Jean-Marie Galano

Yiu Lee

Camille Oger

Claire Vigor

Joseph Vercauteren

Thierry Durand

Martin Giera

Jetty Chung-Yung Lee

Isoprostanes, neuroprostanes and phytoprostanes: An overview of 25 years of research in chemistry and biology

Keywords: Isoprostanes Neuroprostanes Phytoprostanes Lipid Peroxidation Polyunsaturated fatty acids Arachidonic acid, AD, Alzheimer's disease, AdA, Adrenic acid, ALA, α-Linolenic acid, APCI, Atmospheric pressure chemical ionization, BHT, Butylated hydroxytoluene, BSTFA, bis-

Since the beginning of the 1990's diverse types of metabolites originating from polyunsaturated fatty acids, formed under autooxidative conditions were discovered. Known as prostaglandin isomers (or isoprostanoids) originating from arachidonic acid, neuroprostanes from docosahexaenoic acid, and phytoprostanes from α-linolenic acid proved to be prevalent in biology. The syntheses of these compounds by organic chemists and the development of sophisticated mass spectrometry methods has boosted our understanding of the isoprostanoid biology. In recent years, it has become accepted that these molecules not only serve as markers of oxidative damage but also exhibit a wide range of bioactivities. In addition, isoprostanoids have emerged as indicators of oxidative stress in humans and their environment. This review explores in detail the isoprostanoid chemistry and biology that has been achieved in the past three decades.

Introduction

The discovery of isoprostanes (IsoPs) nearly three decades ago as biomarker of oxidative stress [START_REF] Morrow | A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism[END_REF] opened a new field of research in arachidonic acid (AA) and its eicosanoid metabolism. Today, it is accepted that IsoPs are more than only biomarkers and bystanders of physiological processes. IsoPs have been shown to act as lipid mediators in vasoconstriction and platelet aggregation, and may participate in intracellular signaling through the activation of prostanoid receptors [START_REF] Fukunaga | Evidence for the existence of F2-isoprostane receptors on rat vascular smooth muscle cells[END_REF]. Unlike the prostaglandins (PGs), IsoP biosynthesis is not dependent on the cyclooxygenase enzyme, instead it is propagated by free radical reactions, mainly driven by reactive oxygen species (ROS). Presently, it is well accepted that IsoP generation takes place in situ by the reaction of ROS with glycerophospholipids, mainly phosphatidylcholine. The esterified IsoPs can be released from the phospholipid by the action of phospholipase A 2 and platelet activating factor acetylhydrolase. While a plethora of isomeric IsoPs have been described, undoubtedly 15-F 2t -Isoprostane (15-F 2t -IsoP) is the predominant one investigated. Once released into the circulation, the free 15-F 2t -IsoP is β-oxidized to form an intermediate compound, 2,3-dinor-15-F 2t -IsoP that can further undergo reduction to 2,3-dinor-5,6-dihydro-15-F 2t -IsoP for urinary excretion [START_REF] Morrow | The isoprostanes: unique bioactive products of lipid peroxidation[END_REF]. However, an alternative β-oxidation processes takes place in rodents to produce 2,3,4,5-tetranor-15-F 2t -IsoP (Section 2.2) [START_REF] Chiabrando | Identification and measurement of endogenous beta-oxidation metabolites of 8epi-Prostaglandin F2alpha[END_REF]5].

Unlike the IsoPs, the metabolism of neuroprostanes (NeuroPs) and phytoprostanes (PhytoPs) originating from docosahexaenoic acid (DHA) and α-linolenic acid (ALA) are not well elucidated. While the formation of NeuroPs and PhytoPs follows the same pathways as the IsoPs, their metabolism and excretion are yet poorly explored. Nevertheless, the importance of NeuroPs and PhytoPs as significant lipid mediators has clearly been established only in recent years [START_REF] Roy | Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid[END_REF][START_REF] Roy | Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F4t-neuroprostane protects the heart against reperfusion injury[END_REF][START_REF] Karg | Biologically active oxidized lipids (phytoprostanes) in the plant diet and parenteral lipid nutrition[END_REF][START_REF] Minghetti | Nonenzymatic oxygenated metabolites of alpha-linolenic acid B1-and L1-phytoprostanes protect immature neurons from oxidant injury and promote differentiation of oligodendrocyte progenitors through PPAR-gamma activation[END_REF].

In turn, understanding both, the chemistry and biology of the isoprostanoids (IsoPs, NeuroPs and PhytoPs) are necessary to improve the analytical approaches in order to understand the metabolism and biology of isoprostanoids. In this review, we present a concise overview of the current knowledge concerning the chemistry and biology of IsoPs, NeuroPs and PhytoPs and hope that our compendium will help others to further explore the biological relevance of isoprostanoids.

Understanding isoprostanoids in vivo formation

The word isoprostanoid refers to isomers of PGs. In fact, the lateral chains bearing by the cyclopentane ring are in 1,2-trans relationship (spatially opposed) for the PGs as they are in 1,2-cis relationship (in the same plane) for the isoprostanes (IsoPs). The biosynthesis of PGs is well established since the 1970s and involves enzymatic COX-mediated mechanisms. However, the formation of IsoPs was uncovered in the 1990s through publication in the field of PGs [START_REF] Morrow | A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism[END_REF]. Morrow and coworkers showed that arachidonic acid (AA, C20:4 n-6) exposed to carbon tetrachloride (CCl 4 ) was oxidized in vivo to racemic IsoPs and racemic PGs, independent from any enzymatic COX action.

The biosynthesis of these metabolites, described in Scheme 1 is now well-established and proceeds through several radical steps [START_REF] Morrow | A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism[END_REF][START_REF] Yin | Separation and identification of F2-isoprostane regioisomers and diastereomers by novel liquid chromatographic/mass spectrometric methods[END_REF]. Polyunsaturated fatty acids (PUFA) such as AA are composed of bisallylic structures; double bonds separated by a methylene group (eCH]CHeCH 2 eCH]CHe), where α-hydrogen atoms are particularly easy to remove by the actions of free radicals, supported by the mesomeric stabilization of the resulting radical (Scheme 1). Physiologically, after oxidative stress injury and the release of free radicals in the cellular membranes, one hydrogen atom is abstracted from AA (intermediate A). The resulting carbon radical, in the presence of oxygen, further proceeds to form a peroxyl radical (compound B) and eventually the formation of an endoperoxide carbon centred radical (compound C). This intermediate then proceeds through a cyclization step to form the cyclopentane ring. The second consecutive 5-exo-trig cyclization follows the radical chemistry rules (Baldwin rules [START_REF] Baldwin | Rules for ring closure[END_REF][START_REF] Baldwin | Rules for ring closure: ring formation by conjugate addition of oxygen nucleophiles[END_REF]) and is the determinant step going along with the main PGs and IsoPs difference (e. g. lateral chains relationships), as it predominantly leads to a cis configuration of the lateral chains along with the trans configuration (PG isomers). The generation of the cyclopentane ring results in the formation of another radical which reacts with molecular oxygen to produce an endoperoxide-hydroperoxide intermediate after final Hatom transfer, also known as G 2 -IsoP. Prior to the endoperoxide reduction, the hydroperoxide is first reduced to form the H 2 -IsoP.

Depending on the reductive conditions H 2 -IsoP may subsequently form several IsoP families. Once the endoperoxide is completely reduced (black and green arrows simultaneously in Scheme 1) it leads to the F-type of IsoPs; a cyclopentane ring with two alcohol functions (in green). If the endoperoxide is partially reduced (arrow in blue and black, one side of the ring only in Scheme 1), the types D-and E-of the IsoPs are produced where the cyclopentane bears a hydroxy-ketone (in blue). The D-type refers to the ketone (eC]O) moiety on the cyclopentane on the same side as the ω-chain. In the E-type the ketone moiety is on the same side as the α-chain. The ratio between F-type, and D-and E-types mainly depends on the number of reductive agents, e.g. glutathione and α-tocopherol, in cells [START_REF] Montine | Antioxidants significantly affect the formation of different classes of isoprostanes and neuroprostanes in rat cerebral synaptosomes[END_REF]. Moreover, under physiological conditions, dehydration can occur especially in the hydroxylketone structures (type D-and E-). Subsequently, A-and J-types (in red Scheme 1) of the IsoPs are formed by the dehydration of E-and D-type respectively. As like D-and E-types, A-and J-types are recognizable with the ketone moieties on the side of the α-chain (A-type) or ω-chain (J-type).

Other IsoP metabolites, such as the epoxy-isoprostanes (epoxy-IsoPs) are also formed in vivo and detected in mildly oxidized LDL of atherosclerotic lesions [14,15] epoxy-J 2 -IsoPs. Recently, epoxy-IsoPs were shown to exert anti-inflammatory activity and may be a valuable group of compounds in inflammatory diseases [15,[START_REF] Bretscher | Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2[END_REF].

Two other types of isoprostanoids should also be noted; the B-and L-types (Scheme 2). Under basic conditions, A-and J-types undergo facile isomerization of the double bond. This isomerization is easily explained by the formation of the thermodynamically more stable metabolites. Therefore, the A-type isomerizes into B-type, the J-type leads to the L-type.

However, as AA and other PUFA have several bis-allylic positions in their structures allowing for numerous opportunities for free radical attack, not only the 15-series isoprostanes as shown in Scheme 1 but also 5-, 8-and 12-series isomers can be produced. As described in Scheme 3, hydrogen abstraction on C7 (in red Scheme 3) will give the 5-series of IsoPs, whereas 8-and 12-series are produced through C10 hydrogen abstraction. Consequently, starting from AA, 4 series of IsoPs may be formed, 5-, 8-, 12-and 15-series, and it should be highlighted that the 5-and the 15-series are the most abundant [START_REF] Waugh | Mass spectrometric analysis of four regioisomers of F2isoprostanes formed by free radical oxidation of arachidonic acid[END_REF][START_REF] Waugh | Identification and relative quantitation of F2-isoprostane regioisomers formed in vivo in the rat[END_REF]. Considering the unique formation of F-type IsoPs, the formation of 5 stereogenic centres give rise to 64 different IsoP isomers (enantiomers included).

Both n-6 and n-3 are essential PUFA in humans. The n-3 PUFA are frequently recommended because of possible health benefits. AA is the main n-6 PUFA in human cell membranes, whereas α-linolenic acid (ALA, C18:3 n-3) is the main n-3 PUFA in plant leaves. In fact, ALA metabolites, were first discovered by Mueller and co-workers in 1998, and were named phytoprostanes (PhytoPs) [START_REF] Parchmann | Evidence for the formation of dinor isoprostanes E1 from alpha-linolenic acid in plants[END_REF]. As shown in Scheme 4, ALA contains two bis-allylic positions (C11 and C14) leading to two series of F-type PhytoPs; the 9-series and the 16-series, namely 32 isomers (enantiomers included).

Eicosapentaenoic acid (EPA, C20:5 n-3) together with docosahexaenoic acid (DHA, C22:6 n-3) are mostly provided by the diet from marine resources such as fish or algae. The peroxidation of EPA [START_REF] Lawson | Oxidized derivatives of omega-3 fatty acids: identification of IPF3 alpha-VI in human urine[END_REF] and its four bis-allylic positions will provide 6 series of IsoPs (5-, 8-, 11-, 12-, 15-and 18-, Scheme 5). The 5-and 18-series are highlighted to be the most abundant series among the other. As for DHA, 8 series can be formed (4-, 7-, 10-, 11-, 13-, 14-, 17-and 20-, Scheme 6). Predominant in the grey matter of the brain, the term neuro-was affixed and the DHA metabolites [START_REF] Nourooz-Zadeh | F4-isoprostanes: a novel class of prostanoids formed during peroxidation of docosahexaenoic acid (DHA)[END_REF][START_REF] Roberts | Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid[END_REF] were named NeuroPs. Among the metabolites, the 4-and 20-series were shown to be the most abundant [START_REF] Yin | Regiochemistry of neuroprostanes generated from the peroxidation of docosahexaenoic acid in vitro and in vivo[END_REF].

