Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipid mediators play a crucial role in human parturition and phospholipase A(2) (PLA(2)) is a key regulator of the production of these compounds. We have investigated by PCR the expression of different groups of PLA(2) and COX enzymes in human fetal membranes (amnion and chorion), placenta and three chorionic cell lines (JEG-3, Jar, BeWo). Our data show that the cytosolic Group IV PLA(2) and COX-1 are expressed in all of them, whereas the secretory forms of PLA(2), (Groups IIA, and V), have a more restricted expression. Group IIA mRNA is most abundant in placenta and chorion, whereas Group V PLA(2) mRNA is most abundant in placenta and amnion. On the other hand, COX-2 is present in placenta, chorion and amnion, but was not detected in any of the chorionic cell lines. These results suggest that both cytosolic and distinct secreted forms of PLA(2) could be involved in arachidonic acid (AA) release preceding prostaglandin production at the fetal/maternal interface.
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PMID:Expression of cytosolic and secreted forms of phospholipase A(2) and cyclooxygenases in human placenta, fetal membranes, and chorionic cell lines. 1075 42

There is strong evidence showing that chronic and excessive ethanol consumption may enhance oxidative damage to neurons and result in cell death. Although not yet well understood, ethanol may enhance ROS production in brain through a number of pathways including increased generation of hydroxyethyl radicals, induction of CYP2E1, alteration of the cytokine signaling pathways for induction of iNOS and sPLA(2), and production of prostanoids through the PLA(2)/COX pathways. Since many neurodegenerative diseases are also associated with oxidative and inflammatory mechanisms in the brain, it would be important to find out whether chronic and excessive ethanol consumption may exacerbate the progression of these diseases. There is evidence that the polyphenolic antioxidants, especially those extracted from grape skin and seed, may protect the brain from neuronal damage due to chronic ethanol administration. Among the polyphenols from grapes, resveratrol seems to have unique antioxidant properties. The possible use of this compound as a therapeutic agent to ameliorate neurodegenerative processes should be further explored.
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PMID:Ethanol and oxidative mechanisms in the brain. 1117 74

Although transforming growth factor alpha (TGF-alpha) is known to be an important survival factor for granulosa cells, the cellular and molecular mechanisms involved are uncertain. The purpose of the present study was to investigate the possible involvement of prostaglandins in the anti-apoptotic action of TGF-alpha. Hen granulosa cells from healthy prehierarchical follicles (2-6 mm) cultured in serum-free medium underwent spontaneous apoptosis as demonstrated by DNA fragmentation and nuclear chromatin condensation. TGF-alpha (20 ng ml(-1)) stimulated maximum synthesis of prostaglandins (PGE and PGF) in granulosa cells and completely inhibited serum deprivation-induced apoptosis. The addition of an inhibitor of cyclooxygenase (COX; N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS398) or ibuprofen) or phospholipase A(2) (PLA(2); aristolochic acid, 2-p-amylcinnamoyl amino-4-chlorobenzoic acid (ONO-RS-82) or arachidonyl triflouro methyl ketone (TFMK)), to the culture medium markedly suppressed the TGF-alpha-induced prostaglandin synthesis and significantly increased granulosa cell apoptosis. The apoptotic effect of NS398 and aristolochic acid was completely inhibited by exogenous prostaglandins (PGF(2 alpha), PGE(1), PGE(2)) and arachidonic acid, respectively. However, exogenous prostaglandins failed to inhibit the PLA(2) inhibitor-induced apoptotic DNA fragmentation, implying that in addition to prostaglandins, arachidonic acid or leukotrienes may be important in transducing the anti-apoptotic action of TGF-alpha. In the absence of exogenous TGF-alpha, prostaglandins had no significant influence on granulosa cell apoptosis induced by serum withdrawal. These findings indicate that prostaglandin synthesis is a necessary, but not sufficient, event in the suppression of granulosa cell apoptosis by TGF-alpha. Whether arachidonic acid or leukotrienes are important in the anti-apoptotic action of TGF-alpha in hen granulosa cells remains to be determined.
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PMID:Role of prostaglandins in the suppression of apoptosis in hen granulosa cells by transforming growth factor alpha. 1142 33

Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1). Our data point to endothelial bradykinin (Bk) as a trigger for protective endothelial mechanisms. In cultured endothelial cells (CEC) Bk through kinin B2 receptors raised in a concentration-dependent manner (1pM-10 nM) free cytoplasmic calcium ions [Ca2+]i. This rise was accompanied by the release of NO as quantified by a porphyrinic sensor. Other endothelial agonists were weaker-stimulators of [Ca2+]i than Bk. In vivo we analyed the effects of exogenous Bk and of amplifiers of endogenous Bk, such as perindopril and quinapril ("tissue type" angiotensin converting enzyme inhibitors, ACE-I) on endothelial function using our original thrombolytic bioassay and EIA assays for 6-keto-PGF1alpha and t-PA antigen. A major difference found between exogenuous Bk and endogenous Bk (that rendered by "tissue ACE-I") was a) prolonged thrombolytic action (> 4h) of quinapril or perindopril. Moreover, only exogenous Bk evoked an immediate and profound hypotensive action. In vivo, Bk-induced thrombolysis was B2 kinin receptor-dependent, PGI2-mediated. The unexpected action of Bk came to light in CEC. Then appeared incubated for 4 h increased expression of mRNAs for haemoxygenase (HO-1), cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGE-S), but hardly for nitric oxide synthase 2(NOS-2). We hypothesize that a network of interactions of Bk-induced enzymes may constitute a delayed phase of Bk effects in the endothelium, whereas the primary phase would be activation by BK of [Ca2+]i-dependent constitutive endothelial enzymes. In blood-perfused rat endotoxemic lungs, NO is the most eminent cytoprotective mediator. Summing up, in peripheral circulation endogenous Bk is the most efficient activator of protective endothelial function. Thrombolytic action of "tissue-type" ACE-Is relies on receptor B-2-mediated, [Ca2+]i-dependent release of PGI2. Bk also may act as a "microcytokine" by inducing mRNAs for HO-1, COX-2, or PGE-S. Activation of HO-1 may lead to a deficiency in intracellular heme required as a cofactor for both COX and NOS. This network of interactions triggered by Bk call for further studies.
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PMID:Bradykinin as a major endogenous regulator of endothelial function. 1205 3

The organic anion transport system of the kidney is of major importance for the excretion of a variety of endogenous compounds, drugs, and potentially toxic substances. The basolateral uptake into proximal tubular cells is mediated by a tertiary active transport system. Epidermal growth factor (EGF) leads to an increase in the basolateral uptake rate of the model substrate para-aminohippuric acid (PAH) in opossum kidney (OK) cells. This stimulation is mediated by successive activation of the mitogen-activated protein kinases,mitogen-activated/extracellular signal-regulated kinase kinase (MEK) and extracellular regulated kinase isoforms 1 and 2 (ERK1/2). This study investigates the regulatory network of EGF action on PAH uptake downstream ERK1/2 in more detail. EGF stimulation of the basolateral uptake rate of [(14)C]PAH was abolished by the phospholipase A(2) inhibitor AACOCF3.[(14)C]PAH uptake was enhanced by arachidonic acid. Furthermore, EGF led to an increase in arachidonic acid release and to the generation of prostaglandins. AACOCF3 did not influence EGF-induced ERK1/2 activation, indicating that ERK1/2 is upstream of PLA(2). In addition, EGF stimulated the influx of extracellular Ca(2+). However, Ca(2+)-influx was not required for the stimulatory action of EGF on [(14)C]PAH uptake. Inhibitors of COX and lipoxygenases reduced [(14)C]PAH uptake dose-dependently, whereas inhibition of cytochrome P450 did not. In the presence of indomethacin, EGF had no stimulatory effect on [(14)C]PAH uptake. The inhibitory effect of indomethacin was not due to competitive action on PAH uptake. Furthermore, prostaglandin E(2) (PGE(2)) increased basolateral [(14)C]PAH uptake rate dose-dependently, and this increase was also observed in the presence of indomethacin. Selective inhibition of COX2 by indomethacin amid or indomethacin n-heptyl ester did not inhibit [(14)C]PAH uptake, whereas selective inhibition of COX1 dose-dependently inhibited [(14)C]PAH uptake. This and previous data lead to the conclusion that EGF successively activates MEK, ERK1/2, and PLA(2), leading to an increased release of arachidonic acid. Subsequently, arachidonic acid is metabolized to prostaglandins via COX1, which then mediate EGF-induced stimulation of basolateral organic anion uptake rate.
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PMID:Short-term regulation of basolateral organic anion uptake in proximal tubular OK cells: EGF acts via MAPK, PLA(2), and COX1. 1213 28

