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Obesity is a complex disease highly related to diet and lifestyle and is associated with low amount of thermogenic adipocytes. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to fight overweight and associated comorbidities. Recent studies suggest a role for several fatty acids and their metabolites, called lipokines, in the control of thermogenesis. The purpose of this work was to analyze the role of several lipokines in the control of brown/brite adipocyte formation. We used a validated human adipocyte model, human multipotent adipose-derived stem cell model (hMADS). In the absence of rosiglitazone, hMADS cells differentiate into white adipocytes, but convert into brite adipocytes upon rosiglitazone or prostacyclin 2 (PGI2) treatment. Gene expression was quantified using RT-qPCR and protein levels were assessed by Western blotting. We show here that lipokines such as 12,13-diHOME, 12-HEPE, 15dPGJ2 and 15dPGJ3 were not able to induce browning of white hMADS adipocytes. However, both fatty acid esters of hydroxy fatty acids (FAHFAs), 9-PAHPA and 9-PAHSA potentiated brown key marker UCP1 mRNA levels. Interestingly, CTA2, the stable analog of thromboxane A2 (TXA2), but not its inactive metabolite TXB2, inhibited the rosiglitazone and PGI2-induced browning of hMADS adipocytes. These results pinpoint TXA2 as a lipokine inhibiting brown adipocyte formation that is antagonized by PGI2. Our data open new horizons in the development of potential therapies based on the control of thromboxane A2/prostacyclin balance to combat obesity and associated metabolic disorders.

Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids, and influence cellular function via effects on membrane properties, and also by acting as a precursor pool for lipid mediators. These lipid mediators are formed via activation of pathways involving at least one step of dioxygen-dependent oxidation, and are consequently called oxylipins. Their biosynthesis can be either enzymatically-dependent, utilising the promiscuous cyclooxygenase, lipoxygenase, or cytochrome P450 mixed function oxidase pathways, or nonenzymatic via free radical-catalyzed pathways. The oxylipins include the classical eicosanoids, comprising prostaglandins, thromboxanes, and leukotrienes, and also more recently identified lipid mediators. With the advent of new technologies there is growing interest in identifying these different lipid mediators and characterising their roles in health and disease. This review brings together contributions from some of those at the forefront of research into lipid mediators, who provide brief introductions and summaries of current understanding of the structure and functions of the main classes of nonclassical oxylipins. The topics covered include omega-3 and omega-6 PUFA biosynthesis pathways, focusing on the roles of the different fatty acid desaturase enzymes, oxidized linoleic acid metabolites, omega-3 PUFA-derived specialized pro-resolving mediators, elovanoids, nonenzymatically oxidized PUFAs, and fatty acid esters of hydroxy fatty acids., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recently, new bioactive compounds were identified in olive oil, lipophenols, which are composed of a fatty acid (FA) and a phenolic core, such as HT (HT-FA). However, their bioaccessibility remains unknown. Thus, the present study uncovers the impact of the separate phases of gastrointestinal digestion on the release and stability of HT-FAs from oily matrices under in vitro simulated conditions. Accordingly, it was found that the bioaccessibility of HT derivatives is largely dependent on the type of FA that esterifies HT, as well as the food matrix. Also, the generation of HT-FAs during intestinal digestion was observed, with pancreatin being the enzyme responsible, to a higher extent, for the de novo formation of lipophenolic derivatives. These findings prompt us to identify new applications to oily matrices and their byproducts as potential functional ingredients for the promotion of health, where the possible formation of new lipophenols during digestion should be taken into consideration.

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) are a new endogenous lipid class with recently uncovered interesting biological effects and which have been detected in food of plant and animal origins. Some FAHFAs can improve glucose tolerance and insulin sensitivity, stimulate insulin secretion, and exert anti-inflammatory effects. Other beneficial health effects have also been suggested, in particular against some cancers. FAHFAs could therefore be a potential therapeutic target for the treatment of numerous metabolic disorders such as type II diabetes, hepatic steatosis, cardiovascular diseases and various cancers. Their recent discovery has generated a great interest in the field of human health. This short review aims at bringing together the information available to date in the literature concerning their chemical synthesis, biosynthesis and degradation pathways as well as their potential physio-pathological beneficial effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Since skeletal muscle is a major target for insulin, the aim of this study is to explore for the first time the influence of several FAHFAs in C2C12 myoblasts and in skeletal muscle phenotype in mice. Here, we show that eleven FAHFAs belonging to different families inhibit C2C12 myoblast proliferation. In addition, all FAHFAs decreased mitochondrial cytochrome c oxidase activity without affecting reactive oxygen species production and the mitochondrial network. During C2C12 myoblasts differentiation, we found that two of the most active lipids, 9-PAHPA and 9-OAHPA, did not significantly affect the fusion index and the expression of myosin heavy chains. However, we found that three months' intake of 9-PAHPA or 9-OAHPA in mice increased the expression of more oxidative myosin in skeletal muscle without affecting skeletal muscle mass, number, and mean fiber area, mitochondrial activity, and oxidative stress parameters. In conclusion, our study indicated that the eleven FAHFAs tested decreased the proliferation rate of C2C12 myoblasts, probably through the inhibition of mitochondrial activity. In addition, we found that 9-PAHPA or 9-OAHPA supplementation in mice induced a switch toward a more oxidative contractile phenotype of skeletal muscle. These data suggest that the increase in insulin sensitivity previously described for these two FAHFAs is of muscular origin.

Pistachio ( Pistacia vera L.) is a drought-tolerant species grown under the semiarid conditions of the Mediterranean basin. For this reason, it is essential to make an exhaustive quantification of yield and quality benefits of the kernels because the regulated deficit irrigation will allow significant water savings with a minimum impact on yield while improving kernel quality. The goal of this scientific work was to study the influence of the rootstock, water deficit during pit hardening, and kernel roasting on pistachio ( P. vera , cv. Kerman) fruit yield, fruit size, and kernel content of fatty acids phytoprostanes (PhytoPs) and phytofurans (PhytoFs) for the first time. Water stress during pit hardening did not affect the pistachio yield. The kernel cultivar showed a lower oleic acid and a higher linoleic acid contents than other cultivars. Kernels from plants grafted on the studied rootstocks showed very interesting characteristics. P. integerrima led to the highest percentage of monounsaturated fatty acids. Regarding the plant oxylipins, P. terebinthus led to the highest contents of PhytoPs and PhytoFs (1260 ng/100 g and 16.2 ng/100 g, respectively). In addition, nuts from trees cultivated under intermediate water deficit during pit hardening showed increased contents of the 9-series F 1 -phytoprostanes and ent -16( RS )-9- epi -ST-Δ 14 -10-phytofuran. However, roasting of pistachios led to PhytoP degradation. Therefore, plant cultivar, deficit irrigation, rootstock, and roasting must be considered to enhance biosynthesis of these secondary metabolites. New tools using agricultural strategies to produce hydroSOS pistachios have been opened thanks to the biological properties of these prostaglandin-like compounds linking agriculture, nutrition, and food science technology for further research initiatives.