Mostly found in the white matter of the brain, adrenic acid (AdA, C22:4 n-6) was probably the least considered PUFA, but due to its potential beneficial activities in humans AdA is now more and more studied. In order to differentiate AdA isoprostanoids from the AA derived ones, the term dihomo-isoprostanes (dihomo-IsoPs) was introduced by VanRollins et al. in 2008 [START_REF] Vanrollins | F2-dihomo-isoprostanes arise from free radical attack on adrenic acid[END_REF]. Four series of dihomo-IsoPs are produced by AdA oxidation, namely the 7-, 10-, 14-and 17-series (Scheme 7), with the 7-and 17-series as the most abundant. Scheme 3. The main F 3 -isoprostane isomers derived from arachidonic acid. IsoP: isoprostane. (For interpretation of the references to color in this figure, the reader is referred to the web version of this article.)

The use of organic synthesis to acquire isoprostanoid standards

The biosynthesis previously described, clearly demonstrates that isoprostanoids are found in biological systems as a complex mixture of isomers. In turn, this raises the question which isomer(s) is of physiological relevance or a possible biomarker? A single solution exists to efficiently answer the questions -by having the pure isomers at hand. Pure synthetic standards are often available from commercial sources, however even if the first IsoPs were discovered almost three decades ago, up to now, less than 10 pure isoprostanoid isomers are commercially available. Pure isoprostanoid sources are needed to better evaluate their role in lipid biology. Through total synthesis, research on isoprostanoids has been significantly advanced in the last decade [START_REF] Jahn | Beyond prostaglandins-chemistry and biology of cyclic oxygenated metabolites formed by free-radical pathways from polyunsaturated fatty acids[END_REF][START_REF] Jahn | Recent approaches to the total synthesis of phytoprostanes, isoprostanes and neuroprostanes as important products of lipid oxidative stress and biomarkers of disease[END_REF].

Throughout the years, the organic chemists' community developed several synthetic strategies that can be assembled together in three main concepts (Scheme 8). To clearly understand this chemistry part of this review, the structure of those isoprostanoids should be perceived. They are composed of one main cyclic core, which can possess different substituents, and to this core are attached two different lateral chains.

The first concept of the synthesis to be applied for these metabolites is to design the full structure of the molecule in a linear fashion and proceed to the formation of the core at the end of the synthesis (route no. 1, Scheme 8). The groups of Taber [START_REF] Taber | Enantioselective rhodium-mediated synthesis of (-)-PGE2 methyl ester[END_REF][START_REF] Taber | Diastereoselective Synthesis of an Isoprostane: (+/-)-8-epi-PGF(2)(alpha) Ethyl Ester[END_REF][START_REF] Taber | Synthesis of the four enantiomerically-pure isomers of 15-F2t-isoprostane[END_REF][START_REF] Taber | A synthetic approach to 15-D2c-isoprostane ethyl ester[END_REF][START_REF] Taber | Synthesis of 2, 3-Dinor-5, 6-dihydro-15F2t-isoprostane[END_REF][START_REF] Taber | Total synthesis of the four enantiomerically pure diastereomers of 8-F(2t)-isoprostane[END_REF][START_REF] Taber | Total synthesis of the ethyl ester of the major urinary metabolite of prostaglandin E(2)[END_REF][START_REF] Taber | Synthesis of the eight enantiomerically pure diastereomers of the 12-F(2)-isoprostanes[END_REF][START_REF] Taber | 5-F2t-isoprostane, a human hormone?[END_REF] and Durand/Rossi [START_REF] Guy | Total synthesis of 15 (RS)-5, 6-dehydro-8-epi-PGF 2α methyl ester by a biomimetic process[END_REF][START_REF] Durand | Total synthesis of (15R)-and (15S)-F(2t)isoprostanes by a biomimetic process using the cyclization of acyclic dihydroxylated octa-5,7-dienyl radicals[END_REF] used this strategy (Scheme 9). This approach has the advantage to mimic the biosynthesis and the chemist can expect that the late cyclization is accomplishable. However, toward the final intermediate the route is long, often difficult and at the end can be used for a limited variety of compounds. Then, a second concept was developed. The idea is to realize the cyclization with one of the chains already present in the structure and add the second lateral chain thereafter (route no. 2, Scheme 8). Few groups used this strategy, such as Jahn [START_REF] Jahn | Oxidative enolate cyclizations of 6, 8nonadienoates: towards the synthesis of prostanes[END_REF][START_REF] Jahn | Total synthesis of 15-F2t-isoprostane by using a new oxidative cyclization of distonic radical anions as the key step[END_REF] (Scheme 10) and Carreira [START_REF] Egger | Synthesis of epoxyisoprostanes: effects in reducing secretion of pro-inflammatory cytokines IL-6 and IL-12[END_REF], Weng/Lu [START_REF] Weng | Stereoselective synthesis of epoxyisoprostanes: an organocatalytic and "pot-economy" approach[END_REF] for the synthesis of epoxy-IsoPs. The biomimetic side is conserved while convergence and flexibility are brought on.

Finally, today's most preferred strategy is to synthesize the core and introduce the lateral chains one after the other (route nos. 2 and 3, Scheme 8). This strategy was largely applied by Larock/Lee [START_REF] Larock | Organopalladium approaches to prostaglandins. 11. Synthesis of PGF2. alpha. and 12-epi PGF2. alpha. by the controlled, one step, palladium-promoted, intermolecular coupling of three different alkenes[END_REF], Rokach [START_REF] Hwang | Total Synthesis of 8-epi-PGF2. alpha. A novel strategy for the synthesis of isoprostanes[END_REF][START_REF] Pudukulathan | Diels -Alder approach to isoprostanes. total synthesis of iPF2α-V[END_REF][START_REF] Rokach | The isoprostanes, a new class of natural products: synthesis and biosynthesis[END_REF][START_REF] Jacobo | Total synthesis of 8,12-iso-iPF3alpha-VI, an EPA-derived isoprostane: stereoselective introduction of the fifth asymmetric center[END_REF], Zanoni [START_REF] Zanoni | First total synthesis of A(2) isoprostane[END_REF][START_REF] Zanoni | First total synthesis of JS isoprostane[END_REF], Durand/Rossi [START_REF] Rondot | A free radical route to syn lactones and other prostanoid intermediates in isoprostaglandin synthesis[END_REF][START_REF] Durand | Total syntheses of iso-, neuro-and phytoprostanes: new insight in lipid chemistry[END_REF][START_REF] Fangour | Total synthesis of the eight diastereomers of the syn-anti-syn phytoprostanes F1 types I and II[END_REF], Vionnet/Renaud [START_REF] Vionnet | Facile Preparation of ( ± )-12-Epiprostaglandins from 7-Oxabicyclo [2.2. 1] hept-5-en-2-one via an all-cis-formyllactone related to Corey lactone[END_REF], Snapper [START_REF] Schrader | Ring opening metathesis approach to the isoprostanes[END_REF][START_REF] Schrader | Stereodivergent synthesis of all 15-F(2) isoprostanes[END_REF][START_REF] Shizuka | Synthesis of isoprostanyl phosphatidylcholine and isoprostanyl phosphatidylethanolamine[END_REF][START_REF] Shizuka | Selective synthesis of ent-15-epi-F2t-isoprostane and a deuterated derivative[END_REF] and Galano/Oger [START_REF] Oger | Stereocontrolled access to isoprostanes via a bicyclo[3.3.0]octene framework[END_REF] introduction of the first lateral chain, bicyclic (Zanoni, Snapper, Galano/Oger) or with the desired cyclopentane ring and two side groups (the side chains introduced in Galano/Oger Scheme) already in place. This approach is far from the biosynthetic route but has the major advantage to be flexible and will give access to a wide range of isoprostanoids i.e. different types (A, D, E, F and J), different stereochemistry's (cis or trans IsoPs) and allow starting from only one common intermediate. This strategy was also used for the synthesis of epoxy-IsoPs by the groups of Acharya/Kobayashi, Jung, Zhong [START_REF] Acharya | Total synthesis of 2-(5,6-epoxyisoprostane A2)phosphorylcholine and elucidation of the relative configuration of the isoprostane moiety[END_REF][START_REF] Acharya | Synthesis of phosphorylcholines possessing 5, 6-or 14, 15-epoxyisoprostane A 2 at sn-2 position[END_REF][START_REF] Jung | Total synthesis of the epoxy isoprostane phospholipids PEIPC and PECPC[END_REF][START_REF] Jung | Improved synthesis of the epoxy isoprostane phospholipid PEIPC and its reactivity with amines[END_REF][START_REF] Kawashima | Synthesis of the PMB ether of 5,6-epoxyisoprostane E2 through aldol reaction of the alpha-bromocyclopentanone[END_REF][START_REF] Zhong | An epoxyisoprostane is a major regulator of endothelial cell function[END_REF].

To date, chemists are still developing syntheses of isoprostanoids to gain access to all the families together with their isomers and epimers. The research in the field of isoprostanoids is focused in their use as biomarkers and their biological activities.

Metabolism

While the metabolism of the IsoPs, particularly 15-F 2t -IsoP has been described in detail [START_REF] Roberts | Identification of the major urinary metabolite of the F2-isoprostane 8-iso-prostaglandin F2alpha in humans[END_REF], the metabolism of the NeuroPs and PhytoPs is much less studied. As shown in Fig 1, the main metabolic reactions are β-oxidation and reduction, respectively. The NeuroPs, 4-F 4t -NeuroP and 10-F 4t -NeuroP have been investigated in human and animal studies related to neurological disorders [START_REF] Yin | Regiochemistry of neuroprostanes generated from the peroxidation of docosahexaenoic acid in vitro and in vivo[END_REF][START_REF] De Felice | Partial rescue of Rett syndrome by omega-3 polyunsaturated fatty acids (PUFAs) oil[END_REF], and interestingly, 4-F 4t -NeuroP was found mainly in the circulation and to a lesser extend in the urine whereas 10-F 4t -NeuroP were detectable in both body fluids (Fig 1). The metabolism of PhytoPs is even less well studied where only two reports were found in the literature. Karg's group identified that ingestion of plant oils by healthy males displayed slow absorption and excretion of PhytoPs and likewise, Barden et al. showed that ingestion of ALA (flaxseed oil) augmented F 1 -PhytoP production in healthy human plasma but not in urine [START_REF] Karg | Biologically active oxidized lipids (phytoprostanes) in the plant diet and parenteral lipid nutrition[END_REF][START_REF] Baldwin | Rules for ring closure[END_REF].

Although not yet experimentally proven, it is expected that the metabolism of NeuroPs and PhytoPs proceeds along the same pathways as observed for the IsoPs. As postulated in Fig 1 (dotted lines) β-oxidation and reduction would lead to 2,3,4,5-tetranor-10-F 4t -NeuroP and 2,3,4,5,6,7-hexanor-10-F 4t -NeuroP and 2,3,4,5,6,7-hexanor-16-F 1 -PhytoP, three possible urinary metabolites. However, more work will be needed to map the metabolism and excretion routes of the NeuroPs and PhytoPs, helping to establish their use as possible new oxidative stress biomarkers. Scheme 6. Neuroprostane (NeuroP) isomers derived from docosahexaenoic acid. Scheme 7. F 2 -dihomo-isoprostane (dihomo-IsoP) isomers derived from adrenic acid.