The Ca(2+)- and phospholipid-binding protein Anx-A1 (annexin 1; lipocortin 1) has been described both as an inhibitor of phospholipase A(2) (PLA(2)) activity and as a mediator of glucocorticoid-regulated cell growth and eicosanoid generation. Here we show that, when compared with Anx-A1(+/+) cells, lung fibroblast cell lines derived from the Anx-A1(-/-) mouse exhibit an altered morphology characterized by a spindle-shaped appearance and an accumulation of intracellular organelles. Unlike their wild-type counterparts, Anx-A1(-/-) cells also overexpress cyclo-oxygenase 2 (COX 2), cytosolic PLA(2) and secretory PLA(2) and in response to fetal calf serum, exhibit an exaggerated release of eicosanoids, which is insensitive to dexamethasone (10(-8)- 10(-6) M) inhibition. Proliferation and serum-induced progression of Anx-A1(+/+) cells from G(0)/G(1) into S phase, and the associated expression of extracellular signal-regulated kinase 2 (ERK2), cyclin-dependent kinase 4 (cdk4) and COX 2, is strongly inhibited by dexamethasone, whereas Anx-A1(-/-) cells are refractory to the drug. Loss of the response to dexamethasone in Anx-A1(-/-) cells occurs against a background of no apparent change in glucocorticoid receptor expression or sensitivity to non-steroidal anti-inflammatory drugs. Taken together, these observations suggest strongly that Anx-A1 functions as an inhibitor of signal-transduction pathways that lead to cell proliferation and may help to explain how glucocorticoids regulate these processes.
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PMID:Attenuation of glucocorticoid functions in an Anx-A1-/- cell line. 1255 80

In this paper we have determined the different signal pathways involved in M(1) and M(3) muscarinic acetylcholine receptor (mAChR) dependent stimulation of cyclo-oxygenase 1 (cox-1) mRNA gene expression and PGE(2) production on rat cerebral frontal cortex. Carbachol stimulation of M(1) and M(3) mAChR exerts an increase in cox-1 mRNA gene expression without affecting cox-2 mRNA expression and increased PGE(2) generation. Besides, increased phosphoinositide (PI) turnover and stimulation of nitric oxide synthase (NOS) and cyclic GMP (cGMP) production. Inhibitors of phospholipase A(2) (PLA(2)), COX and phospholipase C (PLC), calcium/calmodulin (CaM), NOS and soluble guanylate cyclase prevent the carbachol effect. These results suggest that carbachol-activation of M(1) and M(3) mAChR increased PGE(2) release associated with an increased expression of cox-1 and NO-cGMP production. The mechanism appears to occur directly to PLC stimulation and indirectly to PLA(2) activation. These results may contribute to understand the effects and side effect of non-steroidal anti-inflammatory drugs in patients with cerebral degenerative diseases.
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PMID:Signal transduction underlying carbachol-induced PGE2 generation and cox-1 mRNA expression of rat brain. 1581 9

Phospholipase A(2) (PLA(2))-catalyzed hydrolysis of membrane phospholipids results in the stoichiometric production of a free fatty acid, most importantly arachidonic acid, and a lysophospholipid. Both of these phospholipid metabolites serve as precursors for inflammatory mediators such as eicosanoids or platelet-activating factor (PAF). Since it was initially discovered that non-steroidal anti-inflammatory drugs inhibit prostaglandin synthesis, a vast amount of drug development has been performed to selectively inhibit the production of the inflammatory metabolites of arachidonic acid while preserving their protective role. This research has culminated in the development of selective cyclooxygenase-2 (COX-2) inhibitors that act on the inducible, inflammatory COX enzyme, but do not affect the constitutive prostaglandin synthesis in cells that is mediated via COX-1. The development of PLA(2) inhibitors as potential anti-inflammatory agents has also been extensively pursued since the release of arachidonic acid from membrane phospholipids by PLA(3) is one of the rate-limiting factors for eicosanoid production. In addition to the production of eicosanoids, PLA(2)-catalyzed membrane phospholipid hydrolysis is also the initiating step in the generation of PAF, a potent inflammatory agent. Thus, inhibition of PLA(2) activity should, in theory, be a more effective anti-inflammatory approach. However, developing an inhibitor that would be selective for the production of inflammatory metabolites and not inhibit the beneficial properties of PLA(2) has so far proved to be elusive. This review will focus on agents used currently to inhibit PLA(2) activity and will explore their possible therapeutic use.
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PMID:Phospholipase A2 inhibitors as potential anti-inflammatory agents. 1585 86