Lipophenols have been stressed as an emerging class of functional compounds. However, little is known about their diversity. Thus, this study is aimed at developing a new method for the extraction, cleanup, and ultrahigh-performance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UHPLC-ESI-QqQ-MS/MS)-based analysis of the lipophenols derived from hydroxytyrosol (HT): α-linolenic (HT-ALA), linoleic acid (HT-LA), and oleic acid (HT-OA). The method validated provides reliable analytical data and practical applications. It was applied to an array of oily (extra virgin olive oil, refined olive oil, flaxseed oil, grapeseed oil, and margarine) and aqueous (pineapple juice) matrices, nonfortified and fortified with HT. Also, the present work reported the formation of fatty acid esters of HT (HT-FAs) that seem to be closely dependent on the fatty acid profile of the food matrix, encouraging the further exploration of the theoretical basis for the generation of HT-FAs, as well as their contribution to the healthy attributions of plant-based foods.

The discovery of branched fatty acid esters of hydroxy fatty acids (FAHFAs) in humans draw attention of many researches to their biological effects. Although FAHFAs were originally discovered in insects and plants, their introduction into the mammalian realm opened new horizons in bioactive lipid research. Hundreds of isomers from different families have been identified so far and their role in (patho) physiological processes is currently being explored. The family of palmitic acid esters of hydroxy stearic acids (PAHSAs), especially 5-PAHSA and 9-PAHSA regioisomers, stands out in the crowd of other FAHFAs for their anti-inflammatory and anti-diabetic effects. Beneficial effects of PAHSAs have been linked to metabolic disorders such as type 1 and type 2 diabetes, colitis, and chronic inflammation. Besides PAHSAs, a growing family of polyunsaturated FAHFAs exerts mainly immunomodulatory effects and biological roles of many other FAHFAs remain currently unknown. Therefore, FAHFAs represent unique lipid messengers capable of affecting many immunometabolic processes. The objective of this review is to summarize the knowledge concerning the diversity of FAHFAs, nomenclature, and their analysis and detection. Special attention is paid to the total syntheses of FAHFAs, optimal strategies, and to the formation of the stereocenter required for optically active molecules. Biosynthetic pathways of saturated and polyunsaturated FAHFAs in mammals and plants are reviewed together with their metabolism and degradation. Moreover, an overview of biological effects of branched FAHFAs is provided and many unanswered questions regarding FAHFAs are discussed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a new family of endogenous lipids recently discovered. Several studies reported that some FAHFAs have antidiabetic and anti-inflammatory effects. The objective of this study was to explore the impact of two FAHFAs, 9-PAHPA or 9-OAHPA, on the metabolism of mice. C57Bl/6J male mice, 6 weeks old, were divided into 3 groups of 10 mice each. One group received a control diet and the two others groups received the control diet supplemented with 9-PAHPA or 9-OAHPA for 12 weeks. Mouse weight and body composition were monitored throughout the study. Some days before euthanasia, energy expenditure, glucose tolerance and insulin sensitivity were also determined. After sacrifice, blood and organs were collected for relevant molecular, biochemical and histological analyses. Although high intake of 9-PAHPA or 9-OAHPA increased basal metabolism, it had no direct effect on body weight. Interestingly, the 9-PAHPA or 9-OAHPA intake increased insulin sensitivity but without modifying glucose tolerance. Nevertheless, 9-PAHPA intake induced a loss of glucose-stimulated insulin secretion. Surprisingly, both studied FAHFAs induced hepatic steatosis and fibrosis in some mice, which were more marked with 9-PAHPA. Finally, a slight remodeling of white adipose tissue was also observed with 9-PAHPA intake. In conclusion, the long-term high intake of 9-PAHPA or 9-OAHPA increased basal metabolism and insulin sensitivity in healthy mice. However, this effect, highly likely beneficial in a diabetic state, was accompanied by manifest liver damage in certain mice that should deserve special attention in both healthy and pathological studies., Competing Interests: Conflict of interest The authors confirm that this article content has no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The ecological success of diatoms requires a remarkable ability to survive many types of stress, including variations in temperature, light, salinity, and nutrient availability. On exposure to these stresses, diatoms exhibit common responses, including growth arrest, impairment of photosynthesis, production of reactive oxygen species, and accumulation of triacylglycerol (TAG). We studied the production of cyclopentane oxylipins derived from fatty acids in the diatom Phaeodactylum tricornutum in response to oxidative stress. P. tricornutum lacks the enzymatic pathway for producing cyclopentane-oxylipins, such as jasmonate, prostaglandins, or thromboxanes. In cells subjected to increasing doses of hydrogen peroxide (H 2 O 2 ), we detected nonenzymatic production of isoprostanoids, including six phytoprostanes, three F 2t -isoprostanes, two F 3t -isoprostanes, and three F 4t -neuroprostanes, by radical peroxidation of α-linolenic, arachidonic, eicosapentaenoic, and docosahexanoic acids, respectively. H 2 O 2 also triggered photosynthesis impairment and TAG accumulation. F 1t -phytoprostanes constitute the major class detected (300 pmol per 1 million cells; intracellular concentration, ∼4 µm). Only two glycerolipids, phosphatidylcholine and diacylglycerylhydroxymethyl-trimethyl-alanine, could provide all substrates for these isoprostanoids. Treatment of P. tricornutum with nine synthetic isoprostanoids produced an effect in the micromolar range, marked by the accumulation of TAG and reduced growth, without affecting photosynthesis. Therefore, the emission of H 2 O 2 and free radicals upon exposure to stresses can lead to glycerolipid peroxidation and nonenzymatic synthesis of isoprostanoids, inhibiting growth and contributing to the induction of TAG accumulation via unknown processes. This characterization of nonenzymatic oxylipins in P. tricornutum opens a field of research on the study of processes controlled by isoprostanoid signaling in various physiological and environmental contexts in diatoms., (© 2018 American Society of Plant Biologists. All rights reserved.)