Isoprostanoid analysis

Morrow's group presented their study about, "one fresh plasma vs several months stored plasma" where they observed an increase in the formation of compounds that also occurred in other biological fluids [START_REF] Morrow | A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism[END_REF][START_REF] Morrow | Noncyclooxygenase oxidative formation of a series of novel prostaglandins: analytical ramifications for measurement of eicosanoids[END_REF]. This study marks the discovery of the racemic prostaglandin diastereoisomers which they later termed isoprostanes [START_REF] Milne | The isoprostanes-25 years later[END_REF]. In recent years, a wide variety of non-enzymatic metabolites were identified, including AA, AdA, ALA, EPA, docosapentaenoic (DPA) and DHA derived autoxidation products [START_REF] Galano | Non-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic and α-linolenic acids; bioactivities and potential use as biomarkers[END_REF][START_REF] Milne | Isoprostane generation and function[END_REF]. From an analytical chemistry point of view, several characteristics make the analysis of isoprostanoids a challenging task. Firstly, to distinguish between enzymatic and non-enzymatic products, isomeric compounds including, diastereomers as well as geometric and positional isomers need to be distinguished [START_REF] Kloos | Analysis of biologically-active, endogenous carboxylic acids based on chromatography-mass spectrometry[END_REF]. Secondly, the usually low abundance of isoprostanoids demands high analytical sensitivity and thirdly, artefactual formation of isoprostanoids during sample treatment remains an important concern [START_REF] Barden | Minimizing artifactual elevation of lipid peroxidation products (F2-isoprostanes) in plasma during collection and storage[END_REF]. Several analytical procedures and techniques have arisen over the years; the most important ones will be discussed below.

Sample collection

As mentioned before, due to the high reactivity of the bis-allylic hydrogen atoms, the double bonds found in PUFAs are prone to autoxidation and/or photodegradation, leading to generation of non-enzymatic metabolites including isoprostanoids. In turn, artefactual isoprostanoid formation during bio-sampling, storage, extraction and derivatization is of great concern. It is therefore advised to take several precautions: i) during storage, oxygen should be eliminated from the samples by flushing the samples with nitrogen or argon, ii) a suitable antioxidant such as butylated hydroxytoluene (BHT), triphenylphosphine (TPP), diethylene tri-amine pentaacetic acid (DTPA) and glutathione (GSH) should be used, iii) in order to avoid the ex vivo enzymatic production of eicosanoids, a small amount of a cyclooxygenase inhibitor e.g. indomethacin is commonly added [START_REF] Leung | Microbubble-mediated sonoporation amplified lipid peroxidation of Jurkat cells[END_REF] and iv) most importantly all biological fluids and tissues must be kept at ultra-low temperature (i.e. -80 °C) to ensure long term stability (6 months for plasma, several years for urine), ideally avoiding any freeze-thaw cycle. A detailed procedure for sample collection and storage has recently been described by Barden et al. [START_REF] Barden | Minimizing artifactual elevation of lipid peroxidation products (F2-isoprostanes) in plasma during collection and storage[END_REF].

Sample preparation and extraction

Sample preparation vastly depends on the investigated matrix as well as the subsequently used analysis technique. In general, isoprostanoids can either be extracted from the matrix itself, or after a comprehensive lipid extraction step, following well established protocols such as Folch (chloroform/methanol, 2:1, v/v), Bligh and Dyer (chloroform/methanol, 1:2, v/v) or methyl tert-butyl ether (MTBE) extraction [START_REF] Folch | simple method for the isolation and purification of total lipides from animal tissues[END_REF][START_REF] Bligh | A rapid method of total lipid extraction and purification[END_REF][START_REF] Matyash | Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics[END_REF] are analyzed. For tissues, total (free and bound) isoprostanoids needs to be hydrolysed to release esterified isoprostanoids from the matrix [START_REF] Proudfoot | F2-Isoprostanes in HDL are bound to neutral lipids and phospholipids[END_REF]. Hydrolysis is usually performed by adding a methanolic or ethanolic alkaline solution to the sample, followed by gentle heating (e.g. 1 M KOH in methanol for 30 min at 37 °C) [START_REF] Lee | Measurement of F2-isoprostanes, hydroxyeicosatetraenoic products, and oxysterols from a single plasma sample[END_REF]. In the case of urinary samples, isoprostanoids are present in free form thus hydrolysis is not required, nevertheless some authors recommend pretreatment with glucuronidase to cleave glucuronide bound analytes and to reduce matrix effects [START_REF] Langhorst | Determination of F2-isoprostanes in urine by online solid phase extraction coupled to liquid chromatography with tandem mass spectrometry[END_REF].

The extraction of isoprostanoids from biological matrices usually involves solid phase extraction (SPE). Typical protocols include the use of reversed phase materials [START_REF] Leung | Current development in non-enzymatic lipid peroxidation products, isoprostanoids and isofuranoids, in novel biological samples[END_REF] and in case of urinary samples, weakanion exchange materials [START_REF] Dahl | Rapid quantitative analysis of 8-iso-prostaglandin-F2á using liquid chromatography-tandem mass spectrometry and comparison with an enzyme immunoassay method[END_REF]. The latter allows for dedicated washing procedures resulting in clean extracts, even from a highly challenging matrix including urine samples. Another popular extraction procedure, that has particularly been used in combination with gas chromatography mass spectrometry (GC-MS) is thin layer chromatography (TLC) [START_REF] Milne | Quantification of F2-isoprostanes as a biomarker of oxidative stress[END_REF]. Other less frequently applied techniques, include: combined SPE and TLC [START_REF] Liu | Quantification of F2-isoprostanes as a reliable index of oxidative stress in vivo using gas chromatography-mass spectrometry (GC-MS) method[END_REF] as well as immunoaffinity based techniques, that can be useful for 15-F 2t -IsoP analysis, but not for omega-3 PUFA derived isoprostanoids, due to a lack of specific immobilized antibodies [START_REF] Tsikas | Divergence in urinary 8-iso-PGF(2alpha) (iPF(2alpha)-III, 15-F(2t)-IsoP) levels from gas chromatography-tandem mass spectrometry quantification after thin-layer chromatography and immunoaffinity column chromatography reveals heterogeneity of 8-iso-PGF(2alpha). Possible methodological, mechanistic and clinical implications[END_REF].

Scheme 8. Retrosynthetic analysis of the three main synthetic strategies developed for isoprostanoids.

Scheme 9. Examples of biomimetic synthetic approaches.

Analysis

In principle, the analysis of isoprostanoids can be divided into immunological assays and mass spectrometry based techniques. However, enzyme linked immunosorbent assays (ELISA kits) and radioimmunoassays (RIA) are limited to a single component, 15-F 2t -IsoP and besides their intrinsic issue regarding specificity, it also presents severe limitations.

Mass spectrometry based analysis is usually carried out in combination with either gas or liquid chromatography (GC-MS, LC-MS) [START_REF] Milne | Quantification of F2-isoprostanes as a biomarker of oxidative stress[END_REF]. Both, GC-MS and LC-MS present specific advantages and disadvantages, which will briefly be discussed below. An excellent in-depth discussion has recently been described by Tsikas and Zoerner [START_REF] Tsikas | Analysis of eicosanoids by LC-MS/MS and GC-MS/MS: A historical retrospect and a discussion[END_REF].

Derivatization

For GC-MS analysis, derivatization is mandatory. It is common to initially convert carboxylic acid function into pentafluorobenzyl esters (PFB) by reacting the samples with pentafluorobenzyl bromide (PFBBr) using a base catalyst such as N,N′-diisopropylethylamine. Subsequently, hydroxyl functions are silylated with either bis-(trimethylsilyl)trifluoroacetamide (BSTFA) or N-methyl-N-trimethylsilyltrifluoroacetamide with or without the use of a catalyst [START_REF] Kloos | Analysis of biologically-active, endogenous carboxylic acids based on chromatography-mass spectrometry[END_REF][START_REF] Morrow | Mass spectrometry of prostanoids: F2-isoprostanes produced by non-cyclooxygenase free radical-catalyzed mechanism[END_REF]. Although derivatization is not mandatory for LC based isoprostanoid analysis, some groups addressed the possibility of facilitating electro-spray ionization in positive mode (ESI +) using dedicated derivatization strategies as well as using bromine labelled reagents for isotope pattern recognition [START_REF] Bollinger | ESI-MS/MS detection of FAs by charge reversal derivatization with more than four orders of magnitude improvement in sensitivity[END_REF][START_REF] Kretschmer | Derivatization of carboxylic acids with 4-APEBA for detection by positive-ion LC-ESI-MS(/MS) applied for the analysis of prostanoids and NSAID in urine[END_REF]. However, to date, no study could clearly prove the benefits of isoprostanoid derivatization prior LC-MS analysis [START_REF] Lee | Assessment of isoprostanes in human plasma: technical considerations and the use of mass spectrometry[END_REF]. The reasons for this might be the additional steps needed, kinetic limitation due to the very low analyte concentrations, increased matrix effects caused by residual derivatization reagents as well as over the years increased mass spectrometer sensitivity in negative mode ESI (ESI-), allowing the analysis of native isoprostanoids.

GC-MS and GC-MS/MS analysis

Traditionally, isoprostanoids have been analyzed using GC-MS [START_REF] Milne | Quantification of F2-isoprostanes as a biomarker of oxidative stress[END_REF]. Even though the GC based analysis requires sample derivatization, the resolving power of the GC is unprecedented. Mainly due to a virtually absent eddy diffusion, GC analysis achieves very high plate numbers and in turn, is ideally suited for the analysis of closely related substances, such as the isoprostanoids. With respect to MS detection, over the years several ionization techniques have been tested, however, electron-capture negative ionization (ECNI) using methane as the reagent gas, has become the gold standard. Especially in combination with PFB esters, ECNI allows the generation of molecular ions, which are usually monitored either in selected-ion monitoring (SIM) or multiple-reaction monitoring (MRM) mode, when using tandem mass spectrometry (GC-MS/MS). Particularly, the latter allows gaining selectivity by choosing analyte specific fragments [START_REF] Briskey | Optimized method for quantification of total F(2)-isoprostanes using gas chromatography-tandem mass spectrometry[END_REF]. Advanced protocols for GC-MS and GC-MS/MS analysis have recently been published by Tsikas et al. [START_REF] Tsikas | Protocols for the measurement of the F2-isoprostane, 15(S)-8-iso-prostaglandin F2á, in biological samples by GC-MS or GC-MS/MS coupled with immunoaffinity column chromatography[END_REF].

LC-MS and LC-MS/MS analysis

Due to the isoprostanoids low abundance and the high selectivity needed for proper isoprostanoid analysis, LC is usually coupled to tandem mass spectrometer (LC-MS/MS), making use of MRM on triplequadrupole or quadrupole linear ion trap (QTrap) type instruments. With respect to the commonly applied ionization techniques, some authors have described the use of atmospheric pressure chemical ionization in the negative mode (APCI-) [START_REF] Korecka | Simultaneous HPLC-MS-MS quantification of 8-iso-PGF2á and 8,12-iso-iPF2á in CSF and brain tissue samples with on-line cleanup[END_REF]. However, by far, the most frequently applied technique is ESI-.

LC-MS/MS has the advantage to select analyte characteristic fragment ions, for example related to the position of hydroxyl function within the molecule [START_REF] Brose | MS/MS method for analysis of E2 series prostaglandins and isoprostanes[END_REF]. A complete set of fragmentation and ion transitions from the precursors of the known isoprostanes are compiled in Table 1. While carefully chosen MRM transitions allow to readily classify isoprostanes belonging to the 5, 8, 12 or 15-series, the identification of geometric isomers as well as enantiomers, demands chromatographic separation as well as the availability of synthetic standards. An example for the characteristic fragmentation of positional NeuroP isomers are 4-F 4t -NeuroP and 10-F 4t -NeuroP which can be distinguished based on the MRM transitions m/z 377-> 101 for 4-F 4t -NeuroP and m/z 377-> 153 for 10-F 4t -NeuroP [START_REF] Dupuy | Simultaneous quantitative profiling of 20 isoprostanoids from omega-3 and omega-6 polyunsaturated fatty acids by LC-MS/MS in various biological samples[END_REF] (Table 1).

