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)

Neuroprotection by citicoline (CDP-choline) in transient cerebral ischemia has been demonstrated previously. Citicoline has undergone several Phase III clinical trials for stroke, and is being evaluated for treatment of Alzheimer's and Parkinson's diseases. Phospholipid degradation and generation of reactive oxygen species (ROS) are major factors causing neuronal injury in CNS trauma and neurodegenerative diseases. Oxidative metabolism of arachidonic acid (released by the action of phospholipases) contributes to ROS generation. We examined the effect of citicoline on phospholipase A(2) (PLA(2)) activity in relation to the attenuation of hydroxyl radical (OH.) generation after transient forebrain ischemia of gerbil. PLA(2) activity (requires mM Ca(2+)) increased significantly (P < 0.05) in both membrane (50.2 +/- 2.2 pmol/min/mg protein compared to sham 35.9 +/- 3.2) and mitochondrial fractions (77.0 +/- 1.2 pmol/min/mg protein compared to sham 33.9 +/- 1.2) after cerebral ischemia and 2 hr reperfusion in gerbil, which was significantly attenuated (P < 0.01) by citicoline (membrane, 39.9. +/- 2.2 and mitochondria, 41.9 +/- 3.2 pmol/min/mg protein). In vitro, citicoline and its components cytidine and choline had no effect on PLA(2) activity, and thus citicoline as such is not a PLA(2) inhibitor. Ischemia/reperfusion resulted in significant OH. generation (P < 0.01) and citicoline significantly (P < 0.01) attenuated their formation (expressed as 2,3-dihydroxybenzoic acid/salicylate ratio; ischemia/24 hr reperfusion, 6.30 +/- 0.23; sham, 2.56 +/- 0.27; ischemia/24 hr reperfusion + citicoline, 4.85 +/- 0.35). These results suggest that citicoline affects PLA(2) stimulation and decreases OH. generation after transient cerebral ischemia.
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PMID:Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. 1286 64

Experimental studies have suggested that TNF alpha, a pro-inflammatory cytokine, may contribute to the deterioration of cardiovascular function through various mechanisms, including the generation of reactive oxygen species. It has not yet been demonstrated whether TNF alpha has prooxidant activity in patients with heart failure, and what the mechanism eventually resulting in this effect are. We analyzed 42 patients (38 men and 4 women, aged 26 to 74 years) with heart failure, secondary to idiopathic dilated cardiomyopathy (n=21), coronary artery disease (n=15), and valve disease (n=6), and 20 controls (18 men and 2 women, aged 49 to 67 years). Ten patients were in class I, 9 in class II, 15 in class III and 8 in class IV according to NYHA Classification. Blood samples were obtained from each patient to evaluate basal and collagen-induced platelet O(2)(-) production, and plasma TNF alpha. In vivo results showed increased platelet O(2)(-) production and plasma TNF alpha levels in NYHA class III-IV compared with that in controls or in NYHA I-II (p<0,001); platelet O(2)(-) production correlated significantly (R=0,6; p<0,01) with TNF alpha plasma levels. In vitro studies showed TNF alpha dose-dependently (5-40 pg/ml) induced platelet O(2)(-) production, and that this effect was significantly inhibited by its specific inhibitor, WP9QY (1 microM); aspirin (100 microM), AACOCF(3), a specific PLA(2) inhibitor (14 microM), and DPI, an inhibitor of NADPH oxidase, significantly inhibited TNF alpha-mediated platelet O(2)(-) production. This study suggests that in patients with heart failure, enhanced platelet O(2)(-) production is mediated by TNF alpha via activation of arachidonic acid and NADPH oxidase pathways.
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PMID:Enhanced TNF alpha and oxidative stress in patients with heart failure: effect of TNF alpha on platelet O2- production. 1288 80

