Development of an Optimized LC-MS Method for the Detection of Specialized Pro-Resolving Mediators in Biological Samples

The cardioprotective and anti-inflammatory effects of long chain omega-3 polyunsaturated fatty acids (n3 PUFA) are believed to be partly mediated by their oxygenated metabolites (oxylipins). In the last two decades interest in a novel group of autacoids termed specialized pro-resolving mediators (SPMs) increased. These are actively involved in the resolution of inflammation. SPMs are multiple hydroxylated fatty acids including resolvins, maresins, and protectins derived from the n3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as well as lipoxins derived from arachidonic acid (ARA). In the present paper, we developed an LC-MS/MS method for a comprehensive set of 18 SPMs derived from ARA, EPA, and DHA and integrated it into our targeted metabolomics platform. Quantification was based on external calibration utilizing five deuterated internal standards in combination with a second internal standard for quality assessment of sample preparation in each sample. The tandem mass spectrometric parameters were carefully optimized for sensitive and specific detection. The influence of source parameters of the used AB Sciex 6500 QTRAP instrument as well as electronic parameters and the selection of transitions are discussed. The method was validated/characterized based on the criteria listed in the European Medicines Agency (EMA) guideline on bioanalytical method validation and method performance is demonstrated regarding recovery of internal standards (between 78 ± 4% and 87 ± 3% from 500 μL of human serum) as well as extraction efficacy of SPMs in spiked plasma (intra-day accuracy within ±20 and ±15% at 0.1 and 0.3 nM in plasma, respectively). Based on the lower limit of quantification of 0.02–0.2 nM, corresponding to 0.18–2.7 pg on column, SPMs were generally not detectable/quantifiable in plasma and serum supporting that circulating levels of SPMs are very low, i.e., <0.1 nM in healthy subjects. Following septic shock or peritonitis, SPMs could be quantified in the samples of several patients. However, in these studies with a small number of patients no clear correlation with severity of inflammation could be observed

Total Synthesis of Neuroprotectin D1 Analogues Derived from Omega‑6 Docosapentaenoic Acid (DPA) and Adrenic Acid (AdA) from a Common Pivotal, Late-Stage Intermediate.

International audienceThe first total synthesis of three omega-6 dihydroxylated (E,E,Z)-docosatrienes has been successfully achieved employing a flexible strategy. The key features encompass a Boland semireduction, to create the (E,E,Z)-triene via an (E,E)-ynediene, and a selective deprotection of a tris(tert-butyldimethylsilyl) ether. The main advantage of the present strategy over previous syntheses of noncyclic dihydroxylated PUFA metabolites derived from docosahexaenoic and arachidonic acids comes from the introduction of the polar head chain at the very end of the synthesis from an advanced, pivotal aldehyde. In terms of divergency this enables late-stage modification of the head group

Branched fatty acyl esters of hydroxyl fatty acids (FAHFAs), appealing beneficial endogenous fat against obesity and type-2 diabetes

After a brief overview of the biological significance of FAHFAs, the present Minireview highlights the differentstrategies 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”

A Versatile and Stereocontrolled Total Synthesis of Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z-Triene.

International audienceA versatile strategy featuring a Colvin rearrangement, hydrozirconation, a Sonogashira cross-coupling reaction and a Z-selective Wittig olefination, was successfully developed for the construction of a conjugated E,E,Z-triene subunit, flanked on both sides by two Z-allylic hydroxyl groups. This chemical pattern is found in many endogenous lipid metabolites such as maresin 1 (MaR1), neuroprotectin D1 (NPD1), and its aspirin triggered-isomer AT-NPD1, which not only counter-regulate inflammation but also actively orchestrate (at nanomolar doses) the resolution and termination program of acute inflammation while promoting wound healing, return to homeostasis and neuroprotection. Unlike previous approaches, the advantages of the present strategy are obvious, as it allows us to modify the nonpolar tail, the carboxylated head or both ends of the molecule without repeating the whole synthetic sequence (about 26-34 steps according to the literature). Thus, the first total syntheses of NPD1 methyl ester epimer (which can also be considered as an enantiomer of AT-NPD1) and its n-3 docosapentaenoic acid derived analogue were achieved from a highly functionalized and late advanced pivotal intermediate. This innovative route may be easily adapted to gain access to other dihydroxylated metabolites and analogues of polyunsaturated fatty acids containing a conjugated E,E,Z-triene subunit. Different epimers/diastereoisomers may be obtained by purchasing the suitable optically pure (S)- and/or (R)-1,2,4-butanetriol(s) as a chiral pool for both stereogenic centers