An upcoming technique which in the future might facilitate the separation of isomers, closely eluting in the LC is ion-mobility-spectrometry [START_REF] Jónasdóttir | Differential mobility separation of leukotrienes and protectins[END_REF]. However, to the best of our knowledge applications in the field of isoprostanoid analysis remain very limited [START_REF] Kapron | Simultaneous analysis of prostanoids using liquid chromatography/high-field asymmetric waveform ion mobility spectrometry/tandem mass spectrometry[END_REF]. It should be noted that not all the isoprostanoids have been evaluated in biological specimen and analyses of PhytoPs are mainly conducted in food and plant samples whereas those of IsoPs and NeuroPs are mainly assessed in mammalian tissues and fluid. What is lacking is the evaluation of PhytoPs in mammalian tissues since ALA is an essential PUFA required in mammals. Furthermore, it should be highlighted that not all mammalian specimen may contain all the isoprostanoids [START_REF] Leung | Shorttime UVA exposure to human keratinocytes instigated polyunsaturated fatty acid without inducing lipid peroxidation[END_REF][START_REF] Cuyamendous | Total syntheses and in vivo quantitation of novel phytofurans derived from alpha-linolenic acid[END_REF] and this may depend on the metabolism and the experimental model evaluated [START_REF] Leung | Current development in non-enzymatic lipid peroxidation products, isoprostanoids and isofuranoids, in novel biological samples[END_REF].

As reference material, a list of the most abundant MS/MS transitions for a series of isoprostanoids is provided in Table 1. In addition, an analytical database containing analytical settings and tandem mass spectra of over 20 isoprostanoids can be found in the Supplementary Information (List 1).

Biomarkers in biological systems

Since the discovery of IsoPs, 15-F 2t -IsoP has been labelled as the biomarker for oxidative stress in human diseases. Notably, isoprostanoid measurements have been performed in mammalian plasma, urine, cerebrospinal fluid, sputum, saliva, exhaled breath condensate, brain tissues, atherosclerotic plaques and even gastric mucosa. More recently, the use of IsoPs as biomarkers has been extended to the marine ecosystem and includes environmental studies, and should be recognized that one large part of PUFA in the human diet is obtained through our marine resources, e.g. seafood and algae. Notwithstanding, plant oil is also an important source of PUFA for the human body. Studies on the use of PhytoPs from ALA as biomarkers to evaluate plant oil oxidation from seeds, nuts, leaves, olives and wine have been reported recently. The quality of both marine and plant oils is important for general health and well-being as they are the source of essential fatty acids in our diet; without doubt, increase in oxidative stress biomarkers are good indicators for the PUFA quality. Although NeuroPs were utilized to measure oxidative stress related to diseases, this has not been fully utilized for measurement in the marine ecosystem. Yet, the extent of use as biomarkers in human studies is not large for NeuroPs compared to IsoPs, but has shown to be an important indicator in studies of oxidative stress related to neurodegeneration and neurological conditions. In this part, we will explore reports on the use of isoprostanoid biomarkers and their applications in different biological areas. Not all studies on human diseases and IsoP biomarkers are included, as to date (2017), > 2500 articles related to isoprostanes are found in PubMed. Only those reports on prospective studies will be highlighted.

Isoprostanes

Human diseases

Lipid peroxidation is a critical component of oxidative stress, which is a common biological condition in a wide range of diseases such as, but not limited to, neurological disorders, cardiovascular diseases, diabetes and renal dysfunction [START_REF] Milne | Isoprostane generation and function[END_REF]. Since its discovery, levels of F 2 -IsoPs, especially 5-F 2t -IsoP and 15-F 2t -isoP, and their metabolites are routinely measured in non-invasive patient samples, predominantly in blood plasma and urine. Arachidonic acid is esterified in membranes and it is a ubiquitous component of mammalian cell membranes. Elevation of F 2 -IsoPs in vivo represents the presence of cellular oxidant injury. The detection and quantification of F 2 -IsoPs and its metabolites has been described in Section 3.

So far, ECNI-GC-MS remains the gold standard for F 2 -IsoPs measurement due to its superior selectivity and sensitivity. Table 2 reviews the use of 5-and 15-series F 2 -IsoPs and 15-F 2t -IsoP metabolites as biomarkers in several human diseases relating to oxidative stress. Although in vitro studies and in animal models using F 2 -IsoPs has remarkably shown to be a reliable oxidant injury biomarker, the same does not hold true for all oxidative stress related diseases in humans that was illustrated by van't Erve et al. [START_REF] Van 't Erve | Classifying oxidative stress by F2-isoprostane levels across human diseases: a meta-analysis[END_REF]. After meta-analysis of studies in different disease conditions, the authors pointed out that 'total' 15-F 2t -IsoP should be considered before interpreting non-enzymatic oxidative damage as generation of 'free' 15-F 2t -IsoP can be induced by inflammation-induced prostaglandin endoperoxide synthase [START_REF] Van 't Erve | Classifying oxidative stress by F2-isoprostane levels across human diseases: a meta-analysis[END_REF]; further studies are needed to justify this finding. Similarly, it is worth mentioning that the experimental results in Table 2 indicate, regardless of the samples used, conflicting data is noted and failed to prove that either F 2 -IsoPs or 15-F 2t -IsoP metabolites are suitable biomarkers for widespread diseases, such as Alzheimer's disease and type 2 diabetes. While few reports on less prevalent diseases like dengue fever [START_REF] Lee | Different patterns of oxidized lipid products in plasma and urine of dengue fever, stroke, and Parkinson's disease patients: cautions in the use of biomarkers of oxidative stress[END_REF] and periodontal disease [START_REF] Huang | Mass spectrometry-based metabolomic profiling identifies alterations in salivary redox status and fatty acid metabolism in response to inflammation and oxidative stress in periodontal disease[END_REF] were distinguished, F 2 -IsoPs appear to be significant biomarkers of these diseases. Thus, F 2 -IsoPs or their metabolites might not be suitable biomarkers for all human diseases related to oxidative stress. Nonetheless, it is worth noting that the elevation of 15-F 2t -IsoP in cardiovascular diseases is more consistent than those in neurological disorders, and it is not surprising as 15-F 2t -IsoP is a vasoconstrictor. So far, although F 2 -IsoPs are widely recognised as the biomarker for oxidative stress, no large-scale population study has been conducted using the MS platforms and, therefore, warrants a need to validate if it is a good biomarker for all oxidative stress related diseases, including neurodegenerative diseases.

In contrast to F 2 -IsoPs, AdA-derived F 2 -dihomo-IsoPs have shown to be potential biomarkers for brain white matter related conditions, where AdA is highly abundant. Studies in patients with neurological disorders, such as Rett Syndrome [START_REF] De Felice | F2dihomo-isoprostanes as potential early biomarkers of lipid oxidative damage in Rett syndrome[END_REF] showed significant elevation of plasma F 2 -dihomo-IsoPs, and urinary 7-F 2t -dihomo-IsoPs. 17-F 2t -dihomo-IsoPs were shown to be higher in epileptic patients compared to controls [START_REF] Medina | Dihomo-isoprostanes-nonenzymatic metabolites of AdA-are higher in epileptic patients compared to healthy individuals by a new ultrahigh pressure liquid chromatography-triple quadrupole-tandem mass spectrometry method[END_REF]. In a recent report, F 2 -dihomo-IsoPs were used as biomarker of the neuromotor system in adult triathletes. The study showed that physical exercise exerted different responses in the type of F 2 -dihomo-IsoPs; urinary 17-F 2t -dihomo-IsoPs were elevated and 7-F 2t -dihomo-IsoPs decreased with increment of training load [START_REF] Garcia-Flores | Lipidomic approach in young adult triathletes: effect of supplementation with a polyphenols-rich juice on neuroprostane and F2-dihomo-isoprostane markers[END_REF].

Marine ecosystem and environmental stressors

The use of F 2 -IsoPs as biomarker for in vivo oxidant injury is not only limited to human diseases, but were also found in marine fishes as well as humans and animals that were exposed to environmental stressors such as the ones listed in Table 3. Most of these studies were reported within the last decade, showing that the detection of F 2 -IsoPs is starting to receive significant attention in the environmental and marine science areas. Although not all treated marine fishes showed changes in the level of F 2 -IsoPs in their samples, deep-frozen catfish, Fe 3 + -treated Fathead minnow fish, and H 2 O 2 -treated medaka fish consistently exhibited an elevation of F 2 -IsoPs. Surprisingly, the abundance of F 2 -IsoPs is reduced in baked salmon as compared to raw fish [START_REF] Raatz | Baking reduces prostaglandin, resolvin, and hydroxy-fatty acid content of farm-raised Atlantic salmon (Salmo salar)[END_REF]. Hence, the use of F 2 -IsoPs could also be an indication to the quality of lipids present. The feasibility of using F 2 -IsoPs as a lipid quality indicator is especially important because fatty fishes constitute a large portion of healthy dietary lipids, and there is a risk falling ill if bad quality lipids are ingested. Of note, F 2 -dihomo-IsoPs were also detected in the muscles of marine fish by Chung et al., but were not statistically different from normoxia and hypoxia treatments. However, hyperoxia-stressed medaka fish showed elevation of dihomo-isofurans, which are produced from AdA non-enzymatically under higher oxygen tension [START_REF] Chung | Hyperoxia elevates adrenic acid peroxidation in marine fish and is associated with reproductive pheromone mediators[END_REF].

In environmental stressor studies, F 2 -IsoPs are elevated in human and animal subjects when exposed to air pollutants, such as wood smoke particles, ozone, fine particulate matter (PM2.5), black carbon, and diesel exhaust. Other environmental contaminants also include formaldehyde, organophosphate insecticides, plasticizer, and perfluoroctanesulfonic acid (also an industrial contaminant). Collectively, the exact mechanism of action by these stressors to induce lipid peroxidation remains largely unknown, but has shown to cause discomfort and other complications along with oxidative stress. Remarkably, special attention should be paid to the potential role of 15-F 2t -IsoP as a wastewater biomarker for the assessment of community public health

LC-MS/MS [105]

Juvenile rainbow trout fed with selenium Liver ↔ Before vs after feeding selenium.

ELISA [START_REF] Knight | Dietary selenium disrupts hepatic triglyceride stores and transcriptional networks associated with growth and Notch signaling in juvenile rainbow trout[END_REF] Farmed rainbow trout slaughtered by asphyxia or percussion Plasma ↔ Asphyxia vs percussion slaughtering.

LC-MS/MS [251]

Environmental stressor

Exposure of wood smoke particles to healthy individuals Urine ↑ Clean air vs wood smoke exposure.

RIA [START_REF] Barregard | Experimental exposure to wood-smoke particles in healthy humans: effects on markers of inflammation, coagulation, and lipid peroxidation[END_REF] Ozone exposure to healthy individuals Plasma ↑ High ozone level vs normal level; ↑ Acute ozone exposure after 4 h and then returned to baseline after 18 h. ELISA [START_REF] Chen | Effects of chronic and acute ozone exposure on lipid peroxidation and antioxidant capacity in healthy young adults[END_REF] Welders exposed to fine particulate matter (2.5) Urine ↓ Acute exposure but returned to baseline level after 24 h.

ELISA [START_REF] Nuernberg | Urinary 8-isoprostane and 8-OHdG concentrations in boilermakers with welding exposure[END_REF] Adults with metabolic syndrome exposed to diesel exhaust Urine ↔ Filtered air vs diesel exhaust.

LC-MS/MS [255]

Healthy subjects in living in Beijing, pre-and post air quality during the Olympics

LC-MS/MS [259]

Raw 24 h composite sewage Sewage water F 2 -IsoPs was found in sewage samples.

LC-MS/MS [107]

Pregnant women exposed to formaldehyde and its effect on fetal growth Urine No significant relationship was found with fetal growth and formaldehyde exposure.

