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![A model for PLA 2 -mediated pathways for AA metabolism in P388D 1 macrophages. PAF receptor-mediated AA mobilization in lipopolysaccharide (LPS)-primed P388D 1 macrophages involves the action of two distinct Ca 2 -dependent PLA 2 s, i.e. cPLA 2 and sPLA 2 , acting on different AA pools located at distinct cellular membranes. The iPLA 2 mediates incorporation of AA at these two intracellular locations before further remodeling reactions take place. PGE 2 , prostaglandin E 2 ; PLC, phospholipase C; FA, fatty acid; [1,4,5]-IP 3 , inositol 1,4,5-trisphosphate; R, fatty acid or alcohol; PX, phosphobase. Adapted with permission from Ref. 21.](publication/14023184/figure/fig2/AS:340565624410113@1458208580067/A-model-for-PLA-2-mediated-pathways-for-AA-metabolism-in-P388D-1-macrophages-PAF.png)
A model for PLA 2 -mediated pathways for AA metabolism in P388D 1 macrophages. PAF receptor-mediated AA mobilization in lipopolysaccharide (LPS)-primed P388D 1 macrophages involves the action of two distinct Ca 2 -dependent PLA 2 s, i.e. cPLA 2 and sPLA 2 , acting on different AA pools located at distinct cellular membranes. The iPLA 2 mediates incorporation of AA at these two intracellular locations before further remodeling reactions take place. PGE 2 , prostaglandin E 2 ; PLC, phospholipase C; FA, fatty acid; [1,4,5]-IP 3 , inositol 1,4,5-trisphosphate; R, fatty acid or alcohol; PX, phosphobase. Adapted with permission from Ref. 21.
Citations
... Different classes of PLA2 molecules play a major role in lung cancer through various signaling mechanisms (Laye and Gill, 2003;Cummings et al., 2000;Balsinde and Dennis, 1997) (Fig. 3). The membrane phospholipids are hydrolyzed by the secreted/cytosolic/calcium-independent phospholipases to a variety of lipid mediators that take part in pathways responsible for the induction of cancer (Thotala et al., 2013;. ...
... Release of AA is mediated through the action of the phospholipase A 2 (PLA 2 ) family of enzymes, and this usually represents the rate limiting step in eicosanoid production (Nakanishi and Rosenberg, 2006). The major isoform of PLA 2 implicated in regulated release of AA is Group IVA, designated cPLA 2 (Gronich et al., 1990;Balsinde and Dennis, 1997). This enzyme has specificity for arachidonic acid-containing phospholipids, is ubiquitously expressed and in resting cells is generally located in the cytoplasm (Clark et al., 1990;Bonventre, 1992;Leslie, 1997). ...
Eicosanoids represent a family of active biolipids derived from arachidonic acid primarily through the action of cytosolic phospholipase A2-α. Three major downstream pathways have been defined: the cyclooxygenase (COX) pathway which produces prostaglandins and thromboxanes; the 5-lipoxygenase pathway (5-LO), which produces leukotrienes, lipoxins and hydroxyeicosatetraenoic acids, and the cytochrome P450 pathway which produces epoxygenated fatty acids. In general, these lipid mediators are released and act in an autocrine or paracrine fashion through binding to cell surface receptors. The pattern of eicosanoid production is cell specific, and is determined by cell-specific expression of downstream synthases. Increased eicosanoid production is associated with inflammation and a panel of specific inhibitors have been developed designated non-steroidal anti-inflammatory drugs. In cancer, eicosanoids are produced both by tumor cells as well as cells of the tumor microenvironment. Earlier studies demonstrated that prostaglandin E2, produced through the action of COX-2, promoted cancer cell proliferation and metastasis in multiple cancers. This resulted in the development of COX-2 inhibitors as potential therapeutic agents. However, cardiac toxicities associated with these agents limited their use as therapeutic agents. The advent of immunotherapy, especially the use of immune checkpoint inhibitors has revolutionized cancer treatment in multiple malignancies. However, the majority of patients do not respond to these agents as monotherapy, leading to intense investigation of other pathways mediating immunosuppression in order to develop rational combination therapies. Recent data have indicated that PGE2 has immunosuppressive activity, leading to renewed interest in targeting this pathway. However, little is known regarding the role of other eicosanoids in modulating the tumor microenvironment, and regulating anti-tumor immunity. This article reviews the role of eicosanoids in cancer, with a focus on their role in modulating the tumor microenvironment. While the role of PGE2 will be discussed, data implicating other eicosanoids, especially products produced through the lipoxygenase and cytochrome P450 pathway will be examined. The existence of small molecular inhibitors and activators of eicosanoid pathways such as specific receptor blockers make them attractive candidates for therapeutic trials, especially in combination with novel immunotherapies such as immune checkpoint inhibitors.
