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)

In the present study we have analyzed the relationship between coagulation inhibitors (antithrombin III, protein C and S, thrombomodulin), liver function impairment, and plasma activity of the endothelium-derived proteins plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) in 27 alcoholic cirrhotic patients and 25 controls. Cirrhotics showed decreased values of all the mentioned parameters except for thrombomodulin, PAI-1, and t-PA. Thrombomodulin and t-PA levels were higher in cirrhotics. No relationship was observed between thrombomodulin and t-PA or PAI-1. Protein C and antithrombin III levels were significantly lower in Child's C patients, whereas no correlation was found between t-PA and thrombomodulin and hepatic function derangement. PAI-1 activity was normal in our patients.
Alcohol 1998 Jan
PMID:Coagulation inhibitors in alcoholic liver cirrhosis. 942 33

Epidemiological studies have suggested that moderate alcohol consumption reduces the risk of cardiovascular mortality. This cardioprotective benefit may be mediated, in part, by promoting fibrinolysis through changes in fibrinolytic components and/or activity, resulting in the decreased risk for thrombosis, coronary artery disease, and eventual myocardial infarction. Endothelial cells (ECs) play a pivotal role in maintaining normal hemostasis by regulating fibrinolysis through the synthesis of plasminogen activators (PAs), tissue-type plasminogen activator (t-PA), and urokinase-type plasminogen activator (u-PA). The studies described herein were conducted to determine whether a single brief preincubation (1 hr, 37 degrees C) of cultured human umbilical vein ECs (HUVECs) with low ethanol (0.1%, v/v), will upregulate t-PA and/or u-PA gene expression at the transcriptional level, using a combination of nuclear transcription run-on assays and transient transfections of cultured HUVECs with the pPA/luc promoter constructs. Nuclear run-on assays showed approximately 2- to 3-fold and approximately 6- to 7-fold increase in the transcription of new t-PA and u-PA mRNAs, respectively. In addition, transient transfections of cultured HUVECs with the pt-PA363/luc and pu-PA236/luc promoter constructs, using lipofectamine, demonstrated approximately 4- to 6-fold and approximately 6- to 9-fold increase in luciferase activity for t-PA and u-PA, respectively. These combined results demonstrate that low ethanol transcriptionally upregulates both t-PA and u-PA gene expression in cultured HUVECs and provides a molecular basis for the ethanol-induced increase in EC-mediated fibrinolytic activity that may underlie and contribute, in part, to the cardioprotective benefit associated with moderate alcohol consumption.
Alcohol Clin Exp Res 1998 Jun
PMID:Ethanol transcriptionally upregulates t-PA and u-PA gene expression in cultured human endothelial cells. 966 Mar 11

The mechanism by which moderate alcohol ingestion lowers the risk of cardiovascular disease is unknown but may be due, in part, to the ability of alcohol to increase the level of tissue-type plasminogen activator (t-PA). Human endothelial cells were treated with low concentrations of ethanol (0.25-25 mM, 0-24 h), which are associated with moderate alcohol consumption. Although treatment with ethanol alone did not affect t-PA gene transcription or mRNA expression, it augmented isoproterenol (ISO)-stimulated t-PA gene transcription and mRNA levels by 3.4- and 2.8-fold, respectively, and decreased plasminogen activator inhibitor-1 mRNA levels by 65%. These effects of ethanol correlated with 2.5- and 6.9-fold increases in ISO-stimulated cyclic AMP levels and 4x-cyclic AMP response element heterologous promoter activity, respectively. To determine whether alcohol-induced changes in agonist-stimulated cyclic AMP levels were because of modulation of guanine nucleotide-binding proteins (G proteins), we assessed the effects of ethanol on Galphas and Galphai2. Although ethanol did not affect the expression of Galphas or Galphai2, it increased ISO-stimulated Galphas GTPase and GTP binding activity by 2.2- and 2.9-fold and decreased UK14304-stimulated Galphai2 GTPase and GTP binding activity by 38 and 80%. These results indicate that treatment with relatively low concentrations of ethanol enhances agonist-stimulated cyclic AMP-dependent t-PA gene transcription in vascular endothelial cells through differential modulation of G protein.
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PMID:Activation of guanine nucleotide-binding proteins and induction of endothelial tissue-type plasminogen activator gene transcription by alcohol. 1020 29