ELISA [START_REF] Amiri | The roles of formaldehyde exposure and oxidative stress in fetal growth in the second trimester[END_REF] Organophosphate insecticides exposure to mice with idiopathic autism (BTBR T +tf/ J) Brain ↑ BTBR T + tf/J mice vs control.

ELISA [START_REF] De Felice | Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism[END_REF] Bisphenol A disposal and correlation to human and sewage water

Sewage water and human urine

No association of human urinary F 2 -IsoPs levels and Bisphenol A levels and levels of wastewater disposed.

ELISA [START_REF] Santos | levels in sewage wastewater effluents from metro Detroit communities[END_REF] Framingham due to its high stability [START_REF] Daughton | Using biomarkers in sewage to monitor community-wide human health: isoprostanes as conceptual prototype[END_REF]. Recently, Ryu et al. have successfully detected 15-F 2t -IsoP in sewage samples [START_REF] Ryu | Liquid chromatography-high resolution mass spectrometry with immunoaffinity clean-up for the determination of the oxidative stress biomarker 8-iso-prostaglandin F2alpha in wastewater[END_REF] and found the levels to be associated with trans-3′-hydroxycotinine, a tobacco metabolite in the same samples [START_REF] Ryu | Increased levels of the oxidative stress biomarker 8-iso-prostaglandin F2alpha in wastewater associated with tobacco use[END_REF]. While the concept of 15-F 2t -IsoP as the biomarker for community health assessment has only just been propositioned, the findings indicate tobacco smoking is habitual in the community of the sewage origin. Nevertheless, longer periods of monitoring are required to prove on its suitability as well as the stability in the sewage as it is highly exposed to microbial pathogens.

Phytoprostanes

PhytoPs are predominantly found in higher plants as mammals do not endogenously produce ALA due to the lack of delta-12 and delta-15 desaturases which are needed for the synthesis of essential fatty acids. Identified by Mueller and co-workers, they reported the presence of two series (9 and 16) of E 1 -PhytoPs [START_REF] Parchmann | Evidence for the formation of dinor isoprostanes E1 from alpha-linolenic acid in plants[END_REF] and F 1 -PhytoPs [START_REF] Imbusch | Formation of isoprostane F(2)-like compounds (phytoprostanes F(1)) from alpha-linolenic acid in plants[END_REF] from plant cultures. Other PhytoPs discovered include A 1 -, B 1 -, D 1 -, and L 1 -Phy-toPs. Among which A 1 -and B 1 -PhytoPs are produced in low abundance in plants, where A 1 -PhytoPs are readily isomerised into B 1 -PhytoPs under extreme pH or high temperature. D 1 -and F 1 -PhytoPs are the most dominant PhytoPs in plants [START_REF] Thoma | The isoprostanoid pathway in plants[END_REF]. Plants constitutively produce ROS as signalling molecules for cell growth and development, but also significantly intensify PhytoP production under stress. Therefore, PhytoPs serve as an excellent biomarker for oxidative degradation of plant food. In addition, PhytoP can be esterified to galactolipid and was detected in Arabidopsis thaliana plant by Feussner's group [START_REF] Ibrahim | The alphabet of galactolipids in arabidopsis thaliana[END_REF].

The Gil-Izquierdo group has shown that PhytoPs of walnuts are sensitive biomarkers towards improper storage conditions (e.g. nonvacuum versus vacuum packed, and storing at 24 °C versus 4 °C) [START_REF] Carrasco-Del Amor | Impact of packaging atmosphere, storage and processing conditions on the generation of phytoprostanes as quality processing compounds in almond kernels[END_REF]. This suggests that the quality of plant oils could potentially be assessed by the measurement of PhytoPs. Also, Table 4 illustrates the wide variety of PhytoPs found in different plant samples, like peppermint leave, melon leave, almond cultivars, red wine, and dietary oils (e.g. sunflower, flaxseed, olive, soybean, rapeseed, walnut and grape seed oils). More importantly, olive oil being low in ALA showed the presence of F 1 -PhytoPs in plasma and urine after consumption, but the biological activity to date, are not fully explored. Because Mediterranean diet contains high amount of extra virgin olive oil further investigation regarding the PhytoPs bioactivities is of great importance.

Neuroprostanes

The formation of neuroprostanes (NeuroPs) proceeds via the nonenzymatic oxygenation of DHA. They are widely used as a specific biomarker for oxidative damage of brain tissues. Clinical and experimental results in human and animal models consistently showed that oxidative damage to the brain induces an increment of F 4 -NeuroPs production as depicted in Table 5. Interestingly, studies which measured different series of F 4 -NeuroPs showed that 10-F 4t -NeuroP, but rarely 4-F 4t -NeuroP, was found in the urine samples. Probably, this implies that the excretion of 10-F 4t -NeuroP might be subjected to further metabolism.

In some studies, A 4 /J 4 -NeuroPs were similarly elevated from ROS insult. For example, rats exposed to alcohol [START_REF] Luczaj | Sweet grass protection against oxidative stress formation in the rat brain[END_REF] and in tick-borne encephalitis patients [START_REF] Luczaj | Tick-borne encephalitis-lipid peroxidation and its consequences[END_REF] had higher amounts of A 4 /J 4 -NeuroPs compared to control group brain tissue and plasma, respectively. Apparently, F 4 -NeuroPs appears to be a more suitable biomarker for neurodegeneration and brain injury, including the Rett Syndrome and ischemic-stroke, compared to F 2 -IsoPs. The advancement of quantifying F 4 -NeuroPs clinically for early detection of debilitating neurological disorders has been slow, mostly due to the lack of commercially available standards for human testing. Currently, only a handful of studies were conducted in neurodegenerative disease patients, and more work is required to fully understand their biological role in these diseases.

In summary, F 4 -NeuroPs continue to serve as a reliable biomarker for brain oxidative damages, but whether the correlation of brain F 4 -NeuroPs and plasma or urine F 4 -NeuroPs can be established for an early detection of neurological disorder, such as neurodegenerative diseases, requires further experimental data.

Bioactivities of isoprostanoids

In addition to their application as biomarkers of oxidative stress, isoprostanoids were reported to exert biological activities. They serve as homeostatic mediators in keeping physiological functions, or involve in inflammation and immunity that are associated to the pathology of diseases. The following section reviews the current knowledge of the bioactivities of isoprostanoids, namely IsoPs, NeuroPs and PhytoPs.

Isoprostanes

AA derived 15-F 2t -IsoP was initially found to be a potent renal vasoconstrictor in the low nanomolar range [START_REF] Takahashi | Glomerular actions of a free radical-generated novel prostaglandin, 8epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors[END_REF]. In subsequent studies of 15-F 2t -IsoP, a similar constriction effect was observed in the vascular systems such as the liver, heart, lung [START_REF] Banerjee | Effects of a novel prostaglandin, 8-epi-PGF2 alpha, in rabbit lung in situ[END_REF][START_REF] Kang | Airway and vascular effects of 8-epi-prostaglandin F2 alpha in isolated perfused rat lung[END_REF], smooth muscle [START_REF] Fukunaga | Evidence for the existence of F2-isoprostane receptors on rat vascular smooth muscle cells[END_REF] and retina [START_REF] Lahaie | A novel mechanism for vasoconstrictor action of 8-isoprostaglandin F2 alpha on retinal vessels[END_REF], in peripheral lymphatics [START_REF] Sinzinger | Isoprostane 8-epi-prostaglandin F2 alpha is a potent contractor of human peripheral lymphatics[END_REF] and the airways [START_REF] Okazawa | Lotvall, 8-Epi-PGF2alpha induces airflow obstruction and airway plasma exudation in vivo[END_REF]. Other biological activities of 15-F 2t -IsoP also include inhibition of angiogenesis [START_REF] Benndorf | Isoprostanes inhibit vascular endothelial growth factor-induced endothelial cell migration, tube formation, and cardiac vessel sprouting in vitro, as well as angiogenesis in vivo via activation of the thromboxane A(2) receptor: a potential link between oxidative stress and impaired angiogenesis[END_REF] and modulation of glutamate release from the bovine retinae [START_REF] Opere | Dual effect of isoprostanes on the release of [3H]D-aspartate from isolated bovine retinae: role of arachidonic acid metabolites[END_REF]. The biological activities of 15-F 2t -IsoP are generally thought to be exerted as an agonist for the activation of thromboxane receptors (TPR), that can be abrogated by the TPR antagonist SQ29548 [START_REF] Takahashi | Glomerular actions of a free radical-generated novel prostaglandin, 8epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors[END_REF][START_REF] Banerjee | Effects of a novel prostaglandin, 8-epi-PGF2 alpha, in rabbit lung in situ[END_REF][START_REF] Morrow | Roberts 2nd, The F2-isoprostane, 8-epi-prostaglandin F2 alpha, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist[END_REF]. Interestingly, unlike other TPR ligands, e.g. thromboxane A2, the binding mechanism of 15-F 2t -IsoP to the active site of the platelet TPRs revealed a unique coordination profile as studied by site-directed mutagenesis. While Phe 184 and Asp 193 are shared among 15-F 2t -IsoP and other TPR ligands, the binding of 15-F 2t -IsoP to TPRs requires an additional interaction with Phe 196 [START_REF] Khasawneh | Characterization of isoprostane signaling: evidence for a unique coordination profile of 8-iso-PGF(2alpha) with the thromboxane A(2) receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets[END_REF]. In the same study, the second 15-F 2t -IsoP binding site on platelet was identified which constitutes to a total opposite effect. This was realised via an unknown cAMP-coupled receptor that inhibits the activation of platelet [START_REF] Khasawneh | Characterization of isoprostane signaling: evidence for a unique coordination profile of 8-iso-PGF(2alpha) with the thromboxane A(2) receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets[END_REF]. Therefore, the biological activities of 15-F 2t -IsoP can be platelet activating or inhibiting, depending on of the active sites that is occupied. Nonetheless, not all F 2 -IsoPs are homogenous in their bioactivity and mode of actions. For example, 15-F 2c -IsoP activates the PGF 2α receptor at high concentration and induces hypertrophy of cardiomyocytes via intracellular signalling pathways different from those of PGF 2α [START_REF] Kunapuli | Functional characterization of the ocular prostaglandin f2alpha (PGF2alpha) receptor. Activation by the isoprostane, 12-iso-PGF2alpha[END_REF][START_REF] Kunapuli | Prostaglandin F2alpha (PGF2alpha) and the isoprostane, 8, 12-iso-isoprostane F2alpha-III, induce cardiomyocyte hypertrophy. Differential activation of downstream signaling pathways[END_REF]. Also, 5-F 2t -IsoP, another abundantly generated F 2 -IsoP isomer analogous to 15-F 2t -IsoP, showed no vasomotor activity [START_REF] Marliere | The 5-series F(2)-isoprostanes possess no vasomotor effects in the rat thoracic aorta, the human internal mammary artery and the human saphenous vein[END_REF][START_REF] Hou | Isomerspecific contractile effects of a series of synthetic f2-isoprostanes on retinal and cerebral microvasculature[END_REF]. Exploration into the bioactivity of 12-and 8-series F 2 -IsoPs has been limited largely due to the low abundance in vivo, except for one study that revealed 12-F 2t -IsoP and its epimer, 12-epi-12-F 2t -IsoP, induced pig retinal and brain vasoconstriction in a dose-dependent manner [START_REF] Hou | Isomerspecific contractile effects of a series of synthetic f2-isoprostanes on retinal and cerebral microvasculature[END_REF].

