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)

Macrophages express P2X(7) and other nucleotide (P2) receptors, and display the phenomena of extracellular ATP (ATP(e))-induced P2X(7)-dependent membrane permeabilization and cell death by apoptosis and necrosis. P2X(7) receptors also cooperate with toll-like receptors (TLRs) to induce inflammasome activation and IL-1beta secretion. We investigated signaling pathways involved in the induction of cell death by ATP(e) in intraperitoneal murine macrophages. Apoptosis (hypodiploid nuclei) and necrosis (LDH release) were detected 6h after an induction period of 20 min in the presence of ATP. Apoptosis was blocked by caspase 3 and caspase 9 inhibitors and by cyclosporin A. The MAPK inhibitors PD-98059, SB-203580 and SB-202190 provoked no significant effect on apoptosis, but SB-203580 blocked LDH release. Neither apoptosis nor necrosis was inhibited when both intra- and extracellular Ca(2+) were chelated during the induction period. Mepacrine, a generic PLA(2) inhibitor and BEL, an inhibitor of Ca(2+)-independent PLA(2) (iPLA(2)) blocked apoptosis, while pBPB and AACOOPF(3), inhibitors of secretory and Ca(2+)-dependent PLA(2) respectively, had no significant effect. Cycloxygenase inhibitors had no effect on apoptosis, while the inhibitors of lipoxygenase (LOX) and leukotriene biosynthesis nordihydroguaiaretic acid (NDGA), zileuton, AA-861, and MK-886 significantly decreased apoptosis. Neither NDGA nor MK-886 blocked apoptosis of 5-LOX(-/-) macrophages. CP-105696 and MK-571, antagonists of leukotriene receptors, had no significant effect on apoptosis. None of the inhibitors of PLA(2) and LOX/leukotriene pathway had a significant inhibitory effect on LDH release. Our results indicate that a Ca(2+)-independent step involving an iPLA(2) and 5-LOX are involved in the triggering of apoptosis but not necrosis by P2X(7) in macrophages.
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PMID:ATP-induced apoptosis involves a Ca2+-independent phospholipase A2 and 5-lipoxygenase in macrophages. 1898 60

Myocardial phospholipids serve as primary reservoirs of arachidonic acid (AA), which is liberated through the rate-determining hydrolytic action of cardiac phospholipases A2 (PLA2s). A predominant PLA2 in myocardium is calcium-independent phospholipase A2beta (iPLA2beta), which, through its calmodulin (CaM) and ATP-binding domains, is regulated by alterations in local cellular Ca2+ concentrations and cardiac bioenergetic status, respectively. Importantly, iPLA2beta has been demonstrated to be activated by ischaemia through elevation of the concentration of myocardial fatty acyl-CoA, which abrogates Ca2+/CaM-mediated inhibition of iPLA2beta. AA released by PLA2-catalysed hydrolysis of phospholipids serves as a precursor for eicosanoids generated by pathways dependent on cyclooxygenases (COX), lipoxygenases (LOX), and cytochromes P450 (CYP). Eicosanoids initiate and propagate diverse signalling cascades, primarily through their interaction with cellular receptors and ion channels. However, during pathologic states such as ischaemia or congestive heart failure, eicosanoids contribute to multiple maladaptive changes including inflammation, alterations of cellular growth programmes, and activation of multiple transcriptional events leading to the deleterious sequelae of these pathologic states. This review summarizes the central roles of myocardial PLA(2)s in eicosanoid signalling in the heart, the major COX, LOX, and CYP pathways of eicosanoid generation in the myocardium, and the effects of important eicosanoids on receptor-, ion channel-, and transcription-mediated processes that facilitate cardiac hypertrophy, mediate ischaemic preconditioning, and precipitate arrhythmogenesis in response to pathologic stimuli.
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PMID:Eicosanoid signalling pathways in the heart. 1907 24