This study assesses the effects of cyclic fatty acid monomers (CFAM) from heated vegetable oils on oxidative stress and inflammation. Wistar rats were fed either of these four diets for 28 days: canola oil (CO), canola oil and 0.5% CFAM (CC), soybean oil (SO), and soybean oil and 0.5% CFAM (SC). Markers of oxidative stress and inflammation were determined by micro liquid chromatography tandem mass spectrometry (micro-LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA) kits, respectively. Analysis of variance (ANOVA) for a 2 × 2 factorial design was performed to determine the CFAM and oil effects and interactions between these two factors at P ≤ 0.05. For significant interactions, a post hoc multiple comparison test was performed, i.e., Tukey HSD (honest significant difference) test. CFAM induced higher plasma levels of 15-F 2t -IsoP (CC, 396 ± 43 ng/mL, SC, 465 ± 75 ng/mL vs CO, 261 ± 23 ng/mL and SO, 288 ± 35 ng/mL, P < 0.05). Rats fed the SC diet had higher plasma 2,3-dinor-15-F 2t -IsoP (SC, 145 ± 9 ng/mL vs CC, 84 ± 8 ng/mL, CO, 12 ± 1 ng/mL, and SO, 12 ± 1 ng/mL, P < 0.05), urinary 2,3-dinor-15-F 2t -IsoP (SC, 117 ± 12 ng/mL vs CC, 67 ± 13 ng/mL, CO, 15 ± 2 ng/mL, and SO, 18 ± 4 ng/mL, P < 0.05), and plasma IL-6 (SC, 57 ± 10 pg/mL vs CC, 48 ± 11 pg/mL, CO, 46 ± 9 pg/mL, and SO, 44 ± 4 pg/mL, P < 0.05) than the other three diet groups. These results indicate that CFAM increased the levels of markers of oxidative stress, and those effects are exacerbated by a CFAM-high-linoleic acid diet.

After a brief overview of the biological significance of FAHFAs, the present Minireview highlights the different strategies developed for their chemical syntheses. The term "FAHFAs" has been introduced in 2014 for fatty acyl esters of hydroxyl fatty acids, found in adipocytes, with antidiabetic properties. However, many other natural products contain this type of branched lipids in their structure. This review was then extended to the synthesis of these subunits, even though the length of the lipid chains and the location of the ester linkages are different, since the developed strategies may be applied to the synthesis of "FAHFA"., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2) gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6) and compared to RTT (subjects n = 24) and healthy condition (subjects n = 12). Patients with MECP2 gain-of-function mutations showed increased oxidative stress marker levels (plasma non-protein bound iron, intraerythrocyte non-protein bound iron, F2-isoprostanes, and F4-neuroprostanes), as compared to healthy controls (P ≤ 0.05). Such increases were similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P < 0.0196). Moreover, plasma levels of F2-isoprostanes were significantly correlated (P = 0.0098) with the size of the amplified region. The present work shows unique data in patients affected by MDS. For the first time MECP2 gain-of-function mutations are indicated to be linked to an oxidative damage and related clinical symptoms overlapping with those of MECP2 loss-of-function mutations. A finely tuned balance of MECP2 expression appears to be critical to oxidative stress homeostasis, thus shedding light on the relevance of the redox balance in the central nervous system integrity.

The levels of nitro fatty acids (NO2-FA), such as nitroarachidonic, nitrolinoleic, nitrooleic, and dinitrooleic acids, are elevated under various inflammatory conditions, and this results in different anti-inflammatory effects. However, other multiply nitrated and nitro-oxidized FAs have not been studied so far. Owing to the low concentrations in vivo, NO2-FA analytics usually relies on targeted gas chromatography-tandem mass spectrometry (MS/MS) or liquid chromatography-MS/MS, and thus require standard compounds for method development. To overcome this limitation and increase the number and diversity of analytes, we performed in-depth mass spectrometry (MS) profiling of nitration products formed in vitro by incubating fatty acids with NO2BF4, and ONOO(-). The modified fatty acids were used to develop a highly specific and sensitive multiple reaction monitoring LC-MS method for relative quantification of 42 different nitrated and oxidized species representing three different groups: singly nitrated, multiply nitrated, and nitro-oxidized fatty acids. The method was validated in in vitro nitration kinetic studies and in a cellular model of nitrosative stress. NO2-FA were quantified in lipid extracts from 3-morpholinosydnonimine-treated rat primary cardiomyocytes after 15, 30, and 70 min from stress onset. The relatively high levels of dinitrooleic, nitroarachidonic, hydroxynitrodocosapenataenoic, nitrodocosahexaenoic, hydroxynitrodocosahexaenoic, and dinitrodocosahexaenoic acids confirm the presence of multiply nitrated and nitro-oxidized fatty acids in biological systems for the first time. Thus, in vitro nitration was successfully used to establish a targeted LC-MS/MS method that was applied to complex biological samples for quantifying diverse NO2-FA. Graphical Abstract Schematic representation of study design which combined in vitro nitration of different fatty acids, MS/MS characterization and optimization of MRM method for relative quantification, which was applied to follow dynamic of fatty acid nitration in cellular model of SIN-1 treated cardiomyoctes.

Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids, and influence cellular function via effects on membrane properties, and also by acting as a precursor pool for lipid mediators. These lipid mediators are formed via activation of pathways involving at least one step of dioxygen-dependent oxidation, and are consequently called oxylipins. Their biosynthesis can be either enzymatically-dependent, utilising the promiscuous cyclooxygenase, lipoxygenase, or cytochrome P450 mixed function oxidase pathways, or nonenzymatic via free radical-catalyzed pathways. The oxylipins include the classical eicosanoids, comprising prostaglandins, thromboxanes, and leukotrienes, and also more recently identified lipid mediators. With the advent of new technologies there is growing interest in identifying these different lipid mediators and characterising their roles in health and disease. This review brings together contributions from some of those at the forefront of research into lipid mediators, who provide brief introductions and summaries of current understanding of the structure and functions of the main classes of nonclassical oxylipins. The topics covered include omega-3 and omega-6 PUFA biosynthesis pathways, focusing on the roles of the different fatty acid desaturase enzymes, oxidized linoleic acid metabolites, omega-3 PUFA-derived specialized pro-resolving mediators, elovanoids, nonenzymatically oxidized PUFAs, and fatty acid esters of hydroxy fatty acids.