Stroke ranks as the third leading cause of death and the most common cause of permanent disability in adults. Timely recognition and treatment is imperative to reduce stroke-related morbidity and mortality. Patients with acute ischemic stroke should be evaluated for administration of intravenous tissue plasminogen activator (t-PA); those who do not qualify for t-PA should receive aspirin therapy in the absence of a contraindication. In all stroke patients, intravenous hydration with normal saline should be administered, hypoxia should be corrected with supplemental oxygen, and hyperglycemia and fever should be treated aggressively. Blood pressure management should be individualized on the basis of stroke pathophysiology and specific treatment plan (e.g., planned thrombolysis) following published guidelines. Evaluation of stroke etiology should be undertaken, and the results should be used to guide secondary stroke prevention efforts.
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PMID:Management of acute stroke. 1291 57

One type of therapy for thromboembolism is plasmatic thrombolysis. Several plasminogen activators (PA) are clinically available, including urokinase (u-PA), tissue plasminogen activator (t-PA), streptokinase (SK), plasminogen-streptokinase-activator-complex (PSAC), or mutants of t-PA such as reteplase (RP) or tenecteplase (TP). Therapeutic plasmatic fibrinolysis was simulated, using the PA at relevant plasma concentrations, and plasmin (Pli) and PA activities were determined. Normal citrated plasma was supplemented with 31 to 1,000 IU/mL u-PA, 0.31 to 20 microg/mL t-PA, 125 to 4,000 IU/mL SK, 12.5 to 400 U/mL PSAC, 125 to 4,000 U/mL RP, or 0.31 to 10 microg/mL TP. Ten IU/mL urokinase was also incubated with pooled plasma of stroke patients, that was previously oxidized with the singlet oxygen (1O2) donor chloramine T (CT), to destroy plasmatic PAI-1 and alpha2-antiplasmin. After 0 to 80 minutes (37 degrees C), 50-microL samples were withdrawn and added to 100 microL 1.5 M arginine, pH 8.7, and oxidized with 50 microL of 20 mM CT. For determination of plasmin activity, 10 microL thereof was incubated with 150 microL 1.5 M arginine, pH 8.7, and 100 microL 20 mM CT preoxidized (15 minutes 37 degrees C) pooled normal citrate buffered EDTA-plasma for 30 minutes (37 degrees C). For determination of [PA+Pli]-activity, arginine was added after this incubation. 25-microL 6 mM Val-Leu-Lys-pNA were added and deltaA/h at room temperature (RT) was monitored, using a microtiterplate reader. [PA+Pli]-Pli = PA. The PA concentration required to induce 25% [ED25] of the maximally inducible Pli-activity in plasma (= 1 U/mL = 45 mg/L = 0.53 micromol/L active Pli; deltaA = 363 +/- 8 mA/h RT) after 10 minutes (37 degrees C) were 320 IU/mL u-PA, 8 microg/mL t-PA, 140 U/mL PSAC, 6,000 IU/mL SK, 720 U/mL RP, and approximately 150 microg/mL TP. The approximate activity half-lives of the PA in plasma were 30 minutes for u-PA, 30 minutes for t-PA, greater than 80 minutes for SK, greater than 80 minutes for PSAC, 50 minutes for RP, and 80 minutes for TP. The present study shows--for the first time--a combined kinetic in vitro simulation of the plasmatic activity of six different PAs. At clinically used concentrations, RP induces the highest plasmatic Pli activity. Due to unselective generation of plasmin in plasma, all PA are of some danger in inducing severe hemorrhagias. Clinical thrombolysis might be improved by usage of more physiologic activators of thrombolysis, such as activators of polymorphonuclear neutrophils.
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PMID:In vitro simulation of therapeutic plasmatic fibrinolysis. 1450 9

Remodeling of blood vessels underlies the pathogenesis of major cardiovascular disorders, including atherosclerosis, restenosis, and hypertension. Because remodeling of arteries is highly dependent on degradation of the extracellular matrix, which enables cells to migrate and proliferate, there is intense interest in the regulation and the roles of matrix metalloproteinases (MMPs) and the plasminogen activator-plasmin (PA-P) systems in vessel remodeling. Factors that promote vessel remodeling have been shown to be important in upregulating the activities of both proteolytic systems and include chronic changes in hemodynamics, vessel injury, cytokines involved in inflammation, and elevations in reactive oxygen species. The two proteolytic systems utilize common transcription factors to activate their respective genes and are frequently coexpressed in remodeling and atherosclerotic arteries. In this review, we discuss the effects of activating the MMP and PA-P systems on processes involved in vascular remodeling, factors regulating their expression and activation, their roles in restenosis, and the development and progression of atherosclerosis, as well as the ability of currently available inhibitors to prevent unfavorable remodeling and atherosclerosis.
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PMID:Metalloproteinases and plasminogen activators in vessel remodeling. 1459 65