Group IVA phospholipase A(2) (GIVA PLA(2)) catalyzes the release of arachidonic acid (AA) from the sn-2 position of glycerophospholipids. AA is then further metabolized into terminal signaling molecules including numerous prostaglandins. We have now demonstrated the involvement of phosphatidic acid phosphohydrolase 1 (PAP-1) and protein kinase C (PKC) in the Toll-like receptor-4 (TLR-4) activation of GIVA PLA(2). We also studied the effect of PAP-1 and PKC on Ca+2 induced and synergy enhanced GIVA PLA(2) activation. We observed that the AA release induced by exposure of RAW 264.7 macrophages to the TLR-4 specific agonist Kdo(2)-Lipid A is blocked by the PAP-1 inhibitors bromoenol lactone (BEL) and propranolol as well as the PKC inhibitor Ro 31-8220; however these inhibitors did not reduce AA release stimulated by Ca+2 influx induced by the P2X7 purinergic receptor agonist ATP. Additionally, stimulation of cells with diacylglycerol (DAG), the product of PAP-1 mediated hydrolysis, initiated AA release from unstimulated cells as well as restored normal AA release from cells treated with PAP-1 inhibitors. Finally, neither PAP-1 nor PKC inhibition reduced GIVA PLA(2) synergistic activation by stimulation with Kdo(2)-Lipid A and ATP.
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PMID:TLR-4 mediated group IVA phospholipase A(2) activation is phosphatidic acid phosphohydrolase 1 and protein kinase C dependent. 1923 Aug 51

Latitudinal comparisons of the Southern Ocean limpet, Nacella concinna, and clam, Laternula elliptica, acclimated to 0.0 degrees C, were used to assess differences in thermal response to two regimes, 0.0, 5.1 to 10.0 degrees C and 2.5, 7.5 to 12.5 degrees C, raised at 5.0 degrees C per week. At each temperature, tissue energy status was measured through a combination of O(2) consumption, intracellular pH, cCO(2), citrate synthase (CS) activity, organic acids (succinate, acetate, propionate), adenylates (ATP, ADP, AMP, ITP, PLA (phospho-L-arginine)) and heart rate. L. elliptica from Signy (60 degrees S) and Rothera (67 degrees S), which experience a similar thermal regime (-2 to +1 degrees C) had the same lethal (7.5-10.0 degrees C), critical (5.1-7.5 degrees C) and pejus (<5.1 degrees C;=getting worse) limits with only small differences in biochemical response. N. concinna, which experiences a wider thermal regime (-2 to +15.8 degrees C), had higher lethal limits (10.0-12.5 degrees C). However, at their Northern geographic limit N. concinna, which live in a warmer environment (South Georgia, 54 degrees S), had a lower critical limit (5.1-10.0 degrees C; O(2), PLA and organic acids) than Rothera and Signy N. concinna (10.0-12.5 degrees C). This lower limit indicates that South Georgia N. concinna have different biochemical responses to temperatures close to their thermal limit, which may make them more vulnerable to future warming trends.
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PMID:Geographical variation in thermal tolerance within Southern Ocean marine ectotherms. 1953 33

A molecular docking investigation has been carried out on cytotoxic prenylated flavonoids from Lonchocarpus haberi with cancer-relevant chemotherapeutic targets known to be inhibited by flavonoids. Two molecular docking programs, Molegro and ArgusDock, were used to compare the binding energies of Lonchocarpus flavonoids with other flavonoids, inhibitors, or known ligands, to aromatase (CYP 19), fatty acid synthase (FAS), xanthine oxidase (XO), cyclooxygenases (COX-1 and COX-2), lipoxygenase (LOX-3), ornithine decarboxylase (ODC), protein tyrosine kinase (PTK), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), topoisomerase II (ATP binding site), ATP binding cassette (ABC) transporter, and phospholipase A(2) (PLA). The Lonchocarpus flavonoids examined in this study exhibited docking energies comparable to or stronger than other flavonoids that had been previously shown to be effective inhibitors of these enzymes. Furthermore, prenylated flavonoids, such as the Lonchocarpus flavonoids and xanthohumol, generally showed greater binding energies than the non-prenylated flavonoids. We conclude, therefore, that the Lonchocarpus flavonoids possibly owe their cytotoxic activity by inhibition of one or more of these enzymes.
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PMID:Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis. 1960 3