TREK-1 is a mechanosensitive channel activated by polyunsaturated fatty acids (PUFAs). Its activation is supposed to be linked to changes in membrane tension following PUFAs insertion. Here, we compared the effect of 11 fatty acids and ML402 on TREK-1 channel activation using the whole cell and the inside-out configurations of the patch-clamp technique. Firstly, TREK-1 activation by PUFAs is variable and related to the variable constitutive activity of TREK-1. We observed no correlation between TREK-1 activation and acyl chain length or number of double bonds suggesting that the bilayer-couple hypothesis cannot explain by itself the activation of TREK-1 by PUFAs. The membrane fluidity measurement is not modified by PUFAs at 10 µM. The spectral shift analysis in TREK-1-enriched microsomes indicates a KD,TREK1 at 44 µM of C22:6 n-3. PUFAs display the same activation and reversible kinetics than the direct activator ML402 and activate TREK-1 in both whole-cell and inside-out configurations of patch-clamp suggesting that the binding site of PUFAs is accessible from both sides of the membrane, as for ML402. Finally, we proposed a two steps mechanism: first, insertion into the membrane, with no fluidity or curvature modifications at 10 µM, and then interaction with TREK-1 channel to open it. [ABSTRACT FROM AUTHOR]

The anti-atherogenic effects of omega 3 fatty acids, namely eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are well recognized but the impact of dietary intake on bioactive lipid mediator profiles remains unclear. Such a profiling effort may offer novel targets for future studies into the mechanism of action of omega 3 fatty acids. The present study aimed to determine the impact of DHA supplementation on the profiles of polyunsaturated fatty acids (PUFA) oxygenated metabolites and to investigate their contribution to atherosclerosis prevention. A special emphasis was given to the non-enzymatic metabolites knowing the high susceptibility of DHA to free radical-mediated peroxidation and the increased oxidative stress associated with plaque formation. Atherosclerosis prone mice (LDLR(-/-)) received increasing doses of DHA (0, 0.1, 1 or 2% of energy) during 20 weeks leading to a dose-dependent reduction of atherosclerosis (R(2) = 0.97, p = 0.02), triglyceridemia (R(2) = 0.97, p = 0.01) and cholesterolemia (R(2) = 0.96, p

Several families of naturally occurring fatty acid conjugates are presented. Chemical and chemoenzymatic syntheses are exemplified for fatty acid conjugates with (poly)phenols, glycerol, hydroxyfatty acids, aminoacids and small peptides. [ABSTRACT FROM AUTHOR]

γ‐Linolenic (GLA; C18 : 3 n‐6), dihomo‐γ‐linolenic (DGLA; C20 : 3 n‐6) and stearidonic (SDA; C18 : 4 n‐3) acids are found in several botanic and marine oils and are sustainable sources of omega‐6 and omega‐3 polyunsaturated fatty acids (PUFAs). During oxidative stress (pollution, UV, hydric or nutrient stress), lipid peroxidation occurred to produce non‐enzymatic oxylipins named phytoprostanes (PhytoPs). We report herein the first syntheses of six non‐enzymatic PUFA metabolites originated from GLA, DGLA and SDA peroxidation. Our syntheses follow a straightforward synthetic pathway from enantiopure common intermediates (lactol or monoacetates), further used Horner‐Wadsworth‐Emmons and Wittig reactions to set up the side chains, and Corey‐Bakshi‐Shibata enantioselective reduction. Our strategy once again proved to be highly efficient as the compounds were obtained after only 4 to 12 consecutive steps, starting from previously prepared intermediates, and in a range from 6.5 to 41.5 % yield. [ABSTRACT FROM AUTHOR]

The identification of bacterial metabolites produced by the microbiota is a key point to understand its role in human health. Among them, lipo-amino acids (LpAA), which are able to cross the epithelial barrier and to act on the host, are poorly identified. Structural elucidation of few of them was performed by high-resolution tandem mass spectrometry based on electrospray combined with selective ion dissociations reach by collision-induced dissociation (CID). The negative ions were used for their advantages of yielding only few fragment ions sufficient to specify each part of LpAA with sensitivity. To find specific processes that help structural assignment, the negative ion dissociations have been scrutinized for an LpAA: the N-palmitoyl acyl group linked to glutamic acid (C16Glu). The singular behavior of [C16Glu-H]¯ towards CID showed tenth product ions, eight were described by expected fragment ions. In contrast, instead of the expected product ions due to CONH-CH bond cleavage, an abundant complementary dehydrated glutamic acid and fatty acid anion pair were observed. Specific to glutamic moiety, they were formed by a stepwise dissociation via molecular isomerization through ion–dipole formation prior to dissociation. This complex dissociated by partner splitting either directly or after inter-partner proton transfer. By this pathway, surprising regeneration of deprotonated fatty acid takes place. Such regeneration is comparable to that occurred from dissociation to peptides containing acid amino-acid. Modeling allow to confirm the proposed mechanisms explaining the unexpected behavior of this glutamate conjugate. [ABSTRACT FROM AUTHOR]

Purpose: Fatty acid esters of hydroxy fatty acids (FAHFAs) are a large family of endogenous bioactive lipids. To date, most of the studied FAHFAs are branched regioisomers of Palmitic Acid Hydroxyl Stearic Acid (PAHSA) that were reported to possess anti-diabetic and anti-inflammatory activity in humans and rodents. Recently, we have demonstrated that 9-PAHPA or 9-OAHPA intake increased basal metabolism and enhanced insulin sensitivity in healthy control diet-fed mice but induced liver damage in some mice. The present work aims to explore whether a long-term intake of 9-PAHPA or 9-OAHPA may have similar effects in obesogenic diet-fed mice. Methods: C57Bl6 mice were fed with a control or high fat-high sugar (HFHS) diets for 12 weeks. The HFHS diet was supplemented or not with 9-PAHPA or 9-OAHPA. Whole-body metabolism was explored. Glucose and lipid metabolism as well as mitochondrial activity and oxidative stress status were analyzed. Results: As expected, the intake of HFHS diet led to obesity and lower insulin sensitivity with minor effects on liver parameters. The long-term intake of 9-PAHPA or 9-OAHPA modulated favorably the basal metabolism and improved insulin sensitivity as measured by insulin tolerance test. On the contrary to what we have reported previously in healthy mice, no marked effect for these FAHFAs was observed on liver metabolism of obese diabetic mice. Conclusion: This study indicates that both 9-PAHPA and 9-OAHPA may have interesting insulin-sensitizing effects in obese mice with lower insulin sensitivity. [ABSTRACT FROM AUTHOR]