... PLA 2 s have been classified into I-XVI groups according to several criteria such as amino acid sequence similarity, cellular function and active splice variants [1][2][3][4][5][6]. Among them, group IIA PLA 2 s are secreted enzymes (14)(15)(16) and include mammalian enzymes found in inflammatory exudates and those from viperid snake venoms. Group IIA secreted PLA 2 s (sPLA 2 s) from snake venoms can be further subdivided into two subgroups: (a) the Asp49 enzymes which have an aspartic acid residue at position 49 and high catalytic activity on artificial phospholipid substrates, and (b) the Lys49 enzyme homologues, which have a lysine residue at position 49 and are devoid of hydrolytic activity [7]. ...
... Similarly to sPLA 2 , this iPLA 2 exhibits no substrate specificity for arachidonic acid-containing phospholipids. This iPLA 2 also shares the size, intracellular localization and elements of catalytic mechanism with cPLA 2 [14]. ...
Phagocytosis, a process involved in host defense, requires coordination of a variety of signaling reactions. MT-II, a catalytically-inactive Lys49-PLA2¸ and MT-III, an active Asp49-PLA2isolated from Bothrops asper snake venom, activate phagocytosis in macrophages. In this study the signal pathways mediating zymosan phagocytosis, focusing in lipidic second messengers, were investigated. Macrophages collected from male Swiss mouse peritoneum were obtained 96 h after i.p. injection of thioglycollate. Phagocytosis was evaluated with non-opsonized zymosan in the presence or absence of specific inhibitors. Data showed that both venom PLA2s increased phagocytosis. Zileuton, Etoricoxib, PACOCF3(5-LO, COX-2 and iPLA2inhibitors, respectively), as well as WEB2170 (PAF receptor antagonist) significantly reduced phagocytosis induced by both venom PLA2s. However, Indomethacin (COX-1/COX-2 inhibitor) and Montelukast (CysL receptor antagonist) did not affect the toxins-induced phagocytosis. Moreover, while PACOCF3 (iPLA2inhibitor), reduced the phagocytosis induced by MT-II and MT-III, AACOCF3(cPLA2inhibitor) significantly reduced the MT-II, but not MT-III-induced phagocytosis. These data suggest the effect of both sPLA2s depends on iPLA2and that the effect of MT-II depends on activation of cPLA2. COX-2 and 5-LO-derived metabolites as well as PAF are involved in the signaling events required for phagocytosis induced by both venom sPLA2s.
... Although the observed downregulation of iPLA 2 was relatively small, it may play an important role in the process of CIH-adaptation because iPLA 2 represents the majority of PLA 2 s activity in the heart (McHowat and Creer 2004). The role of iPLA 2 is generally regarded as housekeeping enzyme in phospholipid remodeling (Balsinde and Dennis 1997). However, they also act as phospholipid repair enzymes preferentially splitting oxidatively damaged FA from phospholipids (Cummings et al. 2002). ...
Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia/reperfusion injury. Phospholipases A<sub>2</sub> (PLA<sub>2</sub>s) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8h/day, 5 weeks) on the expression of cytosolic PLA<sub>2</sub> (cPLA<sub>2</sub>α), its phosphorylated form (p-cPLA<sub>2</sub>α), calcium-independent (iPLA<sub>2</sub>) and secretory (sPLA<sub>2</sub>IIA) at protein and mRNA levels as well fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats. Chronic administration of antioxidant tempol was used to verify the ROS involvement in CIH effect on PLA<sub>2</sub>s expression and phospholipid FA remodeling. While CIH did not affect PLA<sub>2</sub>s mRNA levels, it increased the total cPLA<sub>2</sub>α protein in cytosol and membranes (by 191% and 38%, respectively) and p-cPLA<sub>2</sub>α (by 23%) in membranes. On the other hand, both iPLA<sub>2</sub> and sPLA<sub>2</sub>IIA were down-regulated by CIH. CIH further decreased phospholipid n-6 polyunsaturated FA (PUFA) and increased n-3 PUFA proportion. Tempol treatment prevented only CIH-induced cPLA<sub>2</sub>α up-regulation and its phosphorylation on Ser<sup>505</sup>. Our results show that CIH diversely affect myocardial PLA<sub>2</sub>s and suggest that ROS are responsible for the activation of cPLA<sub>2</sub>α under these conditions.
... The term eicosanoids derives from the Greek term eicosa (20) which refers to the peculiarity that all these arachidonic acid derivatives retain the parent 20-carbon structure. In resting cells, arachidonic acid is stored within the cell membrane and esterified to glycerol in the phospholipids, which are the most abundant structural lipid components in mammalian cells [1,2]. Phospholipids are amphipathic molecules composed of a glycerol backbone with two fatty acids esterified to the sn (stereospecific numbering) 1 and 2 positions (sn1 and sn2) and a phosphate group bound to the third hydroxyl group. ...
