First Total Syntheses of Novel Non-Enzymatic Polyunsaturated Fatty Acid Metabolites and Their Identification in Edible Oils.

Oxidative stress (OS) is an in vivo process leading to free radical overproduction, which triggers polyunsaturated fatty acid (PUFA) peroxidation resulting in the formation of racemic non-enzymatic oxygenated metabolites. As potential biomarkers of OS, their in vivo quantification is of great interest. However, since a large number of isomeric metabolites is formed in parallel, their quantification remains difficult without primary standards. Three new PUFA-metabolites, namely 18-F3t -isoprostane (IsoP) from eicosapentaenoic acid (EPA), 20-F4t -neuroprostane (NeuroP) from docosahexaenoic acid (DHA) and 20-F3t -NeuroP from docosapentaenoic acid (DPAn-3 ) were synthesized by two complementary synthetic strategies. The first one relied on a racemic approach to 18(RS)-18-F3t -IsoP using an oxidative radical anion cyclization as a key step, whereas the second used an enzymatic deracemization of a bicyclo[3.3.0]octene intermediate obtained from cyclooctadiene to pursue an asymmetric synthesis. The synthesized metabolites were applied in targeted lipidomics to prove lipid peroxidation in edible oils of commercial nutraceuticals.

An update of isoprostanoid nomenclature.

Polyunsaturated fatty acids (PUFAs) play numerous roles in living organisms but are also prone to rapid aerobic oxidation, resulting in the production of a wide range of isomeric metabolites called oxylipins. Among these, isoprostanes, discovered in the 1990s, are formed non-enzymatically from ω-3 and ω-6 PUFAs with 16 to 22 carbon atoms. Over nearly 35 years of research, two nomenclature systems for isoprostanes have been proposed and have evolved. However, as research progresses, certain aspects of the current nomenclature remain unclear and require further clarification to ensure precise identification of each metabolite and its corresponding parent PUFA. Therefore, we propose an update to the current nomenclature system, along with practical guidelines for assessing isoprostanoid diversity and identifying their PUFA origins.

Inflammasome activity regulation by PUFA metabolites.

Oxidative stress and the accompanying chronic inflammation constitute an important metabolic problem that may lead to pathology, especially when the body is exposed to physicochemical and biological factors, including UV radiation, pathogens, drugs, as well as endogenous metabolic disorders. The cellular response is associated, among others, with changes in lipid metabolism, mainly due to the oxidation and the action of lipolytic enzymes. Products of oxidative fragmentation/cyclization of polyunsaturated fatty acids (PUFAs) [4-HNE, MDA, 8-isoprostanes, neuroprostanes] and eicosanoids generated as a result of the enzymatic metabolism of PUFAs significantly modify cellular metabolism, including inflammation and the functioning of the immune system by interfering with intracellular molecular signaling. The key regulators of inflammation, the effectiveness of which can be regulated by interacting with the products of lipid metabolism under oxidative stress, are inflammasome complexes. An example is both negative or positive regulation of NLRP3 inflammasome activity by 4-HNE depending on the severity of oxidative stress. 4-HNE modifies NLRP3 activity by both direct interaction with NLRP3 and alteration of NF-κB signaling. Furthermore, prostaglandin E2 is known to be positively correlated with both NLRP3 and NLRC4 activity, while its potential interference with AIM2 or NLRP1 activity is unproven. Therefore, the influence of PUFA metabolites on the activity of well-characterized inflammasome complexes is reviewed.

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

There 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.