Docosahexaenoic acid (DHA), an abundant fatty acid in the brain, is susceptible to auto‐oxidation in situ and releases metabolites such as F4‐neuroprostane (4‐F4t‐NeuroP). The presence of 4‐F4t‐NeuroP in the brain is not well explored. In this study, 4‐F4t‐NeuroP was introduced into neuroblastoma cells (SH‐SY5Y) and, by in vivo infusion, into rodents. Targeted lipidomic analysis of liver and brain tissues shows significant elevation of anti‐inflammatory hydroxylated DHA metabolites and an isomer of neuroprotectin D1, suggesting potential beneficial bioactivities of 4‐F4t‐NeuroP. Additionally, 4‐F4t‐NeuroP treatment in SH‐SY5Y cells and primary neuronal culture consistently upregulates the transcriptional level of the antioxidant enzyme heme oxygenase‐1, but the effect is reduced when 4‐F4t‐NeuroP is further oxidized. Our data suggest that 4‐F4t‐NeuroP could be neuroprotective in the native state but may have disadvantageous bioactivity when oxidized extensively. [ABSTRACT FROM AUTHOR]

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis. [ABSTRACT FROM AUTHOR]

Abstract: After a brief overview of the biological significance of FAHFAs, the present Minireview highlights the different strategies developed for their chemical syntheses. The term “FAHFAs” has been introduced in 2014 for fatty acyl esters of hydroxyl fatty acids, found in adipocytes, with antidiabetic properties. However, many other natural products contain this type of branched lipids in their structure. This review was then extended to the synthesis of these subunits, even though the length of the lipid chains and the location of the ester linkages are different, since the developed strategies may be applied to the synthesis of “FAHFA”. [ABSTRACT FROM AUTHOR]

Phytoprostanes (PhytoPs) are produced in plants and seeds by non-enzymatic free-radical pathways from α-linolenic acid (ALA). We recently highlighted the formation of a new class of compounds from ALA, namely phytofurans (PhytoFs). In biological samples, these compounds are produced as mixtures, and their analytical exploration remains challenging without their pure synthetic forms. The synthesis of some phytofurans is described here. The use of an enantiomerically enriched intermediate allowed for the first time access to both families of PhytoFs, the alkenyl and enediol classes. For the first time, PhytoF metabolites have been quantitated in the liver tissue of rats treated with an ALA-rich flaxseed or flaxseed oil diet. [ABSTRACT FROM AUTHOR]

The enantioselective total synthesis of the highly reactive isoketal 5-D2-IsoK was accomplished. The synthesis involved construction of the isoketal core by an organocatalyzed Michael addition between ideally functionalized aldehyde and nitroolefin partners with good enantioselectivity. The lateral chains were branched through Horner-Wadsworth-Emmons and Wittig olefinations to provide flexibility, whereas the final deprotection and oxidation steps were performed under mild conditions to avoid known racemization and/or degradation of the very sensitive isoketal. [ABSTRACT FROM AUTHOR]

Neurofurans (NeuroFs) and dihomo-isofurans (dihomo-IsoFs) are produced in vivo by non-enzymatic free-radical pathways from docosahexaenoic and adrenic acids, respectively. As these metabolites are produced in minute amounts, their analyses in biological samples remain challenging. Syntheses of neurofuran and dihomo-isofurans described are based on a pivotal strategy, thanks to an enantiomerically enriched intermediate, which allowed, for the first time, access to both families: the alkenyl and enediol. Owing to this formation, quantitation of specific NeuroF and dihomo-IsoFs in biological samples was attainable. [ABSTRACT FROM AUTHOR]

Carbonyl and oxidative stress play a substantial role in various neurodegenerative diseases such as Alzheimer's Disease, Parkinsonism, and Age-related Macular Degeneration (AMD). In retinal pathologies, both mechanisms are involved in the transformation of all- trans-retinal (A tR, reactive aldehyde) into bis-retinoid A2E. Since an accumulation of A tR and A2E contributes to photoreceptor apoptosis, we designed and synthesized a series of O-alkylated resorcinol derivatives featuring enhanced anti-carbonyl-stress properties. Additionally, these phenolic structures are linked to a polyunsaturated fatty acid such as docosahexaenoic acid (C22:6 n-3; DHA) or to a lysophosphatidylcholine-DHA conjugate, in order to specifically increase their bioavailability, and thus, to target the retina. Selective syntheses of phloroglucinol-DHA, resveratrol-DHA, and phloroglucinol-DHA-PC (PC = phosphatidylcholine) conjugates using silyl protecting group strategies are presented, along with results of testing that demonstrate their ability to lower A tR toxicity in ARPE-19 cell lines. [ABSTRACT FROM AUTHOR]

The growing importance of lipidomics, and the interest of non-enzymatic metabolites of polyunsaturated fatty acids (PUFAs) prompted us to initiate the synthesis of novel dihomo-IsoF compounds. Such metabolites of adrenic acid, the main PUFA in white matter, were synthesized using a divergent approach based on an orthoester cyclization. LC-MS/MS investigation on pig brains showed the potential of this novel biomarker for the first time, as a powerful new tool for brain lipid peroxidation assessment. [ABSTRACT FROM AUTHOR]

A wide variety of metabolic products of polyunsaturated fatty acids is of paramount importance for improving our medical knowledge in the field of oxidized lipids. Two novel metabolites of n-3 polyunsaturated fatty acids, 8-F3t-IsoP and 10-F4t-NeuroP as well as a deuterated derivative thereof were synthesized based on an acetylenic intermediate. An original approach achieved lateral chain insertion of 8-F3t-IsoP by a ring-closing alkyne metathesis/semi-reduction strategy together with a temporary tether. [ABSTRACT FROM AUTHOR]

