alcohols (HETEs, HEPEs and HDoHEs), ketones (KETEs), epoxides (as EpETrEs, EpETEs, and EpDPEs). Results: At baseline, arachidonate-Oxylipins (HETEs, KETEs, and EpETrEs) were most abundant in plasma with the greatest fraction of total abundance (mean |95% CI|) being carried in high density lipoproteins (HDL); 42% |31, 57| followed by very low density lipoproteins (VLDL); 27% |20, 36|; and LDL 21% |16, 28|. EPA- and DHA-derived Oxylipins constituted less than 11% of total. HDL carried alcohols and epoxides but VLDL was also rich in ketones. Treatment decreased AA-derived Oxylipins across lipoprotein classes (223% |233, 212|, p=0.0003), and expanded EPA2(322% |241, 422|, p,0.0001) and DHA-derived Oxylipins (123% |80, 176|, p,0.0001). Conclusions: Each lipoprotein class carries a unique oxylipin complement. P-OM3 treatment alters the oxylipin content of all classes, reducing pro-inflammatory and increasing anti-inflammatory species, consistent with the improved inflammatory and vascular status associated with the treatment. Trial Registration: ClinicalTrials.gov NCT00959842
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detection of omega 3 Oxylipins in human plasma and response to treatment with omega 3 acid ethyl esters
Journal of Lipid Research, 2010Co-Authors: Gregory C Shearer, John W. Newman, Theresa L Pedersen, William S HarrisAbstract:The long-chain omega-3 fatty acids (n-3 FA) eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) have beneficial health effects, but the molecular mediators of these effects are not well characterized. Oxygenated n-3 FAs (Oxylipins) may be an important class of mediators. Members of this chemical class include epoxides, alcohols, diols, and ketones, many of which have bioactivity in vitro. Neither the presence of n-3 Oxylipins in human plasma nor the effect of n-3 FA ingestion on their levels has been documented. We measured plasma Oxylipins derived from both the n-3 and n-6 FA classes in healthy volunteers (n = 10) before and after 4 weeks of treatment with prescription n-3 FA ethyl esters (4 g/day). At baseline, EPA and DHA Oxylipins were detected in low (1–50 nM) range, with alcohols > epoxides ≥ diols. Treatment increased n-3 oxylipin levels 2- to 5-fold and reduced selected n-6 Oxylipins by ∼20%. This is the first documentation that endogenous n-3 oxylipin levels can be modulated by n-3 FA treatment in humans. The extent to which the beneficial cardiovascular effects of n-3 FAs are mediated by increased n-3 and/or reduced n-6 oxylipin levels remains to be explored.