In addition to F 2 -IsoPs exhibiting biological activities, arachidonic acid-derived E-ring IsoPs were widely studied. For instance, 15-E 2t -IsoP, one of the two IsoPs (together with 15-F 2t -IsoP) that was available for biological testing in the early years, has shown to be a renal vasoconstrictor that caused a reduction in the glomerular capillary pressure and filtration rate at low nanomolar range [START_REF] Morrow | Free radical-induced generation of isoprostanes in vivo. Evidence for the formation of D-ring and E-ring isoprostanes[END_REF]. This 15-E 2t -IsoP was even more potent than 15-F 2t -IsoP in activation of TP and EP 3 receptors [START_REF] Janssen | Involvement of TP and EP3 receptors in vasoconstrictor responses to isoprostanes in pulmonary vasculature[END_REF][START_REF] Cracowski | Isoprostaglandin E2 type-III (8-iso-prostaglandin E2) evoked contractions in the human internal mammary artery[END_REF]. Furthermore, 15-E 2t -IsoP has been reported to activate intestinal epithelial cells contraction [START_REF] Elmhurst | Intestinal effects of isoprostanes: evidence for the involvement of prostanoid EP and TP receptors[END_REF], stimulate the binding of monocytes to the endothelial cells [START_REF] Huber | The isoprostane 8-iso-PGE2 stimulates endothelial cells to bind monocytes via cyclic AMP-and p38 MAP kinase-dependent signaling pathways[END_REF], exert contractile activity on gastrointestinal smooth muscle [START_REF] Sametz | Characterization of prostanoid receptors mediating actions of the isoprostanes, 8-iso-PGE(2) and 8iso-PGF(2alpha), in some isolated smooth muscle preparations[END_REF] and act as a regulator of the airways [START_REF] Catalli | Receptors and signaling pathway underlying relaxations to isoprostanes in canine and porcine airway smooth muscle[END_REF][START_REF] Joy | 8-iso-PGE2 stimulates anion efflux from airway epithelial cells via the EP4 prostanoid receptor[END_REF]. In contrast, the analogous 15-D 2 -IsoP has received less attention while its chemical total synthesis has been described but being rather an instable compound [START_REF] Brinkmann | Total synthesis of 15-D (2t)-and 15-epi-15-E(2t)-isoprostanes[END_REF].

While D 2 -and E 2 -IsoPs are not the final metabolites of the AA peroxidation pathway, they are subjected to dehydration for the formation of J 2 -and A 2 -IsoP, respectively. Since the depiction of A 2 - [START_REF] Zanoni | First total synthesis of A(2) isoprostane[END_REF] Table 4 Phytoprostanes identified in plants food and algae.

Study

GC-MS [266]

Measurement of plant oils, and urine after plant oil ingestion Olive (OO), linseed (LO), soybean (SO), rapeseed (RO), walnut (WO) and grape seed (GO) oils Urine and plasma before and after grapeseed, soybean or olive oil intake A 1 -, B and J 2 -IsoPs [START_REF] Zanoni | First total synthesis of JS isoprostane[END_REF], their total syntheses and biological activities were investigated extensively. For example, Musiek et al. reported that 15-A 2t -IsoP induced caspase-3 cleavage, leading to apoptosis in the cortical cultures at sub-micromolar concentrations [START_REF] Musiek | Cyclopentenone isoprostanes are novel bioactive products of lipid oxidation which enhance neurodegeneration[END_REF]. Conversely, anti-inflammatory effects of 15-A 2 -IsoPs were also reported by inhibition of the NF-κB pathway in lipopolysaccharide (LPS)-induced macrophages [START_REF] Musiek | Cyclopentenone isoprostanes inhibit the inflammatory response in macrophages[END_REF] and human gestational tissues [START_REF] Lappas | Antiinflammatory effects of the cyclopentenone isoprostane 15-A(2)-IsoP in human gestational tissues[END_REF]. Further, it was mentioned that 15-J 2 -IsoPs, but not 15-A 2 -IsoPs, inhibited inflammatory response via the PPARγ activation and induced RAW264.7 cells apoptosis in a PPARγ-independent manner [START_REF] Musiek | Cyclopentenone isoprostanes inhibit the inflammatory response in macrophages[END_REF].

In comparison to 15-F 2t -IsoPs, EPA-derived IsoPs were discovered only about a decade ago and rendered as one of the least studied IsoPs. Although 5-and 18-series F 3t -IsoPs are theoretically predominant over other regioisomers [START_REF] Gao | Formation of F-ring isoprostane-like compounds (F3-isoprostanes) in vivo from eicosapentaenoic acid[END_REF], no accounts on the bioactivity of 18-F 3t -IsoPs have been reported. The 5-F 3t -IsoPs was able to modulate the release of neurotransmitters in isolated bovine retina [START_REF] Jamil | Role of the nonenzymatic metabolite of eicosapentaenoic acid, 5-epi-5-F3t-isoprostane in the regulation of [(3)H]D-aspartate release in isolated bovine retina[END_REF]. One report on the bioactivity of F 3 -IsoPs by Brooks et al. showed that 15-A 3t -IsoP has antiinflammatory effects on LPS-stimulated macrophages via the inhibition of NF-κB pathways, and inhibitory effect on the formation of foam cells a major step in the pathogenesis of atherosclerosis [START_REF] Brooks | The fatty acid oxidation product 15-A3t-isoprostane is a potent inhibitor of NFkappaB transcription and macrophage transformation[END_REF]. Moreover, Gao et al. reported that 15-J 3 -IsoPs induced Nrf2 expression by inhibiting its negative regulator Keap1 [START_REF] Gao | Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3[END_REF].

Phytoprostanes

Although the primary source of PhytoPs comes from plants, this section reviews their biological activities when exposed to humans. Uptake of PhytoPs in humans is predominantly through ALA-enriched diets because we do not endogenously synthesize ALA. High levels of F 1 -, E 1 -, A 1 -and B 1 -PhytoPs have been found in vegetable oils with the concentration ranging from 0.09 to 99 mg/L [START_REF] Karg | Biologically active oxidized lipids (phytoprostanes) in the plant diet and parenteral lipid nutrition[END_REF]. In the same study, Karg et al. reported that A 1 -PhytoPs, and B 1 -PhytoPs to a lesser extent, inhibited dose-dependently NF-κB transactivation in transfected HEK 293 and LPS-activated RAW264.7 cells [START_REF] Karg | Biologically active oxidized lipids (phytoprostanes) in the plant diet and parenteral lipid nutrition[END_REF]. Also, it was reported that A 1 -PhytoPs, but not B 1 -PhytoPs, induced apoptosis in Jurkat T-cells [START_REF] Karg | Biologically active oxidized lipids (phytoprostanes) in the plant diet and parenteral lipid nutrition[END_REF].

An alternative exposure to PhytoPs is through the inhalation of pollen, of which E 1 -PhytoPs are the most abundant. Studies on human dendritic cells showed that E 1 -PhytoPs inhibited LPS-induced interleukin (IL)-12 production and enhanced T-helper 2 cell polarization [START_REF] Traidl-Hoffmann | Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization[END_REF] via a PPARγ-dependent mechanism [START_REF] Gilles | Pollenderived E1-phytoprostanes signal via PPAR-gamma and NF-kappaB-dependent mechanisms[END_REF]. Recently, the study of PhytoPs has been extended to cells from the central nervous system. Minghetti and co-workers demonstrated B 1 -PhytoPs to be neuroprotective for undifferentiated, but not differentiated, SH-SY5Y cells from H 2 O 2 insult, and promoted oligodendrocyte differentiation partly via PPARγ activation [START_REF] Minghetti | Nonenzymatic oxygenated metabolites of alpha-linolenic acid B1-and L1-phytoprostanes protect immature neurons from oxidant injury and promote differentiation of oligodendrocyte progenitors through PPAR-gamma activation[END_REF]. To date, despite the availability of F 1 -PhytoPs chemical standards [START_REF] Fangour | Total synthesis of the eight diastereomers of the syn-anti-syn phytoprostanes F1 types I and II[END_REF], information about their biological activity in mammals is still missing, and they remain biomarkers for oxidative damage to plants.

Neuroprostanes

Within the regioisomers of NeuroPs, the 4-and 20-series NeuroPs are the most abundant form of NeuroPs while, the other type can be further oxidized. Some of the NeuroP compounds and internal standards were successfully synthesized by the groups of Vidari-Zanoni [START_REF] Zanoni | Asymmetric synthesis of 14-A4tneuroprostane: hunting for a suitable biomarker for neurodegenerative diseases[END_REF], Taber [START_REF] Taber | potential route to neuroprostanes and isoprostanes: preparation of the four enantiomerically pure diastereomers of 13-F4t-neuroP[END_REF] and Durand [START_REF] Durand | Total synthesis of 4(RS)-F4tisoprostane methyl ester[END_REF][START_REF] Oger | The handy use of Brown's P2-Ni catalyst for a skipped diyne deuteration: application to the synthesis of a [D4]-labeled F4t-neuroprostane[END_REF][START_REF] Guy | Oxygenated metabolites of n-3 polyunsaturated fatty acids as potential oxidative stress biomarkers: total synthesis of 8-F3t-IsoP, 10-F4t-NeuroP and [D4]-10-F4t-NeuroP[END_REF]. Remarkably, elevation of F 4 -NeuroPs was detected in the brain tissue of patients with neurodegenerative diseases like Alzheimer's diseases (AD) and hence it has been recognised as a reliable biomarker for neural oxidative damage. The first study on the bioactivity of NeuroP used 14-A 4 -NeuroPs by Musiek and colleagues described 14-A 4 -NeuroPs as a potent anti-inflammatory mediator, inhibiting NF-κB activation in LPS-induced macrophages [START_REF] Musiek | Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid[END_REF]. Similarly, Majkova et al. showed that A 4 /J 4 -NeuroPs, prepared from DHA, to down-regulate PCB77-induced monocyte chemo-attractant protein-1 expression and Nrf2 activation in primary pulmonary endothelial cells [START_REF] Majkova | Omega-3 fatty acid oxidation products prevent vascular endothelial cell activation by coplanar polychlorinated biphenyls[END_REF]. It is worth noting that IsoPs/PhytoPs/NeuroPs with A-or J-ring structure displayed anti-inflammatory effects, primarily via the inhibition of NF-κB pathways with or without the activation of PPARγ, whereas F-ring isoprostanoids consistently failed to exhibit any beneficial effects in these models. Nevertheless, 4(RS)-4-F 4t -NeuroP has recently displayed cardiac anti-arrhythmic properties in vitro and in vivo via the protection of the ryanodine receptor [START_REF] Roy | Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid[END_REF]. In another follow up study by the same group, 4(RS)-4-F 4t -NeuroP has shown to protect ischemia-reperfusion damages by down-regulating the release of cytochrome c and caspase 3 activity [START_REF] Roy | Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F4t-neuroprostane protects the heart against reperfusion injury[END_REF]. In addition, 4(RS)-4-F 4t -NeuroP exerted anti-proliferative effects in the human breast cancer cell line (MDA-MB-231), and even more potently when encapsulated in poly-ε-caprolactone (PεCL) nanocapsules [START_REF] Roy | Polymeric nanocapsules prevent oxidation of core-loaded molecules: evidence based on the effects of docosahexaenoic acid and neuroprostane on breast cancer cells proliferation[END_REF]. More recently, the anti-inflammatory effects of 4(RS)-4-F 4t -NeuroP and 14-A 4t -NeuroP were compared with the well-known enzymatically derived anti-inflammatory lipid mediators NDP1 and PDX. The result suggested cyclopentenone NeuroPs or F-type NeuroP i.e. 4(RS)-4-F 4t -NeuroP and 14-A 4t -NeuroP possess anti-inflammatory activities similar to the protectins in human macrophages [START_REF] Bosviel | DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose-dependently modulate the inflammatory response in human macrophages: putative mechanisms through PPAR activation[END_REF]. Consequently, 4(RS)-4-F 4t -NeuroP is the very first F-ring isoprostanoid compound to show bioactivities in mammalian cells, this could potentially be extrapolated into other cell types and species. This gives rise to the question whether the elevated amount of F 4 -NeuroPs in AD patients is the cause or the consequence of neurodegenerative diseases, and if these F 4 -NeuroPs play a role in diseases regulation.