Recent studies have shown that the activated endocannabinoid system participates in the increase in IHR (intrahepatic resistance) in cirrhosis. The increased hepatic production of vasoconstrictive eicosanoids is involved in the effect of endocannabinoids on the hepatic microcirculation in cirrhosis; however, the mechanisms of these effects are still unknown. The aim of the present study was to investigate the effects of chronic CB(1) (cannabinoid 1) receptor blockade in the hepatic microcirculation of CBL (common bile-duct-ligated) cirrhotic rats. After 1 week of treatment with AM251, a specific CB(1) receptor antagonist, IHR, SMA (superior mesenteric artery) blood flow and hepatic production of eicosanoids [TXB(2) (thromboxane B(2)), 6-keto PGF(1alpha) (prostaglandin F(1alpha)) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB(1) receptor, TGF-beta(1) (transforming growth factor beta(1)), cPLA(2) [cytosolic PLA(2) (phospholipase A(2))], sPLA(2) (secreted PLA(2)) and collagen deposition were also measured. In AM251-treated cirrhotic rats, a decrease in portal venous pressure was associated with the decrease in IHR and SMA blood flow. Additionally, the protein levels of hepatic CB(1) receptor, TGF-beta(1), cPLA(2) and hepatic collagen deposition, and the hepatic levels of 5-LOX and COX-2 and the corresponding production of TXB(2) and Cys-LTs in perfusates, were significantly decreased after 1 week of AM251 treatment in cirrhotic rats. Furthermore, acute infusion of AM251 resulted in a decrease in SMA blood flow and an increase in SMA resistance in CBL rats. In conclusion, the chronic effects of AM251 treatment on the intrahepatic microcirculation were, at least partly, mediated by the inhibition of hepatic TGF-beta(1) activity, which was associated with decreased hepatic collagen deposition and the activated PLA(2)/eicosanoid cascade in cirrhotic livers.
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PMID:Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis. 1717 48

We provide novel evidence that human melanoma cell lines (M10, M14, SK-MEL28, SK-MEL93, 243MEL, 1074MEL, OCM-1, and COLO38) expressed, at mRNA and protein levels, either Ca(2+)-independent phospholipase A(2) (iPLA(2)) or cytosolic phospholipase A(2) (cPLA(2)) and its phosphorylated form. Normal human melanocytes contained the lowest levels of both PLA(2)s. Cyclooxygenase-1 and -2 (COX-1 and COX-2) were also expressed in cultured tumor cells as measured by Western blots. The most pronounced overexpression of iPLA(2) and COX-1 was found in two melanoma-derived cells, M14 and COLO38. Normal human melanocytes and the M10 melanoma cell line displayed no COX-2 expression. Using subcellular fractionation, Western blot and confocal microcopy analyses, in paradigmatic SK-MEL28 and SK-MEL93 cells we showed that iPLA(2), COX-1 and even cPLA(2) were equally located in the cytosol, membrane structures and perinuclear region while COX-2 was preferentially associated with the cytosol. Specific inhibitors of these three enzymes significantly reduced the basal proliferation rate either in melanocytes or in melanoma cell lines. These results, coupled with the inhibition of the cell proliferation by electroporation of melanoma cells with cPLA(2) or COX-2 antibodies, demonstrate that a possible correlation between PLA(2)-COX expression and tumor cell proliferation in the melanocytic system does exist. In addition, the high expression level of both PLA(2)s and COXs suggests that eicosanoids modulate cell proliferation and tumor invasiveness.
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PMID:Expression of Ca(2+)-independent and Ca(2+)-dependent phospholipases A(2) and cyclooxygenases in human melanocytes and malignant melanoma cell lines. 1872 48


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