GYY 4137 morpholine salt synthesis Eicosanoids are locally a

Eicosanoids are locally acting signaling lipids that are produced from C20 polyunsaturated fatty acids (PUFAs), including arachidonic GYY 4137 morpholine salt synthesis (AA, C20:4), eicosapentaenoic acid (C20:5) and eicosatrienoic acid (C20:3) (Dennis and Norris, 2015; Funk, 2001; Stables and Gilroy, 2011). According to their biosynthesis, they are subdivided into three major groups (Fig. 1): i) cyclooxygenase (COX)-derived prostanoids, i.e., prostaglandin (PG)E2, D2, F2α, I2 and thromboxane (Tx)A2, ii) lipoxygenase (LO)-derived (poly)hydroxylated and/or epoxydated PUFAs, including leukotrienes (LTs), lipoxins, and E-series resolvins, and iii) cytochrome P450 monooxygenase-derived epoxyeicosatrienoic acids (EETs) and PUFA (di)hydroxides. As part of a complex network of bioactive lipid mediators, eicosanoids regulate multiple homeostatic and inflammatory processes through G-protein-coupled and nuclear receptors (Back et al., 2014; Shimizu, 2009). Oxygenized metabolites of AA, in particular PGE2 and LTs, have been early recognized to promote inflammation (Funk, 2001), whereas lipoxins, epoxyeicosatrienoic acids and E-series resolvins possess anti-inflammatory activity by modulating leukocyte activation and cytokine release (Fig. 1) (Serhan, 2014; Stables and Gilroy, 2011). Moreover, many eicosanoids, including PGE2, combine immunomodulatory, pro-inflammatory and pro-resolving activities dependent on their local concentration, kinetics and responsive tissue, the latter due to tissue-specific expression of eicosanoid receptor isoforms (Koeberle and Werz, 2015; Shimizu, 2009). The enzymatic machinery that oxygenizes C20 PUFAs also accepts C22 fatty acids leading to docosanoids (D-series resolvins, protectins, maresins) that actively participate in the resolution of inflammation (Serhan, 2014). The biosynthesis of eicosanoids is initiated by phospholipases (PL)A2, which release C20 PUFAs from the sn-2 position of membrane phospholipids (Dennis et al., 2011; Funk, 2001). PLA2s represent a large family of >30 different enzymes (Leslie, 2015). The isoenzyme cytosolic PLA2α (cPLA2α) is essential for the massive eicosanoid biosynthesis during inflammation (Leslie, 2015) and regulates the supply of AA in concert with secretory PLA2s (Quach et al., 2014), monoacylglycerol lipase (Tuo et al., 2017) and lysophospholipid acyltransferases (Shindou et al., 2013). Activation of cPLA2α depends on (receptor-mediated) intracellular Ca2+-influx and phosphorylation (Dennis et al., 2011; Leslie, 2015). Prostanoid biosynthesis involves the dioxygenation of AA to the hydroperoxide PGG2 and the subsequent reduction to PGH2 by COX, an integral enzyme of the endoplasmic reticulum and perinuclear region (Dennis and Norris, 2015; Funk, 2001; Smith et al., 2000). The isoform COX-1 is expressed in most cell types and contributes to the production of prostanoids with important physiological, homeostatic functions but also provides AA for eicosanoid biosynthesis under specific inflammatory conditions. The expression of COX-2 is strongly upregulated by pro-inflammatory stimuli, such as pathogen-associated molecular patterns (PAMPs), cytokines and hormones, both in specialized and non-specialized immune cells (monocytes, neutrophils and fibroblasts). Constitutively expressed COX-2 is found in brain, kidney and stomach and possesses physiological functions in immune regulation, tissue repair as well as water and salt balance (Rainsford, 2007; Smith et al., 2000). The multi-facetted prostanoid profiles are shaped by downstream prostanoid synthases which convert PGH2 to respective prostanoids and are tissue- and cell-type specifically expressed (Koeberle and Werz, 2015). For example, PGE2 - the major pro-inflammatory PG that promotes inflammation, fever and pain - is generated by three different prostaglandin E2 synthase isoenzymes, namely microsomal prostaglandin E2 synthase-1 (mPGES-1), mPGES-2 and cytosolic prostaglandin E2 synthase (cPGES) (Hara et al., 2010; Koeberle and Werz, 2009). mPGES-1 is an inducible enzyme that preferentially receives its substrate from co-induced COX-2 and is responsible for excessive PGE2 formation during acute and chronic inflammation (Koeberle and Werz, 2009; Samuelsson et al., 2007).