Abstract: The anti-atherogenic effects of omega 3 fatty acids, namely eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are well recognized but the impact of dietary intake on bioactive lipid mediator profiles remains unclear. Such a profiling effort may offer novel targets for future studies into the mechanism of action of omega 3 fatty acids. The present study aimed to determine the impact of DHA supplementation on the profiles of polyunsaturated fatty acids (PUFA) oxygenated metabolites and to investigate their contribution to atherosclerosis prevention. A special emphasis was given to the non-enzymatic metabolites knowing the high susceptibility of DHA to free radical-mediated peroxidation and the increased oxidative stress associated with plaque formation. Atherosclerosis prone mice (LDLR−/−) received increasing doses of DHA (0, 0.1, 1 or 2% of energy) during 20 weeks leading to a dose-dependent reduction of atherosclerosis (R2 = 0.97, p = 0.02), triglyceridemia (R2 = 0.97, p = 0.01) and cholesterolemia (R2 = 0.96, p<0.01). Targeted lipidomic analyses revealed that both the profiles of EPA and DHA and their corresponding oxygenated metabolites were substantially modulated in plasma and liver. Notably, the hepatic level of F4-neuroprostanes, a specific class of DHA peroxidized metabolites, was strongly correlated with the hepatic DHA level. Moreover, unbiased statistical analysis including correlation analyses, hierarchical cluster and projection to latent structure discriminate analysis revealed that the hepatic level of F4-neuroprostanes was the variable most negatively correlated with the plaque extent (p<0.001) and along with plasma EPA-derived diols was an important mathematical positive predictor of atherosclerosis prevention. Thus, oxygenated n-3 PUFAs, and F4-neuroprostanes in particular, are potential biomarkers of DHA-associated atherosclerosis prevention. While these may contribute to the anti-atherogenic effects of DHA, further in vitro investigations are needed to confirm such a contention and to decipher the molecular mechanisms of action. [ABSTRACT FROM AUTHOR]

Cerebral adrenoleukodystrophy (ALD) is a rare neuroinflammatory disorder characterized by progressive demyelination. Mutations within the ABCD1 gene result in very long-chain fatty acid (VLCFA) accumulation within the peroxisome, particularly in the brain. While this VLCFA accumulation is known to be the driving cause of the disease, oxidative stress can be a contributing factor. For patients with early cerebral disease, allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care, and this can be supported by antioxidants. To evaluate the involvement of fatty acid oxidation in the disease, F2-isoprostanes (F2-IsoPs), F2-dihomo-isoprostanes (F2-dihomo-IsoPs) and F4-neuroprostanes (F4-NeuroPs)—which are oxygenated metabolites of arachidonic (ARA), adrenic (AdA) and docosahexaenoic (DHA) acids, respectively—in plasma samples from ALD subjects (n = 20)—with various phenotypes of the disease-were measured. Three ALD groups were classified according to patients with: (1) confirmed diagnosis of ALD but without cerebral disease; (2) cerebral disease in early period post-HSCT (<100 days post-HSCT) and on intravenous N-acetyl-L-cysteine (NAC) treatment; (3) cerebral disease in late period post-HSCT (beyond 100 days post-HSCT) and off NAC therapy. In our observation, when compared to healthy subjects (n = 29), in ALD (i), F2-IsoPs levels were significantly (p < 0.01) increased in all patients, with the single exception of the early ALD and on NAC subjects; (ii) significant elevated (p < 0.0001) amounts of F2-dihomo-IsoPs were detected, with the exception of patients with a lack of cerebral disease; (iii), a significant increase (p < 0.003) in F4-NeuroP plasma levels was detected in all ALD patients. Moreover, F2-IsoPs plasma levels were significantly higher (p = 0.038) in early ALD in comparison to late ALD stage, and F4-NeuroPs were significantly lower (p = 0.012) in ALD subjects with a lack of cerebral disease in comparison to the late disease stage. Remarkably, plasma amounts of all investigated isoprostanoids were shown to discriminate ALD patients vs. healthy subjects. Altogether, isoprostanoids are relevant to the phenotype of X-ALD and may be helpful in predicting the presence of cerebral disease and establishing the risk of progression. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative damage has been reported in Rett syndrome (RTT), a pervasive development disorder mainly caused up to 95% of cases by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. We have recently synthesized F2-Dihomo-isoprostanes (F2-Dihomo-IsoP), peroxidation products from adrenic acid (C22:4 n − 6, AdA), a known component of myelin, and tested the potential value of F2-Dihomo-IsoPs as a novel disease marker and its relationship with clinical presentation, and disease progression. F2-Dihomo-IsoPs were determined by a gas chromatography/negative ion chemical ionization tandem mass spectrometry. The ent-7(RS)-F2t-Dihomo-IsoP and 17-F2t-Dihomo-IsoP were used as reference standards. The measured ions were the product ions at m/z 327 derived from the [M − 181]− precursor ions (m/z 597) produced from both the derivatized ent-7(RS)-F2t-Dihomo-IsoP and 17-F2t-Dihomo-IsoP. Average plasma F2-Dihomo-IsoP levels in RTT were about 1 order of magnitude higher than in healthy controls, being higher in typical RTT as compared to RTT variants, with a remarkable increase of about 2 orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. These data indicate for the first time that quantification of F2-Dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT. [Copyright &y& Elsevier]

15-F2t-isoprostane (15-F2t-IsoP), an oxidation product of arachidonic acid (AA), affects vascular and platelet function; however, the bioactivity of other fatty acids oxidation products is unknown. This paper studied rat aortic vascular reactivity and human platelet aggregation in response to 14 oxidation products of AA, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and αα-linolenic acid (ALA) compared with 15-F2t-IsoP. It also compared the F2t-IsoPs profile in human platelets. EPA-derived 15-F3t-IsoP constricted rat aorta less than 15-F2t-IsoP, but none of the other oxidation products affected vascular reactivity. Only 15-F2t-IsoP (10−−4 M) directly affected platelet aggregation. 15-F3t-IsoP, ent-16-F1-phytoprostane (from ALA) and isofurans A and B (from AA) inhibited reversible aggregation to U46619. Unlike plasma, the platelet profile of F2-IsoP showed that 8-F2t-IsoP were higher than 15-F2t-IsoP. Unlike 15-F2t-IsoP, the test compounds derived from fatty acids oxidation did not affect vascular or platelet function. Elevated platelet 8-F2t-IsoP could limit 15-F2t-IsoP-induced aggregation under conditions of oxidant stress. [ABSTRACT FROM AUTHOR]

Isoprostanes (IsoPs) are a complex family of compounds produced, in vivo, from peroxidation of polyunsaturated fatty acids (AA, DHA, EPA, α-linolenic) via a free-radical-catalyzed mechanism. Carbocyclic annulations are extremely important reactions and the stereocontrolled intramolecular free-radical cyclization has emerged as a powerful tool for carbon–carbon bond formation in synthetic chemistry. The hex-5-enyl radical cyclization is the most well-known for the synthesis of cyclopentane rings.After a short review of the literature, concerning the total synthesis of isoprostanes and intermediates, we will present our own contributions on the preparation of chiral cyclopentane rings from glucose leading to new isoprostanes. This study allowed us to control the cyclization outcome to yield the all-syn and/or syn-anti-syn precursors which permit us to the total synthesis of a large set of iso-, neuro-, and phytoprostanes. [Copyright &y& Elsevier]