The effects of Na-butyrate on the physiological behaviour and on the specific productivity of recombinant tissue plasminogen activator (t-PA) Chinese Hamster Ovary (CHO) cells were characterized. Batch cultures were performed in a 3.5-L bioreactor. Na-butyrate was added either at the mid-exponential growth phase (48 h) or at the end of the exponential growth phase (74 h). The cultures with Na-butyrate showed higher net specific productivity of t-PA and lower final cell density and viability. Maximum specific productivity of t-PA for all cultures coincided with the early plateau phase (84 h). The cell's specific oxygen uptake rate (qO2) increased after the Na-butyrate addition and remained higher than that of the controlled culture. Triphosphate nucleotides, ADP, AMP and UDP-sugars all increased after 84 h in the cultures with Na-butyrate, showing different behaviours when Na-butyrate was added at 48 h or 74 h. Na-butyrate did not affect the cell's adenylate energy charge until the cell's viability started to decrease (156-168 h). The controlled culture and the culture with Na-butyrate addition, showed at 74 h, similar time trends as for purine and nucleotide ratios ((ATP+GTP)/(UTP+CTP) and UTP/ATP) with clear shifts in behaviour at 84 h and 168 h. However, the addition of Na-butyrate at 48 h resulted in damped variations of purine and nucleotide ratios in comparison to both the control culture and the culture with Na-butyrate addition at 74 h.
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PMID:Na-butyrate sustains energetic states of metabolism and t-PA productivity of CHO cells. 1961 65

The interaction of purinergic and nitrergic mechanisms was evaluated in the caudal nucleus tractus solitarii (cNTS) using awake animals and brainstem slices. In awake animals, ATP (1.25 nmol/50 nL) was microinjected into the cNTS before and after the microinjection of a selective neuronal nitric oxide synthase (nNOS) inhibitor N-propyl-l-arginine (NPLA, 3 pmoles/50 nL, n=8) or vehicle (saline, n=4), and cardiovascular and ventilatory parameters were recorded. In brainstem slices from a distinct group of rats, the effects of ATP on the NO concentration in the cNTS using the fluorescent dye DAF-2 DA were evaluated. For this purpose brainstem slices (150 microm) containing the cNTS were pre-incubated with ATP (500 microM; n=8) before and during DAF-2 DA loading. Microinjection of ATP into the cNTS increases the arterial pressure (AP), respiratory frequency (f(R)) and minute ventilation (V(E)), which were significantly reduced by pretreatment with N-PLA, a selective nNOS inhibitor (AP: 39+/-3 vs 16+/-14 mm Hg; f(R): 75+/-14 vs 4+/-3 cpm; V(E): 909+/-159 vs 77+/-39 mL kg(-1) m(-1)). The effects of ATP in the cNTS were not affected by microinjection of saline. ATP significantly increased the NO fluorescence in the cNTS (62+/-7 vs 101+/-10 AU). The data show that in the cNTS: a) the NO production is increased by ATP; b) NO formation by nNOS is involved in the cardiovascular and ventilatory responses to microinjection of ATP. Taken together, these data suggest an interaction of purinergic and nitrergic mechanisms in the cNTS.
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PMID:Interaction of purinergic and nitrergic mechanisms in the caudal nucleus tractus solitarii of rats. 1971 50

