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Organisms adapt to their environments by adjusting their biochemistry and physiology; such adaptation is limited by resource availability and physiological constraints. The freshwater crustacean Daphnia magna inhabits a wide range of environments and must survive and reproduce within a range of temperatures. One limit to low-temperature adaptation is thought to be the availability of unsaturated fatty acids necessary to maintain proper fluidity of cellular membranes. D. magna maintained at 10 ºC on a diet poor in unsaturated fatty acids have been observed to produce clutches that fail to develop. However, this has not been observed on a diet rich in unsaturated fatty acids or at a higher temperature regardless of diet. Clonal variation is commonly seen in D. magna life history traits, including heat tolerance, and was also investigated. D. magna were kept at two temperatures and fed two algal diets that differ in unsaturated fatty acid content. To investigate the role of fatty acid composition on the reproductive success of D. magna, fatty acids were extracted from adults and eggs. Of the twenty-one clones studied, no clonal variation was seen in the ability to produce successful clutches at 10 °C on a diet poor in unsaturated fatty acids. Gas chromatography revealed significant differences in 20-carbon fatty acids and suggest a parent-offspring conflict over a limited resource.

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No / Age is characterized by deficits in synaptic function identified by decreased performance of aged animals in spatial learning tasks and reduced ability of animals to sustain long-term potentiation (LTP). Several cellular and molecular events are correlated with these deficits, many of which are indicative of cell stress. Thus there is evidence of age-related neuroinflammatory stress and oxidative stress and these have been linked with microglial activation which is likely to be primarily responsible for the age-related increase in production of proinflammatory cytokines and reactive oxygen species. It is significant that agents which decrease microglial activation are commonly associated with restoration of function. We set out to examine whether the n-3 polyunsaturated fatty acid docosapentaenoic acid (DPA), which is a metabolite of eicosapentaenoic acid (EPA), could modulate the age-related increase in microglial activation and the associated increase in oxidative changes and therefore impact on synaptic function in aged rats. We demonstrate that DPA possesses neurorestorative effects and is capable of downregulating microglial activation. The data show that it also decreases the coupled activation of sphingomyelinase and caspase 3, probably as a result of its ability to decrease age-related oxidative changes, and consequently attenuates the age-related decrease in spatial learning and LTP.

No / Nutritionally important PUFAs (polyunsaturated fatty acids) mediate some of their bioactivities through formation of oxygenated metabolites. These bioactive lipids are formed by COX (cyclo-oxygenase), LOX (lipoxygenase) and cytochrome-P450-catalysed reactions, as well as non-enzymatic lipid peroxidation. These reactions produce numerous species, some of which can be formed through more than one pathway. MS-based lipidomics offers the selectivity and sensitivity required for qualitative and quantitative analysis of multiple lipid species, in a variety of biological systems, and can facilitate the study of these mediators.

No / Lipid mediators are produced from the oxidation of polyunsaturated fatty acids through enzymatic and free radical-mediated reactions. When subject to oxygenation via cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases, polyunsaturated fatty acids give rise to an array of metabolites including eicosanoids, docosanoids, and octadecanoids. These potent bioactive lipids are involved in many biochemical and signaling pathways, with inflammation being of particular importance. Moreover, because they are produced by more than one pathway and substrate, and are present in a variety of biological milieus, their analysis is not always possible with conventional assays. Liquid chromatography coupled to electrospray mass spectrometry offers a versatile and sensitive approach for the analysis of bioactive lipids, allowing specific and accurate quantitation of multiple species present in the same sample. Here we explain the principles of this approach to mediator lipidomics and present detailed protocols for the assay of enzymatically produced oxygenated metabolites of polyunsaturated fatty acids that can be tailored to answer biological questions or facilitate assessment of nutritional and pharmacological interventions.