A recent study has reported that the administration during gestation of a highly rancid hoki liver oil, obtained by oxidation through sustained exposure to oxygen gas and incident light for 30 days, causes newborn mortality in rats. This effect was attributed to lipid hydroperoxides formed in the omega-3 long-chain polyunsaturated fatty acid-rich oil, while other chemical changes in the damaged oil were overlooked. In the present study, the oxidation condition employed to damage the hoki liver oil was replicated, and the extreme rancidity was confirmed. A detailed analysis of temporal chemical changes resulting from the sustained oxidative challenge involved measures of eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) omega-3 oil oxidative quality (peroxide value, para-anisidine value, total oxidation number, acid value, oligomers, antioxidant content, and induction time) as well as changes in fatty acid content, volatiles, isoprostanoids, and oxysterols. The chemical description was extended to refined anchovy oil, which is a more representative ingredient oil used in omega-3 finished products. The present study also analyzed the effects of a different oxidation method involving thermal exposure in the dark in contact with air, which is an oxidation condition that is more relevant to retail products. The two oils had different susceptibility to the oxidation conditions, resulting in distinct chemical oxidation signatures that were determined primarily by antioxidant protection as well as specific methodological aspects of the applied oxidative conditions. Unique isoprostanoids and oxysterols were formed in the over-oxidized fish oils, which are discussed in light of their potential biological activities. [ABSTRACT FROM AUTHOR]

Lipid mediators play an important role as biological messengers involved in inflammatory processes. Deriving from different polyunsaturated fatty acids, endogenously built mediators featuring both pro- and anti-inflammatory properties as well as pro-resolving lipid mediators and their biological precursors have been investigated. A newly developed method using chiral chromatography-tandem mass spectrometry on human plasma has demonstrated its suitability for the simultaneous determination of prostaglandins, lipoxins, D-series derived resolvins as well as protectins, maresin 1, leukotriene B4 and several precursors of them in order to yield information about metabolic pathways. Due to the matrix complexity, a solid phase extraction method using an octadecyl-modified silica gel cartridge was carried out. The developed method allows the determination of 34 analytes in 25 min showing enough selectivity as well as precision and accuracy (≤15% relative standard deviation, ≤15% relative error) in the calibration range of 0.1–10 ng mL −1 or 0.2–20 ng mL −1 depending on the analytes. Stability of the analytes in plasma has been demonstrated for at least 3 h at room temperature, 72 h in the autosampler and 60 days in the freezer at −80 °C. This method has been validated and shown its suitability for the determination of all studied analytes in human plasma samples. [ABSTRACT FROM AUTHOR]

Phytoprostanes (PhytoP's) are formed in higher plants from α-linolenic acid via a nonenzymatic free radical-catalyzed pathway and act as endogenous mediators capable of protecting cells from damage under various conditions related to oxidative stress. Humans are exposed to PhytoP's, as they are present in relevant quantities in vegetable food and pollen. The uptake of PhytoP's through the olfactory epithelium of the nasal mucosa, upon pollen grain inhalation, is of interest as the intranasal pathway is regarded as a direct route of communication between the environment and the brain. On this basis, we sought to investigate the potential activities of PhytoP's on immature cells of the central nervous system, which are particularly susceptible to oxidative stress. In neuroblastoma SH-SY5Y cells, used as a model for undifferentiated neurons, B1-PhytoP's, but not F1-PhytoP's, increased cell metabolic activity and protected them from oxidant damage caused by H2O2. Moreover, B1-PhytoP's induced a moderate depolarization of the mitochondrial inner membrane potential. These effects were prevented by the PPAR-γ antagonist GW9662. When SH-SY5Y cells were induced to differentiate toward a more mature phenotype, they became resistant to B1-PhytoP activities. B1-PhytoP's also influenced immature cells of an oligodendroglial line, as they increased the metabolic activity of oligodendrocyte progenitors and strongly accelerated their differentiation to immature oligodendrocytes, through mechanisms at least partially dependent on PPAR-γ activity. However, B1-PhytoP's did not protect oligodendrocyte progenitors against oxidant injury. Taken together, these data suggest that B1-PhytoP's, through novel mechanisms involving PPAR-γ, can specifically affect immature brain cells, such as neuroblasts and oligodendrocyte progenitors, thereby conferring neuroprotection against oxidant injury and promoting myelination. [ABSTRACT FROM AUTHOR]

• Styrian oil pumpkin seeds contain minute amounts of α-linolenic acid. • Down-stream processing results either in conditioned or cold-pressed seed oils. • High-tech lipidomics identified α-linolenic acid and oxylipin products. • Bioactive phytoprostanes are found in Styrian oil pumpkin seeds and oils. • Bioactive phytofurans were found in Styrian pumpkin seed oils only. Styrian pumpkin seed oil is a conditioned green-colored oil renowned for nutty smell and taste. Due to α-linolenic acid (ALA) contents below 1% of total fatty acids and the prospect of nutritional health claims based on its potential oxidation products, we investigated the fate of ALA and product oxylipins in the course of down-stream processing of seeds and in oils. Lipidomic analyses with Lipid Data Analyzer 2.8.1 revealed: Processing did not change (1) main fatty acid composition in the oils, (2) amounts of triacylglycerol species, (3) structures of triacylglycerol molecular species containing ALA. (4) Minor precursor ALA in fresh Styrian and normal pumpkins produced 6 product phytoprostanes in either cultivar, quantitatively more in the latter. (5) In oil samples 7 phytoprostanes and 2 phytofurans were detected. The latter two are specific for their presence in pumpkin seed oils, of note, quantitatively more in conditioned oils than in cold-pressed native oils. [ABSTRACT FROM AUTHOR]