Activation of phospholipases A(2) (PLA(2)s) leads to the generation of biologically active lipid mediators that can affect numerous cellular events. The Group VIA Ca(2+)-independent PLA(2), designated iPLA(2)beta, is active in the absence of Ca(2+), activated by ATP, and inhibited by the bromoenol lactone suicide inhibitor (BEL). Over the past 10-15 years, studies using BEL have demonstrated that iPLA(2)beta participates in various biological processes and the recent availability of mice in which iPLA(2)beta expression levels have been genetically-modified are extending these findings. Work in our laboratory suggests that iPLA(2)beta activates a unique signaling cascade that promotes beta-cell apoptosis. This pathway involves iPLA(2)beta dependent induction of neutral sphingomyelinase, production of ceramide, and activation of the intrinsic pathway of apoptosis. There is a growing body of literature supporting beta-cell apoptosis as a major contributor to the loss of beta-cell mass associated with the onset and progression of Type 1 and Type 2 diabetes mellitus. This underscores a need to gain a better understanding of the molecular mechanisms underlying beta-cell apoptosis so that improved treatments can be developed to prevent or delay the onset and progression of diabetes mellitus. Herein, we offer a general review of Group VIA Ca(2+)-independent PLA(2) (iPLA(2)beta) followed by a more focused discussion of its participation in beta-cell apoptosis. We suggest that iPLA(2)beta-derived products trigger pathways which can lead to beta-cell apoptosis during the development of diabetes.
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PMID:Group VIA Ca2+-independent phospholipase A2 (iPLA2beta) and its role in beta-cell programmed cell death. 2008 51

Nucleotides, including ADP, ATP and uridine triphosphate (UTP), are discharged profusely in the circulation during many pathological conditions including sepsis. Sepsis can cause hypotension and systemic activation of the coagulation and fibrinolytic systems in humans, which may cause disseminated intravascular coagulation. We investigated whether nucleotide-induced cardiovascular collapse as provoked by systemic infusion of adenosine, ADP, ATP, UTP and nitric oxide affected the haemostatic system as assessed by whole blood thromboelastography (TEG) analysis. Ten pigs received a randomized infusion of adenosine, ADP, ATP, UTP or nitric oxide until mean arterial pressure was reduced to approximately 40% of baseline simulating sepsis-induced hypotension. The effect of the infusions on the haemostatic system was evaluated by TEG, and endothelial release of tissue plasminogen activator and plasminogen activator inhibitor-1 was measured. In contrast to the other infused substrates, ADP caused a reduction in maximum amplitude (71.4 to 64.2; P < 0.05), and reduced the angle, representing the thrombus formation (75.6 to 66.4; P < 0.05), indicating hypocoagulation. Despite increases in t-PA release (2.1 to 2.7 ng/ml; P < 0.05) and reductions in plasminogen activator inhibitor (33.9 +/- 10.9-17.8 +/- 4.4 ng/ml; P < 0.05) no increased fibrinolysis was found when whole blood was evaluated by TEG. Circulating ADP induces hypocoagulation without signs of increased fibrinolysis as evaluated by TEG. The potential clinical significance of these findings should be investigated further because ADP discharged systemically may possibly contribute to the coagulopathy observed in severe sepsis.
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PMID:Effects of nucleotides and nucleosides on coagulation. 2038 37

Mitochondrial beta-oxidation is an important system involved in the energy production of various cells. In this system, the function of L-carnitine is essential for the uptake of fatty acids to mitochondria. However, it is unclear whether or not endogenous respiration, ADP-induced O(2) consumption without substrates, is caused by L-carnitine treatment. In this study, we investigated whether L-carnitine is essential to the beta-oxidation of quarried fatty acids from the mitochondrial membrane by phospholipase A(2) (PLA(2)) using isolated mitochondria from the liver of rats. Intact mitochondria were incubated in a medium containing Pi, CoA and L-carnitine. The effect of L-carnitine treatment on ADP-induced mitochondrial respiration was observed without exogenous respiratory substrate. Increase in mitochondrial respiration was induced by treatment with L-carnitine in a concentration-dependent manner. Treatment with rotenone, a complex I blocker, completely inhibited ADP-induced oxygen consumption even in the presence of L-carnitine. Moreover, the L-carnitine dependent ADP-induced mitochondrial oxygen consumption did not increase when PLA(2) inhibitors were treated before ADP treatment. The L-carnitine-dependent ADP-induced oxygen consumption did contribute to ATP productions but not heat generation via an uncoupling system. These results suggest that L-carnitine might be essential to the beta-oxidation of quarried fatty acids from the mitochondrial membrane by PLA(2).
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PMID:L-carnitine is essential to beta-oxidation of quarried fatty acid from mitochondrial membrane by PLA(2). 2044 48


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