Yes / There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis. Methods and analysis: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%. Ethics and dissemination: Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently. Trial registration number NCT03428477. / The EMT2 trial is funded by Yorkshire Cancer Research (L387) and is sponsored by the University of Leeds. The EMT2 biospecimen collection is funded by the National Institutes of Health (1R01CA243454-01A1) and is sponsored by the University of Leeds ( governance-ethics@ leeds. ac. uk). Both studies have been adopted to the NIHR Clinical Research Network (CRN) Portfolio (CPMS ID 34700 and 47372, respectively) and have benefited from CRN research staff support.

L'acide docosahexaénoïque (DHA, C22 :6 w3), l'acide icosapentaénoïque (EPA, C20 : 5, w3) et l'acide adrénique (AdA, C22 :4 w6) sont présents en quantités importantes dans les membranes neuronales. Lors d'un stress oxydant, l'oxydation radicalaire de ces acides gras polyinsaturés conduit à la formation de métabolites nommés neuroprostanes (NeuroPs). Souhaitant avoir accès à de nouveaux biomarqueurs du stress oxydant neuronal, nous sommes intéréssés à la synthèse de NeuroPs de type F, issues du DHA, de l'EPA et de l'AdA. / Docosahexaenoïc acid (DHA, C22 :6 w3), eicosapentaenoïc acid (EPA, C20 : 5, w3) and adrenic acid (AdA, C22 :4 w6) are the major polyunstaurated acids in neuronal membrane. During an oxidative stress, their lipidic peroxidation led to oxygenated metabolites called neuroprostanes (NeuroPs). In order to access to new neuronal oxidtive stress biomarkers, we were interested in the syntheses of F-type NeuroPs derived from DHA, EPA and AdA.

The important factor in regulation of metabolic processes is regulatory proteins, which are able to react by feed-back to energetic state of the cell. Big attention is focused on the AMP activated kinase (AMPK) and NAD+ activated deacetylase SIRT1. These enzymes interact together and their stimulation increases mitochondrial biogenesis and fatty acid oxidation. Due to this it functions beneficially against the onset of obesity, insulin resistance and ageing. Fasting, exercise and some antidiabetogenic drugs act by these regulators. n-3 polyunsaturated fatty acids (PUFA) are also known because of their stimulative effects on mitochondrial biogenesis and -oxidation. Previous work of our group have showed that intake of higher dose of n-3 polyunsaturated fatty acids (PUFA) in diet lead to increase in activity of AMPK in white adipose tissue. New results presented in this thesis show that SIRT1 is essential for increase in expression of stimulators of -oxidation (PPAR etc) in response to n-3 PUFA in diet. n-3 PUFA futher improve the metabolic profile synergistically with calorie restriction probably through SIRT1.

L'acide arachidonique (AA, C20 :4, n-6) et l'acide docosahexaènoïque (DHA, C22 :6, n-3) sont présents en quantités importantes dans les membranes phospholipidiques. Lors d'un stress oxydant, ces acides gras polyinsaturés sont métabolisés en composés de structure tetrahydrofuranique appelés isofuranes (IsoFs) pour l'AA et neurofuranes (NeuroFs) pour le DHA. Nous nous sommes intéressés à la synthèse de ce type de composés afin d'accéder à de nouveaux biomarqueurs du stress oxydant. Dans ce même objectif, nous nous sommes également penchés sur la synthèse de potentielles structures analogues dérivant de l'acide adrénique (AdA, C22 :4, n-6), que nous avons nommées dihomo-isofuranes (dihomo-IsoFs). / Arachidonic acid (AA, C20 :4, n-6) and docosahexaenoïc acid (DHA, C22 :6, n-3) are phospholipidic membranes polyinsaturated fatty acids. During and oxidative stress, these are metabolized into tetrahydrofuran-containing compounds, known as isofurans (IsoFs) for AA and neurofurans (NeuroFs) for DHA. We were interested in the total synthesis of these compounds in the aim of getting access to novel biomarkers of the oxidative stress. Towards the same goal, we envisaged the total synthesis of potential analog structures coming from adrenic acid (AdA, C22 :4, n-6), that we named dihomo-isofurans (dihomo-IsoFs).