... Phospholipids are amphipathic molecules composed of a glycerol backbone with two fatty acids esterified to the sn (stereospecific numbering) 1 and 2 positions (sn1 and sn2) and a phosphate group bound to the third hydroxyl group. This phosphate group is esterified to another hydroxyl group on another hydrophilic compound, such as choline, ethanolamine, serine, or inositol, forming different phospholipids with unique properties [1,2]. Upon stimulation, the enzyme phospholipase A 2 (PLA 2 ) catalyzes the hydrolysis of phospholipids at the sn2 position in a single-step reaction, releasing arachidonic acid into the intracellular space [1,2]. ...
... This phosphate group is esterified to another hydroxyl group on another hydrophilic compound, such as choline, ethanolamine, serine, or inositol, forming different phospholipids with unique properties [1,2]. Upon stimulation, the enzyme phospholipase A 2 (PLA 2 ) catalyzes the hydrolysis of phospholipids at the sn2 position in a single-step reaction, releasing arachidonic acid into the intracellular space [1,2]. Other phospholipases such as phospholipase C (PLC) or phospholipase D (PLD) do not release free arachidonic acid directly. ...
The cyclooxygenase (COX) pathway as a whole offers an unprecedented number of therapeutic opportunities, especially in the area of inflammation. Indeed, the COX pathway represents the primary target for nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanism of action of these drugs is the inhibition of COX activity and therefore inhibition of the formation of its biologically active products, namely, prostaglandins (PGs) and thromboxane (TX). In the current chapter, we provide a comprehensive review of the most important molecular and cellular aspects of the COX pathway and describe the most relevant biochemical and biological aspects of COX products in the context of inflammation. In addition, we describe the status of the current anti-inflammatory armamentarium based on compounds targeting the COX pathway, including novel agonists and antagonists of PG receptors. This chapter also includes emerging anti-inflammatory strategies such as NSAID-nitric oxide donors or NSAID-H2S-releasing compounds. Finally, we discuss the potentiality of fighting inflammation by promoting its resolution with the design of stable analogues of the naturally occurring aspirin-triggered lipoxins.
... PLA2 are responsible for the hydrolysis of the sn-2 ester of phospholipids resulting in the release of free PUFA. Both secretory and cytosolic forms of PLA2 have been shown to be potent in mobilizing eicosanoid precursors and to play a role in host defense against microbial pathogens (Balsinde and Dennis, 1997;Boyanovsky and Webb, 2009;Park et al., 2005;. Once in their free form, ARA and EPA compete for the same enzymes for further metabolism (Lands, 1992) and are converted by a cyclooxygenase (COX or PXT) to prostanoids. ...
... They can be transmembrane proteins with an extracellular part that interacts with the extracellular environment and an intracellular domain interacting with signal transducers or with cytosolic proteins in the cytoplasmic layer of the membrane [16]. There are also proteins that temporally interact with the membrane, including phospholipases (PL) A1 and A2 (PLA1 and PLA2) that release fatty acids in the SN1 and SN2 positions from the phospholipids; PLC, which releases diacylglycerol (DAG) from phospholipids; and sphingomyelinase (SMase), which hydrolyzes sphingomyelin to ceramide (see section 4) [17]. oligosaccharide forming cerebrosides or gangliosides, respectively [19]. ...
White adipose tissue is recognized as an active endocrine organ implicated in the maintenance of metabolic homeostasis. However, adipose tissue function, which has a crucial role in the development of obesity-related comorbidities including insulin resistance and non-alcoholic fatty liver disease, is dysregulated in obese individuals. This review explores the physiological functions and molecular actions of bioactive lipids biosynthesized in adipose tissue including sphingolipids and phospholipids, and in particular fatty acids derived from phospholipids of the cell membrane. Special emphasis is given to polyunsaturated fatty acids of the omega-6 and omega-3 families and their conversion to bioactive lipid mediators through the cyclooxygenase and lipoxygenase pathways. The participation of omega-3-derived lipid autacoids in the resolution of adipose tissue inflammation and in the prevention of obesity-associated hepatic complications is also thoroughly discussed.
... The mRNA levels of two phospholipases were increased -Pla2g5 (1.6-fold) and Plcg2 (1.5-fold). Pla2g5 encodes phospholipase A2 group V, the enzyme that catalyzes the hydrolysis of membrane phospholipids to generate lysophospholipids and free fatty acids, including arachidonic acid (Balsinde and Dennis, 1997). It also induces leuokotrines (eicosanods) biosynthesis in neighboring inflammatory cells (Wijewickrama et al., 2006). ...