Outlook and conclusions

Insofar, isoprostanoids have generally been used as biomarkers of oxidative damage in mammalian diseases or for plant injuries. Only for 15-F 2t -IsoP, metabolism and excretion has been described. However, the use of isoprostanoids as oxidative stress biomarkers in general has suffered largely from the misconception that a single isomer is suitable to reflect oxidative damage. Obviously, different cells and tissues have different PUFA composition and content. In turn, specific isoprostanoids should serve as tissue and cell specific oxidative stress markers. For example, 15-F 2t -IsoP might reflect blood related oxidative injury of peripheral cells and tissue, while the 4-F 4t -NeuroPs needs to be investigated when concerning neurological conditions. Furthermore, it was shown that isoprostanoids originating from n-3 PUFA have biological activities. Although more research needs to be conducted, protective mechanisms from muscle injuries to cancer have been described. Frequently the limitation for more detailed studies is the lack of pure compounds. This also limits the validation of analytical methods, where poor availability of the unique isoprostanoids restricts quantitative measurements. However, with the precursor and transition ions published here, and mass spectrometry spectra for LC-MS/MS, at least one can undertake qualitative evaluation of the isoprostanoids.

No doubt, there are much needs to understand about the role of isoprostanoids in marine biology. Despite being abundant in PUFA, little is known about isoprostanoids and their physiological and biological presence in marine organisms. Further, due to climate change and environmental pollution, isoprostanoids are probably released in PUFA rich marine species; whether they are detrimental or beneficial in reproduction and development is unknown.

Further, using the appropriate isoprostanoids, large human population studies need to be conducted using mass spectrometry based analysis to warrant specificity, ultimately allowing a final assessment of the usefulness of the isoprostanoids as specific oxidative damage markers [START_REF] Milne | Classifying oxidative stress by F2-Isoprostane levels in human disease: the re-imagining of a biomarker[END_REF]. Additionally, isoprostanoids such as dihomo-IsoPs and NeuroPs may be characteristic for white and grey matter damage respectively possibly presenting diseases specific biomarkers.

This review presents a comprehensive overview of isoprostanoid chemistry and biology over the past three decades hopefully helping the community to understand the role of these non-enzymatic PUFA derivatives in health and disease.

  . The epoxy-IsoPs biosynthesis (in orange Scheme 1) follows the same pathway as the formation of the G 2 -IsoP intermediate, but the endoperoxide is first reduced into the hydroperoxy-D 2 -IsoP compound. Then, dehydration occurs due to the acidity of the α-keto hydrogen atom and the hydroperoxy function, leading to the formation of an epoxide (orange arrows Scheme 1) to give epoxy-D 2 -IsoPs. Epoxy-D 2-IsoPs were shown to dehydrate spontaneously to

5 Scheme 2 .

 52 Scheme 2. Generation of tetrasubstituted phytoprostanes (PhytoP) B 1 and L 1 in basic condition from cyclopentenone derivatives.

Scheme 10 .Scheme 11 .

 1011 Scheme 10. One chain containing structure prior to cyclization synthetic strategy.

. In the three examples shown in Scheme 11, different core structures are prepared before the

	J.-M. Galano et al.	Progress in Lipid Research 68 (2017) 83-108
	Scheme 4. The two F-series of phytoprostane (PhytoP)
	isomers derived from α-linolenic acid
	Scheme 5. F 3 -isoprostane isomers derived from eicosapentaenoic acid. IsoP: isoprostane.

Table 1

 1 Isoprostanoid characteristic fragmentations and sample materials with described appearance. For additional analytical characteristics please refer to Supplementary information (List 1).

	HO				HO					HO
		C 5 H 11	CO 2 H	β-Oxidation -CH 3 CO 2 -	CO 2 H C 5 H 11	Δ 3 -Reductase	CO 2 H C 5 H 11
	HO	OH		Human	HO	OH			Human	HO	OH
	15-F 2t -IsoP		Rat	2,3-Dinor-15-F 2t -IsoP			Rat	2,3-Dinor-5,6-dihydro-15-F 2t -IsoP
										HO	Rat	β-Oxidation -CH 3 CO 2 -
											CO 2 H
											C 5 H 11
										HO	OH
										2,3,4,5-Tetranor-15-F 2t -IsoP
	HO	OH		CO 2 H	dehydrogenase reductase	HO		OH		CO 2 H	isomerase	HO	OH CO 2 H
	HO	C 2 H 5			isomerase β-Oxidation	HO		C 2 H 5		β-Oxidation	HO	C 2 H 5
		10-F 4t -NeuroP				2,3,4,5-tetranor-10-F 4 -NeuroP	2,3,4,5,6,7-hexanor-10-F 4 -NeuroP
	HO	OH		CO 2 H	HO	OH	CO 2 H	HO	(CH 2 ) 7 CO 2 H	HO	CO 2 H
	HO	C 2 H 5 9-F 1 -PhytoP		HO 2,3,4,5-tetranor-9-F 1 -PhytoP C 2 H 5 β-Oxidation		16-F 1 -PhytoP HO OH C 2 H 5	HO 2,3,4,5,6,7-hexanor -16-F 1 -PhytoP OH C 2 H 5 β-Oxidation

Fig. 1. Known metabolic pathways of 15-F 2t -IsoP, 10-F 4t -NeuroP, and 9-F 1 -PhytoP and potential metabolites for excretion. IsoP: isoprostane; NeuroP: neuroprostane; PhytoP: phytoprostane.

Table 1 (

 1 continued)

	Compounds	Precursor/	Presumed fragmentation	Sample	Reference
		product ion m/z
	ent-2,3-dinor-5,6	T1: 327.2/		Human urine	[164]
	dihydro-15-F 2t -	283.2		Fish muscle tissue	[170]
	IsoP			Mouse urine	[157]
		T2: 327.2/
		209.1
	Adrenic acid
	7(RS)-7-F 2t -dihomo-	T1: 381.3/		Human urine	[171]
	IsoP	143.0		Pig brain	[160]
		T2: 381.3/
		363.1
	17(RS)-17-F 2t -	T1: 381.3/		Human urine	[171]
	dihomo-IsoP	319.2		Pig brain tissue	[160]
				Mouse brain	[157]
		T2: 381.3/
		263.1
					(continued on next page)

Table 1 (

 1 continued)

	Compounds	Precursor/	Presumed fragmentation	Sample	Reference
		product ion m/z
	Eicosapentaenoic acid
	5(RS)-5-F 3t -IsoP	T1: 351.2/		Nematode	[172]
		115.0		Fish muscle	[170]
		T2: 351.2/
		333.0
	8(RS)-8-F 3t -IsoP	T1: 351.3/
		127.1
		T2: 351.3/
		155.0
	18(RS)-18-F 3t -IsoP	T1: 351.2/
		289.1
		T2: 351.2/
		275.0
	Docosahexaenoic acid
	4-F 3t -NeuroP	T1: 379.2/		Human urine	[171]
		101.0
		T2: 379.2/
		299.3

(continued on next page)

Table 1 (

 1 continued)

	Compounds	Precursor/	Presumed fragmentation	Sample
		product ion m/z

Table 1 (

 1 continued)

	Compounds	Precursor/	Presumed fragmentation	Sample	Reference
		product ion m/z
	20(RS)-20-F 4t -	T1: 377.3/
	NeuroP	315.2
		T2: 377.3/
		323.0
	α-Linolenic acid
	16(RS)-16-A 1t -	T1: 307.2/		Plant cell culture: N.	[19]
	PhytoP	289.2		tabacum, G. max, R.
				serpentina, A. tenuis
		T2: 307.2/
		249.0
	16-B 1t -PhytoP	T1: 307.2/		Walnut, Macadamia, Pecan	[173]
		235.0		Almonds	[113]
				Olive oil, Sunflower oil	[174]
				Passiflora edulis Sims. Shell	[175]
				Macroalgae	[176]
				Melon leaves	[177]
		T2: 307.2/
		223.0
	9(RS)-9-D 1t -PhytoP	T1: 325.0/		Walnut, Macadamia, Pecan	[173]
		289.0		Almonds	[113]
				Olive oil, Sunflower oil	[174]
				Passiflora edulis Sims. Shell	[175]
				Macroalgae	[176]
				Melon leaves	[177]
		T2: 325.0/
		123.0

(continued on next page)

Table 1 (

 1 continued)

	Compounds	Precursor/	Presumed fragmentation	Sample	Reference
		product ion m/z
	9(RS)-9-F 1t -PhytoP	T1: 327.2/		Walnut, Macadamia, Pecan	[173]
		283.2		Almonds	[113]
				Olive oil, Sunflower oil	[174]
				Passiflora edulis Sims. Shell	[175]
				Macroalgae	[176]
				Melon leaves	[177]
		T2: 327.2/
		171.2
	ent-16(RS)-16-F 1t -	T1: 327.2/		Walnut, Macadamia, Pecan	[173]
	PhytoP	283.2		Almonds	[113]
				Olive oil, Sunflower oil	[174]
				Passiflora edulis Sims. Shell	[175]
				Macroalgae	[176]
				Melon leaves	[177]
		T2: 327.2/
		251.2
	9-L 1t -PhytoP	T1: 307.2/		Walnut, Macadamia, Pecan	[173]
		185.1		Almonds	[113]
				Olive oil, Sunflower oil	[174]
				Passiflora edulis Sims. Shell	[175]
				Macroalgae	[176]
				Melon leaves	[177]

T1: 307.2/ 197.0 Arrow in the compound structure indicates the cleavage of the product ion from the precursor. T1: transition 1; T2: transition 2; IsoP: isoprostane; dihomo-IsoP: dihomo-isoprostane; NeuroP: neuroprostane; PhytoP: phytoprostane.

Table 2

 2 15-F 2t -IsoPs and metabolites (15-F 2t -IsoP-M) and 5-F 2t -IsoPs (+) used as biomarkers to indicate human disease status related to oxidative stress published up to 2016.