L'analyse du travail comme objet et comme moyen d'une « formation action » des manageurs

International audienceCet exposé présente un projet visant à transformer les représentations et les pratiques de management, en particulier par une prise en compte accrue de la « qualité du travail », au sein des entreprises d'une région. Porté par plusieurs institutions, ce projet comprend trois volées : formation-action de groupes de manageurs volontaires, accompagnement de ces manageurs dans leur entreprise et enfin construction d'un diplôme d'université sur la base des deux premières actions. Une des spécificités de ce projet, c'est qu'il mobilise l'analyse du travail et de l'activité, d'une part comme un objectif à travailler avec les manageurs, mais aussi comme moyen pédagogique : les manageurs sont amenés à analyser leurs propres activités managériales et, ce faisant, se préparent à changer de regard sur le travail des salaries qu'ils encadrent Insérer un résumé en français d'environ 1000 caractères espaces compris, ce qui n'est pas le cas de cet exemple

Confusion between protectin D1 (PD1) and its isomer protectin DX (PDX). An overview on the dihydroxy-docosatrienes described to date.

International audienceThere is currently a growing interest in docosahexaenoic acid (DHA) oxygenated metabolites. Among them, protectin D1 (PD1), an endogenous dihydroxylated and non-cyclic docosatriene made through lipoxygenation and hydrolysis of an epoxide intermediate, shows appealing biological effects. However, with the present paper we wish to point out that results are sometimes assigned to PD1 while they are indeed related to its isomer protectin DX (PDX) made through double lipoxygenation only. These misleading conclusions urge us to review herein the structural/chemical and biological differences in the docosatrienes reported to date in the literature i.e. PD1, the related PD1n-3 DPA, AT-NPD1, maresin 1 (MaR1) and MaR1n-3 DPA, as well as their poxytrin analogs such as PDX, and some synthetic diastereoisomers. Hopefully, this will avoid further mistakes and confusion in the future

On unions and dominants of polytopes

A well-known result on unions of polyhedra in the same space gives an extended formulation whose projection is the convex hull of the union. Here in contrast we study the unions of polytopes in different spaces, giving a complete description of the convex hull without additional variables. When the underlying polytopes are monotone, the facets are described explicitly, generalizing results of Hong and Hooker on cardinality rules, and an efficient separation algorithm is proposed. These results are based on an explicit representation of the dominant of a polytope, and an algorithm for the separation problem for the dominant. For non-monotone polytopes, both the dominant and the union are characterized. We also give results on the unions of polymatroids both on disjoint ground sets and on the same ground set generalizing results of Conforti and Laurent

On unions and dominants of polytopes

A well-known result on unions of polyhedra in the same space gives an extended formulation whose projection is the convex hull of the union. Here in contrast we study the unions of polytopes in different spaces, giving a complete description of the convex hull without additional variables. When the underlying polytopes are monotone, the facets are described explicitly, generalizing results of Hong and Hooker on cardinality rules, and an efficient separation algorithm is proposed. These results are based on an explicit representation of the dominant of a polytope, and an algorithm for the separation problem for the dominant. For non-monotone polytopes, both the dominant and the union are characterized. We also give results on the unions of polymatroids both on disjoint ground sets and on the same ground set generalizing results of Conforti and Laurent

Are Alkyne Reductions Chemo‐, Regio‐, and Stereoselective Enough To Provide Pure (Z)‐Olefins in Polyfunctionalized Bioactive Molecules?

International audienc

On unions and dominants of polytopes

A well-known result on unions of polyhedra in the same space gives an extended formulation whose projection is the convex hull of the union. Here in contrast we study the unions of polytopes in different spaces, giving a complete description of the convex hull without additional variables. When the underlying polytopes are monotone, the facets are described explicitly, generalizing results of Hong and Hooker on cardinality rules, and an efficient separation algorithm is proposed. These results are based on an explicit representation of the dominant of a polytope, and an algorithm for the separation problem for the dominant. For non-monotone polytopes, both the dominant and the union are characterized. We also give results on the unions of polymatroids both on disjoint ground sets and on the same ground set generalizing results of Conforti and Laurent.unions of polytopes, cardinality constraints, separation, convex hulls, dominant, matroids, polymatroids.