... PLA was comprised of PLA 1 and PLA 2 subtypes; and it was one of the metal ion-dependent enzymes (Drummond et al., 2000). The PLA 2 activity had a strong record on the continual suppression by an inhibitor of palmityl trifluoromethyl ketone (PTK) (Balsinde and Dennis, 1997). We therefore performed a study by using PTK inhibitor to find out whether PLA 2 can also catalyze the degradation of matrices in work. ...
... The inhibitor was dissolved in ethyl alcohol and controlled to an i.v. injection lower than 20 mg/kg bw, a threshold potential for chronic toxicity (Balsinde and Dennis, 1997). The 0.05 mg/kg/injection i.v. ...
An essential in vivo drug delivery system of a momordica anti-HIV protein, MAP30, was developed through encapsulating in chemically synthesized matrices of zirconium egg-and soy-phosphatidylcholines, abbreviated to Zr/EPC and Zr/SPC, respectively. Matrices were characterized by transmission electron microscopy and powder X-ray diffractometry studies. Zr/EPC granule at an approximate diameter of 69.43±7.78nm was a less efficient encapsulator than the granule of Zr/SPC. Interlayer spacing of the matrices encapsulating MAP30 increased from 8.8 and 9.7Å to 7.4 and 7.9nm, respectively. In vivo kinetics on degradation and protein release was performed by analyzing the serum sampling of intravenously injected SPF chickens. The first order and biphasic variations were obtained for in vivo kinetics using equilibrium dialysis. Antimicrobial and anti-HIV assays yielded greatly decreased MIC50 and EC50 values of nanoformulated MAP30. An acute toxicity of MAP30 encapsulated in Zr/EPC occurred at a single intravenous dose above 14.24mg/kg bw in NIH/KM/ICR mice. The folding of MAP30 from Zr/EPC sustained in vivo chickens for more than 8 days in high performance liquid chromatography assays. These matrices could protect MAP30 efficiently with strong structure retention, lowered toxicity and prolonged in vivo life.
Copyright © 2015. Published by Elsevier B.V.
... Phospholipase A enzymes (PLAs) catalyze the hydrolysis of either the sn-1 (PLA 1 ) or the sn-2 (PLA 2 ) ester bond of phospholipids to produce lysophospholipids and free fatty acids (FAs). They are involved in several biological processes in both animals and plants (Chen et al., 2011): (1) as a component of the acylation/ hydrolysis of phospholipids in the so-called Lands cycle involved in primary lipid metabolism in animals (Lands, 1960;Balsinde and Dennis, 1997;Imae et al., 2010) and plants (Li et al., 2013); (2) in membrane architecture and trafficking (Lee et al., 2010;Kim et al., 2011); (3) in the production of bioactive compounds involved in signaling, pathogen defense, and programmed cell death (Munnik and Testerink, 2009;Canonne et al., 2011); (4) in catalyzing the hydrolysis of oxidized lipids (van Kuijk et al., 1987;Bana s et al., 1992); (5) in seed storage lipid mobilization (Rudolph et al., 2011);and (6) in uncommon and modified FA production in seeds (Bafor et al., 1991;Ståhl et al., 1995;Bates and Browse, 2011). ...
Ricinoleic acid, an industrially useful hydroxy fatty acid (HFA), only accumulates to high levels in the triacylglycerol fraction of castor bean endosperm even though it is synthesized on the membrane lipid phosphatidylcholine (PC) from an oleoyl ester. The acyl chains of PC undergo intense remodeling through the process of acyl editing. The identity of the proteins involved in this process, however, are unknown. A phospholipase A2 (PLA2) is thought to be involved in the acyl editing process. We show here a role RcsPLA2 in the acyl editing of HFA esterified to PC. RcsPLA2 was identified by its high relative expression in the castor (Ricinus communis) endosperm transcriptome. Co-expression in Arabidopsis (Arabidopsis thaliana) seeds of RcsPLA2 with castor hydroxylase RcFAH12 led to a dramatic decrease in seed HFA content when compared to RcFAH12 expression alone, both in PC and the neutral lipid fraction. The low HFA trait was heritable and gene dosage dependent, with hemizygous lines showing intermediate HFA levels. The low seed HFA levels suggested that RcsPLA2 functions in vivo as a PLA2 with HFA specificity. Activity assays with yeast microsomes showed a high specificity of RcsPLA2 for ricinoleic acid, superior to that of the endogenous AtsPLA2. These results point to RcsPLA2 as a phospholipase involved in acyl editing, adapted to specifically removing HFA from membrane lipids in seeds.
Copyright © 2015, American Society of Plant Biologists.