	Subjects	Sample	Disease	Method	Reference
			vs
			control
	Neurological
	Alzheimer's disease	Brain tissue (19)	↑	GC-MS	[178]
		Urine (9)	↔	GC-MS	[179]
		Plasma
		Free (12)	↔
		Total (12	↔
		CSF (41)	↑	GC-MS	[180]
		Urine (56)
		15-F 2t -IsoP	↔
		15-F 2t -IsoP-M	↔
		Urine + (50)	↑	GC-MS	[181]
		Plasma + (50)	↑
		CSF + (50)	↑
		Brain tissue (5)	↔	GC-MS	[182]
		Plasma (49)	↔	GC-MS	[183]
		CSF (9)	↔	GC-MS	[184]
	Parkinson's disease	Brain tissue (6)	↔	GC-MS	[185]
		Brain tissue (7)	↔	GC-MS	[182]
		Plasma (47)	↔	GC-MS	[183]
		Plasma (25)	↔	GC-MS	[99]
		Anterior cingulate	↑	GC-MS	[186]
		cortex (9)	↔
		Occipital cortex
		(9)
	Schizophrenic	Brain tissue (10)	↔	GC-MS	[185]
		Plasma (134)	↑	GC-MS	[187]
	Huntington's disease	Urine (11)	↔	GC-MS	[179]
		Plasma
		Free (20)	↔
		Total (19)	↔
	Mild cognitive	Urine + (33)	↑	GC-MS	[181]
	impairment	Plasma + (33)	↑
		CSF + (33)	↑
		Plasma (47)	↔	GC-MS	[183]
		CSF (9)	↔	GC-MS	[184]
	Multiple system	Brain tissue (4)	↔	GC-MS	[182]
	atrophy
	Dementia	Brain tissue (4)	↔	GC-MS	[182]
	Stroke	Plasma (21)		GC-MS	[99]
		Total	↑
		Free	↔
		Urine	↑
		Plasma (44)	↑	GC-MS	[188]
		Urine (82)	↑	ELISA	[189]
	Brain injury	CSF (18)	↑	GC-MS	[190]
	Aneurysmal
	subarachnoid
	hemorrhage
	(aSAH)
	Traumatic brain injury	CSF (18)	↔	GC-MS	[191]
	(TBI)	Plasma (15)	↑
		CSF (15)	↑
	Epilepsy	Urine (60)	↑	ELISA	[192]
		Plasma (34)	↑	GC-MS	[193]
	Down syndrome	Urine (48)		LC-MS/MS	[194]
		15-F 2t -IsoP-M	↔
	Reversible cerebral	Urine (103)	↑	LC-MS/MS	[195]
	vasoconstriction
	syndrome
	Autism (children)	Plasma (29)	↑	GC-MS	[196]
		Plasma (44)	↑	ELISA	[197]
	Intermittent explosive	Plasma (69)	↑	ELISA	[198]
	disorder
	Hypoxic-ischemic	Cord serum (20)	↑	LC-MS/MS	[199]
	encephalopathy
	Neuroborreliosis	Plasma (22)		LC-MS/MS	[200]
		Total	↑
		Free	↑
		Urine (22)	↑
		CSF (22)	↑
				(continued on next page)

Table 2 (

 2

	continued)					Table 2 (continued)
	Subjects	Sample	Disease	Method	Reference	Subjects	Sample	Disease	Method	Reference
			vs					vs
			control					control
	Cardiovascular					Non-alcoholic fatty	Plasma (90)	↑	ELISA	[233]
	Asymptomatic and	Carotid plaques	↑	LC-MS/MS [201]	liver disease
	symptomatic atherosclerosis Mild-Moderate hypertension Hypertension Obstructive sleep apnea Coronary artery disease Urine (799) (30) Urine (30) Plasma (155) Urine (155) Urine (31) Plasma (22) Urine (22) Urine (116) Plasma (128) Urine (86) Peripheral artery Plasma (115) disease Heart failure Plasma (36)	↔ ↔ ↔ ↑ ↑ ↑ ↔ ↑ ↑ ↑ ↑ ↔	GC-MS GC-MS ELISA ELISA ELISA ELISA LC-MS/MS ELISA ELISA GC-MS	[202] [203] [204] [205] [206] [207] [208] [209] [210] [211]	Others Thalassemia Dengue fever Preeclampsia hepatic, and Sepsis related to renal,	Plasma (17) Urine (17) Plasma (35) Total Free Urine (19) Amniotic fluid (46) Plasma-Maternal (23) Plasma-Cord (23) Plasma (33) Plasma + (33) Plasma (15-19)	↑ ↑ ↑ ↑ ↑ ↑ ↔ ↔ ↔ ↑ ↑	GC-MS GC-MS LC-MS GC-MS LC-MS/MS [237] [234] [99] [235] [236] GC-MS [238]
	Cancer					coagulation failure
	Prostate	Urine (304)	↑	ELISA	[212]	Periodontal disease	Saliva (50)	↑	LC-MS/MS [100]
	Uterine leiomyomas	Urine (20)	↔	ELISA	[213]	Influenza A	Plasma (35)	↑	GC-MS	[239]
	(fibroids)						Urine (35)	↔
	Breast	Urine (79)	↔	RIA	[214]	Oral lichen planus	Plasma (31)	↑	ELISA	[240]
	Esophageal	Proximal gastric	↑	ELISA	[215]	Critically ill patients	Plasma (38)	↑	LC-MS/MS [241]
	adenocarcinoma	mucosa (24)				Community acquired	Serum (50)	↑	ELISA	[242]
	Pulmonary dysfunction Asthma	Sputum (71)	↑	ELISA	[216]	pneumonia Rheumatoid arthritis	Free Plasma (73)	↓	LC-MS/MS [243]
	Diabetes						Esterified	↑
	Type 2 DM	Plasma (10)	↔	ELISA	[217]		Urine (73)	↑
		Urine (10)	↑			Paediatric sepsis	Plasma (42)	↑	ELISA	[244]
		Plasma (20)	↑	ELISA	[216]	Helicobacter pylori	Exhaled breath	↑	ELISA	[245]
		Plasma (21)	↑	LC-MS	[218]	infection	condensate (41)
		Urine (21)	↑
		Plasma (8)	↔	GC-MS	[219]
		Plasma (40)	↑	GC-MS	[220]
		Free	↑
		Esterified
		Urine	↑
		15-F 2t -IsoP	↑
		15-F 2t -IsoP-M
		Atherosclerotic	↓	GC-MS	[221]
		plaques (5)
	Type 1 DM	Plasma (38)	↔	RIA	[222]
		Urine (38)	↔
	Metabolic syndrome	Plasma (10)	↑	ELISA	[223]
		Plasma (45)	↔	GC-MS	[224]
		Free	↔
		Esterified
		Urine	↔
		15-F 2t -IsoP	↔
		15-F 2t -IsoP-M
	Renal dysfunction
	Nephrotic syndrome	Plasma (14)	↔	GC-MS	[225]
		Urine (14)
		15-F 2t -IsoP	↔
		2,3-dinor-8-iso-	↔
		PGF2a
	Chronic kidney disease	Plasma (60)	↑	GC-MS	[226]
		Plasma (184)	↑	GC-MS	[227]
		Plasma (87)	↔	GC-MS	[228]
	Acute renal graft	Serum (55)	↑	ELISA	[229]
	dysfunction
	Liver
	Biliary cirrhosis	Plasma (41)	↑	ELISA	[230]
		Urine (41)	↑
	Autoimmune hepatitis	Plasma (33)	↑	ELISA	[231]
		Urine (33)	↑
	Alcoholic liver disease	Plasma (24)	↑	ELISA	[232]
		Urine (24)	↑
		Plasma (63)	↑	ELISA	[233]

Annotations indicate ↑: increase, ↓ decrease and ↔ no change compared to controls. Numbers in the parentheses are the number of subjects in the study. ELISA: enzymelinked immunosorbent assay; GC: gas chromatography; LC: liquid chromatography; MS: mass spectrometry.

Table 3

 3 Isoprostanes and metabolites, and neuroprostanes detected in marine samples and environmental stressor related studies published up to 2016.

	Study

Table 5

 5 Neuroprostanes (F 4 -NeuroPs and A 4 /J 4 -neuroprostanes) identified and/or used as biomarkers and to indicate human disease status related to oxidative stress published up to 2016. Annotation indicates A 4 /J 4 -neuroprostanes, otherwise it is F 4 -neuroprostanes. Arrows indicate ↑ increase, ↓ decrease and ↔ no change compared to controls. PhytoP: phytoprostane;

	J.-M. Galano et al.		Progress in Lipid Research 68 (2017) 83-108
	Study	Sample	Outcome	Method	Reference
	Biological studies
	Oxidative damage to brain by kainic acid	Rat cerebrum	↑ After 2 h injection;	GC-MS	[180]
		Rat urine	↔ From baseline after injection.
	Characterization of NeuroPs using rat model	Liver treated with	↑ 4-and 10-series NeuroPs were elevated in the	LC-MS	[23]
		CCl 4	liver;	GC-MS
		Brain	NeuroPs were identified in brain.
	Mice supplemented with fish oil (FO) and induced with or without	Lung	↑ FO vs control;	GC-MS	[270]
	inflammation		↑ FO + inflammation vs FO.
	Zebrafish under hypoxia	Brain	↔ Before vs after hypoxia.	GC-MS	[249]
	Sonoporation of Jurkat cells	Cells	↔ Sonoporated vs non-sonoporated.	LC-MS/MS	[72]
	Rats fed with alcohol with or without sweet grass (antioxidant) beverage Brain a	↑ Alcohol vs control;	LC-MS/MS	[113]
			↔ Sweet grass vs control;
			↔ Alcohol + sweet grass vs control;
			↓ Alcohol + sweet grass vs alcohol.
	Rats liver injury by CCl 4 and supplemented with high fat diet of extra	Liver	↑ EVOO, CO, lard vs control;	LC-MS/MS	[271]
	virgin olive oil (EVOO) or corn oil (CO) or lard		↓ EVOO + CCl 4 group vs CCl 4 group;
			↔ CO + CCl 4 or lard + CCl 4 group vs CCl 4 group.
	Human studies
	Healthy and smoker volunteers	Plasma	↑ Smokers' vs healthy;	GC-MS	[272]
			↑ Smokers after cigarette smoking.
	Healthy controls and ischemic-stroke patients	Plasma	↑ Ischemic-stroke vs control.	GC-MS	[273]
	Type 2 diabetic patients with or without zinc supplementation	Plasma	↑ Diabetic vs non-diabetic controls;	GC-MS	[220]
			↔ Diabetic placebo supplementation vs diabetic zinc
			supplementation.
	Normal pregnancy and pre-eclampsia pregnancy	Maternal and cord	↑ Maternal plasma normal vs eclampsia;	GC-MS	[236]
		blood plasma	↑ Cord plasma normal vs eclampsia.
	Female Rett syndrome patients with or without fish oil	Plasma	↓ Before vs after fish oil supplementation.	GC-MS/MS [65]
	Influenza A patients and healthy controls	Plasma	↔ Acute illness vs control;	GC-MS	[239]
			↓ Acute illness vs 3 months post illness.
	Mild Alzheimer's disease (AD), amnestic mild cognitive impairment (a-	CSF	↔ AD or a-MCI vs control;	GC-MS	[184]
	MCI) and healthy control		↔ AD vs a-MCI.
	Female patients with MECP2 gene and Rett syndrome patients with	Plasma	↑ Rett patients vs healthy controls;	GC-MS/MS [274]
	typical presentation, supplemented with or without fish oil		↓ Rett patients before vs after supplementation.
	Preterm infants with bronchopulmonary dysplasia (BPD)	Urine	↔ BPD vs control throughout 4 weeks gestation.	LC-MS/MS	[275]
	Epilepsy and control	Urine	↔ Epileptic group vs control.	LC-MS/MS	[102]
	Rett syndrome patients and healthy controls	Skin fibroblast	↑ RTT patients vs control.	GC-MS/MS [276]
	Traumatic brain injury (TBI) and controls	CSF	↑ TBI patients post-operation vs control.	GC-MS	[191]
	Tick-borne encephalitis (TBE) patients and healthy subjects	Plasma a	↑ TBE vs control.	LC-MS/MS	[114]
	Athletes in altitude training (hypoxia)	Urine	↑ Before vs after training.	LC-MS/MS	[277]
	Neuroborreliosis (NB) patients and antibiotics treatment	Urine, plasma, CSF	↑ NB vs control in CSF and plasma;	LC-MS/MS	[200]
			↓ Before vs after in NB CSF and plasma;
			Urine levels were not detectable.
	Down syndromes and controls	Plasma	↑ Down syndrome vs control.	GC-MS/MS [278]
	Healthy females before and after wine intake	Urine	↓ Before vs after and postulated to be due to	LC-MS/MS	[279]
			phenolic compound, hydroxytyrosol.
	Epilepsy and new generation drug treatment	Urine	↔ Epileptic patient vs control;	LC-MS/MS	[280]
			↑ Epileptic patient or control vs epileptic patients
			with new-generation antiepileptic drugs.
	MECP2 Duplication Syndrome (MDSS), Rett syndrome patients and	Plasma	↑ MDS or Rett vs Control;	GC-MS/MS [281]
	control		↔ MDS vs Rett.
	GC: gas chromatography; LC: liquid chromatography; MS: mass spectrometry.

a

Acknowledgments

JCYL would like to thank Small Project Funding (201409176019), The University of Hong Kong for the support of this work.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.plipres.2017.09.004.