• Detection by the first time of phytoprostanes and phytofurans content in chocolates. • Dark chocolates are featured by differential phytoprostanes and phytofurans profile. • The percentage of cocoa is not a critical factor for oxylipins generation in dark chocolate. • Plant oxylipins are not dependent of FAMEs levels. • PCA separates significantly dark chocolates on their content in plant oxylipins. Phytoprostanes (PhytoPs) and phytofurans (PhytoFs) are plant oxylipins (isoprostane-prostaglandin-like compounds) formed by the free radical-catalyzed oxidation of α-linolenic acid (ALA, C18:3, n-3). These oxylipins have been previously described in an array of plant-based foods with similar concentrations as phenolics in some fruits and vegetables, but their occurrence in dark chocolate has not been addressed so far, neither their content nor the influence of cocoa percent and fatty acid composition on the generation of PhytoPs and PhytoFs, to establish new assays in order to boost the dietary burden of these new bioactive compounds, provided by natural plant-based foods intake. In this regard, 80 dark chocolate samples with cocoa (Theobroma cacao L.) content of up to 100% were assessed on their PhytoP and PhytoF profile. These target analytes were isolated using a dispersive liquid–liquid extraction followed by a solid-phase clean-up of the extracts, and quantified using a UHPLC coupled to a triple quadrupole-MS/MS detection system. The content of PhytoPs and PhytoFs in the array of chocolates analyzed oscillated from 2.45 to 1192.43 ng/g fw and from 144.57 to 840.19 ng/g fw, respectively. The profile of these metabolites was studied in conjunction with the fatty acid methyl esters (FAMEs) content and the percentage of cocoa; however, no relationship between PhytoPs and PhytoFs and FAMEs content nor the cocoa percentage was observed. The assessment of dark chocolates on the content of PhytoPs and PhytoFs is of great importance as there is increasing scientific evidence on their immunomodulatory and inflammatory activity, as well as their role as preventive agents against oxidative stress that could confer this food an additional interest to consumers. [ABSTRACT FROM AUTHOR]

• Maximal modulation of n3-PUFA and their oxylipins by long chain n3-PUFA feeding. • Apparent PD1 signals in LC–MS/MS analysis seem to result from isobaric interference. • Feeding causes increase of n3-isoprostanes / decrease of n6-isoprostanes consistent with modulation of their parent PUFA. • Dietary n3-PUFA did not improve overall renal function following ischemic reperfusion injury. • Moderate protection of tubular function by dietary n3-PUFA and its oxylipins. Acute kidney injury (AKI) is an important complication after major surgery and solid organ transplantation. Here, we present a dietary omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation study to investigate whether pre-treatment can reduce ischemia induced AKI in mice. Male 12–14 week old C57BL/6 J mice received a linoleic acid rich sunflower oil based standard diet containing 10 % fat (STD) or the same diet enriched with n3-PUFA (containing 1 % EPA and 1 % DHA) (STD + n3). After 14 days of feeding bilateral 30 min renal ischemia reperfusion injury (IRI) was conducted to induce AKI and mice were sacrificed at 24 h. Serum creatinine and blood urea nitrogen (BUN) as well as liver enzyme elevation were measured. Kidney damage was analyzed by histology and immunohistochemistry. Furthermore, pro-inflammatory cytokines (IL-6, MCP-1) were determined by qPCR. FA and oxylipin pattern were quantified in blood and kidneys by GC-FID and LC–MS/MS, respectively. n3-PUFA supplementation prior to renal IRI increased systemic and renal levels of n3-PUFA. Consistently, eicosanoids and other oxylipins derived from n3-PUFA including precursors of specialized pro-resolving mediators were elevated while n6-PUFA derived mediators such as pro-inflammatory prostaglandins were decreased. Feeding of n3-PUFA did not attenuate renal function impairment, morphological renal damage and inflammation characterized by IL-6 and MCP-1 elevation or neutrophil infiltration. However, the tubular transport marker alpha-1 microglobulin (A1M) was significantly higher expressed in proximal tubular epithelial cells of STD + n3 compared to STD fed mice. This indicates a better integrity of proximal tubular epithelial cells and thus significant protection of tubular function. In addition, heme oxygenase-1 (HO-1) which protects tubular function was also up-regulated in the treatment group receiving n3-PUFA supplemented chow. We showed that n3-PUFA pre-treatment did not affect overall renal function or renal inflammation in a mouse model of moderate ischemia induced AKI, but tubular transport was improved. In conclusion, dietary n3-PUFA supplementation altered the oxylipin levels significantly but did not protect from renal function deterioration or attenuate ischemia induced renal inflammation. [ABSTRACT FROM AUTHOR]

• Chilean Gevuina avellana nuts were studied for lipid and phenolic composition. • Content and composition of phytochemicals was assessed before and after roasting. • Oleic and 7-hexadecenoic acids were the main fatty acids quantified. • Phytoprostanes and phytofurans were detected in G. avellana for the first time. Roasted cotyledons of the Chilean hazelnut (Gevuina avellana) are appreciated as snacks. The aim of our work was to assess the fatty acid, oxylipin and phenolic composition using gas chromatography (GC) coupled to mass spectrometry (MS), ultra- high performance liquid chromatography (UHPLC) coupled to MS and HPLC coupled to diode array detector (HPLC-DAD). Additionally, various antioxidant activities were assessed. The inhibition of α-glucosidase, α-amylase, lipase, cyclooxygenases-1 and -2 (COX-1/COX-2), and lipoxygenase was determined. The main fatty acids were oleic and 7-hexadecenoic acids. Eight phytoprostanes and three phytofurans were identified and quantified. Hydroxybenzoic and hydroxycinnamic acids were the main phenolic compounds. Oils showed antioxidant activity determined by EPR, and inhibition of COX-1/COX-2. The statistical analysis showed that the roasting does not affect the composition of the samples. The occurrence of oxylipins in this species is reported for the first time. Chilean hazelnuts can be considered a source of health promoting compounds. [ABSTRACT FROM AUTHOR]

• Cytochrome P450 monooxygenases give rise to the generation of cis- epoxy-PUFA (mixture of R,S- and S,R -enantiomers). • Non-enzymatic chemical peroxidation forms cis - and trans -epoxy-PUFA (mixture of R,R - and S,S- enantiomers). • We demonstrate that trans -epoxy-PUFA and the trans/cis- epoxy-PUFA ratio could be a new biomarker of lipid peroxidation. • Five oxidative stress models were used including of three human cell lines as well as Caenorhabditis elegans and a mice. • Correlations of the trans/cis- epoxy-PUFA ratios with the Isoprostane levels were found in all investigated cell lines and C. elegans. In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all- cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis- epoxy-PUFA (mixture of R,S- and S,R -enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis - and trans -epoxy-PUFA (mixture of R,R - and S,S- enantiomers). Here, we investigated for the first time trans -epoxy-PUFA and the trans/cis- epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert -butyl hydroperoxide (t -BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis- epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis -epoxy-PUFA ratio in response to the applied t -BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cis- epoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis- epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation. [ABSTRACT FROM AUTHOR]