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      Omega-6 oxylipins generated by soluble epoxide hydrolase are associated with knee osteoarthritis[S]

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          Abstract

          Omega-6 FAs are inflammatory mediators that are increased in joints with osteoarthritis (OA), but their association with OA progression is not yet well defined. To investigate the relationship between omega-6 FAs and knee OA, we measured with LC-MS the levels of 22 omega-6 lipids (arachidonic acid, linoleic acid, and 20 oxylipins) in synovial fluid (SF) from 112 knees of 102 individuals (58 with knee OA; 44 controls). We hypothesized that oxylipin metabolites would increase in OA knee SF and with radiographically progressive disease. We validated results by comparing samples from affected and unaffected knees in 10 individuals with unilateral OA. In adjusted analysis, SF levels of three omega-6 oxylipins [prostaglandin D2, 11,12-dihydroxyeicosatrienoic acid (DHET), and 14,15-DHET] were associated with OA. Of these, 11,12-DHET and 14,15-DHET were higher in affected versus unaffected knees of people with unilateral disease ( P < 0.014 and P < 0.003, respectively). Levels of these and 8,9-DHET were also associated with radiographic progression over 3.3 years in 87 individuals. Circulating levels of all three were associated with gene variants at the soluble epoxide hydrolase enzyme. Lipidomic profiling in SF identified an additional inflammatory pathway associated with knee OA and radiographic progression.

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          Most cited references22

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          Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines.

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            Cohort Profile: TwinsUK and healthy ageing twin study.

            The UK's largest registry of adult twins, or TwinsUK Registry, started in 1992 and encompasses about 12000 volunteer twins from all over the United Kingdom. More than 70% of the registered twins have filled at least one detailed health questionnaire and about half of them undergone a baseline comprehensive assessment and two follow-up clinical evaluations. The most recent follow-up visit, known as Healthy Ageing Twin Study (HATS), involved 3125 female twins aged >40 years with at least one previous clinical assessment to enable inspection of longitudinal changes in ageing traits and their genetic and environmental components. The study benefits from several state-of-the-art OMICs studies including genome-wide association, next-generation genome and transcriptome sequencing, and epigenetic and metabolomic profiles. This makes our cohort as one of the most deeply phenotyped and genotyped in the world. Several collaborative projects in the field of epidemiology of complex disorders are ongoing in our cohort and interested researchers are encouraged to get in contact for future collaborations.
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              Epoxides and soluble epoxide hydrolase in cardiovascular physiology.

              Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that importantly contribute to vascular and cardiac physiology. The contribution of EETs to vascular and cardiac function is further influenced by soluble epoxide hydrolase (sEH) that degrades EETs to diols. Vascular actions of EETs include dilation and angiogenesis. EETs also decrease inflammation and platelet aggregation and in general act to maintain vascular homeostasis. Myocyte contraction and increased coronary blood flow are the two primary EET actions in the heart. EET cell signaling mechanisms are tissue and organ specific and provide significant evidence for the existence of EET receptors. Additionally, pharmacological and genetic manipulations of EETs and sEH have demonstrated a contribution for this metabolic pathway to cardiovascular diseases. Given the impact of EETs to cardiovascular physiology, there is emerging evidence that development of EET-based therapeutics will be beneficial for cardiovascular diseases.
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                Author and article information

                Journal
                J Lipid Res
                J. Lipid Res
                jlr
                jlr
                jlr
                Journal of Lipid Research
                The American Society for Biochemistry and Molecular Biology
                0022-2275
                1539-7262
                September 2018
                9 July 2018
                9 July 2018
                : 59
                : 9
                : 1763-1770
                Affiliations
                Academic Rheumatology, [* ] Nottingham City Hospital , Nottingham, United Kingdom
                Department of Twin Research, [§ ] King’s College London , St Thomas’ Hospital, London, United Kingdom
                National Institute for Health Research Nottingham Biomedical Research Centre, [] University of Nottingham , Nottingham, United Kingdom
                Centre for Analytical Bioscience, School of Pharmacy, [** ] University of Nottingham , Nottingham, United Kingdom
                School of Life Sciences, [†† ] University of Nottingham , Nottingham, United Kingdom
                Arthritis Research UK Centre of Excellence for Pain, [§§ ] University of Nottingham , Nottingham, United Kingdom
                Author notes
                [1 ]To whom correspondence should be addressed. e-mail: Ana.Valdes@ 123456nottingham.ac.uk
                Article
                p085118
                10.1194/jlr.P085118
                6121933
                29986999
                52c7823b-a091-45be-a4e4-9047728122db
                Copyright © 2018 Valdes et al.

                Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license.

                History
                : 15 March 2018
                : 2 July 2018
                Funding
                Funded by: Arthritis Research UK, open-funder-registry 10.13039/501100000341;
                Award ID: 18769
                Funded by: Medical Research Council, open-funder-registry 10.13039/501100000265;
                Award ID: MR/M016560/1
                Funded by: National Institute for Health Research, open-funder-registry 10.13039/501100000272;
                Funded by: European Commission Framework 7 Programme, open-funder-registry 10.13039/100011102;
                Award ID: EU FP7; HEALTH.2012.2.2.4.5-2, project number 305815
                Categories
                Patient-Oriented and Epidemiological Research

                Biochemistry
                lipids,arachidonic acid,eicosanoids,inflammation,methods/high-performance liquid chromatography,lipidomics

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