In this study, we investigated the involvement of reactive oxygen species (ROS) and calcium in staurosporine (STS)-induced apoptosis in cultured retinal neurons, under conditions of maintained membrane integrity. The antioxidants idebenone (IDB), glutathione-ethylester (GSH/EE), trolox, and Mn(III)tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly reduced STS-induced caspase-3-like activity and intracellular ROS generation. Endogenous sources of ROS production were investigated by testing the effect of the following inhibitors: 7-nitroindazole (7-NI), a specific inhibitor of the neuronal isoform of nitric oxide synthase (nNOS); arachidonyl trifluoromethyl ketone (AACOCF(3)), a phospholipase A(2) (PLA(2)) inhibitor; allopurinol, a xanthine oxidase inhibitor; and the mitochondrial inhibitors rotenone and oligomycin. All these compounds decreased caspase-3-like activity and ROS generation, showing that both mitochondrial and cytosolic sources of ROS are implicated in this mechanism. STS induced a significant increase in intracellular calcium concentration ([Ca(2+)](i)), which was partially prevented in the presence of IDB and GSH/EE, indicating its dependence on ROS generation. These two antioxidants and the inhibitors allopurinol and 7-NI also reduced the number of TdT-mediated dUTP nick-end labeling-positive cells. Thus, endogenous ROS generation and the rise in intracellular calcium are important inter-players in STS-triggered apoptosis. Furthermore, the antioxidants may help to prolong retinal cell survival upon apoptotic cell death.
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PMID:Cytosolic and mitochondrial ROS in staurosporine-induced retinal cell apoptosis. 1464 98

A central tenet of fibrinolysis is that tissue plasminogen activator-dependent (t-PA- dependent) conversion of plasminogen to active plasmin requires the presence of the cofactor/substrate fibrin. However, previous in vitro studies have suggested that the endothelial cell surface protein annexin II can stimulate t-PA-mediated plasminogen activation in the complete absence of fibrin. Here, homozygous annexin II-null mice displayed deposition of fibrin in the microvasculature and incomplete clearance of injury-induced arterial thrombi. While these animals demonstrated normal lysis of a fibrin-containing plasma clot, t-PA-dependent plasmin generation at the endothelial cell surface was markedly deficient. Directed migration of annexin II-null endothelial cells through fibrin and collagen lattices in vitro was also reduced, and an annexin II peptide mimicking sequences necessary for t-PA binding blocked endothelial cell invasion of Matrigel implants in wild-type mice. In addition, annexin II-deficient mice displayed markedly diminished neovascularization of fibroblast growth factor-stimulated cornea and of oxygen-primed neonatal retina. Capillary sprouting from annexin II-deficient aortic ring explants was markedly reduced in association with severe impairment of activation of metalloproteinase-9 and -13. These data establish annexin II as a regulator of cell surface plasmin generation and reveal that impaired endothelial cell fibrinolytic activity constitutes a barrier to effective neoangiogenesis.
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PMID:Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. 1470 7

Poly(lactic acid) (PLA) and poly(acrylic acid) (PAA) biomaterials with luminescent ruthenium tris(bipyridine) centers couple drug delivery and imaging functions. Hydrophobic [Ru(bpyPLA2)3](PF6)2 (1) was generated from [Ru[bpy(CH2OH)2]3](PF6)2 in bulk monomer using 4-(dimethylamino)pyridine as the catalyst. The bromoesters, [Ru[bpy(CH2OR)2]3](PF6)2, [Ru[bpy(C13H27)2][bpy(CH2OR]2](PF6)2 (4), and [Ru[bpy(PLAOR)2]3]2+ (9) (R=COCBr(CH3)2), served as initiators for tert-butyl acrylate (tBA) polymerization. Conversion of PtBA to PAA via hydrolysis affords water soluble materials, [Ru(bpyPAA2)3]2+ (7) and [Ru[bpy(C13H27)2](bpyPAA2)2]2+ (8) and the amphiphilic star polymer [Ru[bpy(PLA-PAA)2]3)](PF6)2 (11), which is soluble in a H2O/CH3CN (1:1) mixture. Luminescence excitation and emission spectra of the Ru polymers were in agreement with the parent [Ru(bpy)3]2+ chromophore (lambdaex=468, lambdaem=621 nm). Lifetimes of tau approximately 700 ns in both air and nitrogen atmospheres are typical for most materials; however, the amphiphilic star block copolymer 11 is quenched by oxygen to some degree. Thermal analysis shows the expected glass transitions for the polymeric ruthenium complex materials.
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PMID:Metalloinitiation routes to biocompatible poly(lactic acid) and poly(acrylic acid) stars with luminescent ruthenium tris(bipyridine) cores. 1500 24

Pulmonary arterial thrombosis (PAT) may complicate the clinical course of pulmonary hypertension associated with congenital heart disease (so-called Eisenmenger syndrome, ES). In this study, variables were sought that could represent risk factors for the occurrence of this complication. Twenty patients aged 11 to 53 (median, 33) years were studied. The presence of PAT (spiral computed tomography angiography) was correlated with age, gender group, PAP, hematocrit, peripheral oxygen saturation (SpO(2)), and plasma levels of endothelial and coagulation dysfunction markers: von Willebrand factor antigen (vWF:Ag), tissue plasminogen activator (t-PA), and D-dimer (enzyme immunoassay). Patients were classified according to the presence (group 1, N=7), or absence (group 2, N=13) of PAT. Group 1 patients were older (42+/-8 vs. 27+/-10 years in group 2, p=0.0051), had lower SpO(2) (82+/-7% vs. 89+/-6% in group 2, p=0.0462) and increased D-dimer levels (637 vs. 149 ng/mL in group 2, median values, p=0.0235). A trend was observed toward an increase in vWF:Ag (125+/-29 vs. 103+/-18 U/dL in group 2, p=0.0789) and t-PA (15.7 vs. 9.4 ng/mL in group 2, median values, p=0.0689). Age was the main variable influencing the occurrence of PAT in multivariate analysis (p=0.0026), with odds ratio of 1.204 per year. The age of 35 years was 86% sensitive and 85% specific for occurrence of PAT. Age correlated positively with t-PA (r=0.57, p=0.0111). Thus, PAT is highly prevalent in ES as an age-dependent event, probably associated with endothelial dysfunction. Prophylactic anticoagulation should be considered before the age of 30 years, in particular in subjects with low SpO(2) and increased D-dimer levels.
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PMID:Age-dependent likelihood of in situ thrombosis in secondary pulmonary hypertension. 1524 78

Brain phosphatidylcholine (PC) levels are regulated by a balance between synthesis and hydrolysis. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1alpha/beta) activate phospholipase A(2) (PLA(2)) and PC-phospholipase C (PC-PLC) to hydrolyze PC. PC hydrolysis by PLA(2) releases free fatty acids including arachidonic acid, and lyso-PC, an inhibitor of CTP-phosphocholine cytidylyltransferase (CCT). Arachidonic acid metabolism by cyclooxygenases/lipoxygenases is a significant source of reactive oxygen species. CDP-choline might increase the PC levels by attenuating PLA(2) stimulation and loss of CCT activity. TNF-alpha also stimulates proteolysis of CCT. TNF-alpha and IL-1beta are induced in brain ischemia and may disrupt PC homeostasis by increasing its hydrolysis (increase PLA(2) and PC-PLC activities) and inhibiting its synthesis (decrease CCT activity). The beneficial effects of CDP-choline may result by counteracting TNF-alpha and/or IL-1 mediated events, integrating cytokine biology and lipid metabolism. Re-evaluation of CDP-choline phase III stroke clinical trial data is encouraging and future trails are warranted. CDP-choline is non-xenobiotic, safe, well tolerated, and can be considered as one of the agents in multi-drug treatment of stroke.
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PMID:Cytidine 5'-diphosphocholine (CDP-choline) in stroke and other CNS disorders. 1575 28


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