Epidemiological studies have associated moderate alcohol consumption with a reduced risk for coronary artery disease (CAD) and myocardial infarction (MI). This cardioprotection may be attributed to alcohol-induced changes in a variety of cellular functions, including increased fibrinolysis. Fibrinolysis is important in regulating normal hemostasis. Endothelial cells (ECs) synthesize fibrinolytic proteins, t-PA, u-PA, and PAs inhibitor, PAI-1. Systemic factors, i.e., alcohol, that affect one or more of these components, resulting in increased EC fibrinolysis, will reduce the risk for thrombosis, CAD, and MI and afford cardioprotection. These studies will identify/define the effects of low ethanol (< 0.1%, v/v) on the expression of PAs, PAI-1, and surface-localized fibrinolytic activity in cultured ECs. Low ethanol exerted a short-term time- and dose-dependent increase (approximately 5- to 8-fold) in activity at approximately 20 min and 0.05% ethanol, which was sustained for approximately 1 hr. On the other hand, a single brief exposure to low ethanol (< 0.1%, < 120 min), followed by 4-24 hr incubation in the absence of ethanol, showed a time- and dose-dependent increase (approximately 2- to 3-fold) in PAs antigen/mRNA and a concomitant approximately 2- to 3-fold sustained increase (approximately 24 hr) in fibrinolytic activity. Further nuclear transcription run-on assays and transient transfection experiments, using pPAs/luc and pPAI-1/luc promoter constructs, demonstrated that low ethanol transcriptionally upregulates t-PA and u-PA gene expression and downregulates PAI-1 gene expression. These combined studies have described a feasible molecular mechanism by which low ethanol can induce and sustain increased surface-localized EC fibrinolysis that may underlie and contribute, in part, to the cardioprotective benefit associated with moderate alcohol consumption.
Alcohol Clin Exp Res 1999 Jun
PMID:Endothelial cell fibrinolysis: transcriptional regulation of fibrinolytic protein gene expression (t-PA, u-PA, and PAI-1) by low alcohol. 1039 1

The effect of alcohol ingestion before exercise on blood haemostasis is not known. The present study examined the effects of moderate alcohol ingestion on blood haemostatic variables at rest and in response to exercise. Eleven normal healthy individuals randomly performed two tests separated by 7 days. A moderate dose of ethanol (0.5 g.kg-1) was administered before one test, whereas an equal volume of an alcohol-free drink was administered before the other. Forty-five minutes after the ingestion of either drink, the participants cycled at 65% VO2max for 30 min followed by a 5-min all-out performance. Venous blood samples were obtained before and 45 min after the ingestion of both drinks, and also immediately after exercise. Exercise induced a significant increase in tissue-type plasminogen activator activity and antigen, and factor VIII procoagulant activity. The post-exercise data also showed a significant decrease in plasminogen activator inhibitor activity and soluble fibrin, with a significant shortening in prothrombin time and activated partial thromboplastin time, but not thrombin time. No significant changes were observed in antithrombin III. Although no significant differences were found between trials in the haemostatic and fibrinolytic variables at rest, a significant decrease in fibrinogen concentration was observed after exercise in the alcohol trial. This suggests that ingesting a moderate dose of alcohol does not alter blood coagulation and fibrinolysis at rest. Apart from fibrinogen concentration, which was significantly decreased after exercise in the alcohol trial, most of the haemostatic and fibrinolytic variables were not affected by alcohol. The mechanism responsible for the decrease in fibrinogen following exercise in the alcohol trial remains unknown, but might be related to inhibition of fibrinogen synthesis by the liver or an enhanced rate of its catabolism.
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PMID:The effect of moderate alcohol ingestion on blood coagulation and fibrinolysis at rest and in response to exercise. 1040

The effects of Pasteurella haemolytica leukotoxin (LKT) on the activity of phospholipase D (PLD) and the regulatory interaction between PLD and phospholipase A(2) (PLA(2)) were investigated in assays using isolated bovine neutrophils labeled with tritiated phospholipid substrates of the two enzymes. Exposure of [(3)H]lysophosphatidylcholine-labeled neutrophils to LKT caused concentration- and time-dependent production of phosphatidic acid (PA), the product of PLD. LKT-induced generation of PA was dependent on extracellular calcium. Both production of PA and metabolism of [(3)H]-arachidonate ([(3)H]AA)-labeled phospholipids by PLA(2) were inhibited when ethanol was used to promote the alternative PLD-mediated transphosphatidylation reaction, resulting in the production of phosphatidylethanol rather than PA. The role of PA in regulation of PLA(2) activity was then confirmed by means of an add-back experiment, whereby addition of PA in the presence of ethanol restored PLA(2)-mediated release of radioactivity from neutrophil membranes. Considering the involvement of chemotactic phospholipase products in the pathogenesis of pneumonic pasteurellosis, development and use of anti-inflammatory agents that inhibit LKT-induced activation of PLD and PLA(2) may improve therapeutic management of the disease.
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PMID:Role of phospholipase D in Pasteurella haemolytica leukotoxin-induced increase in phospholipase A(2) activity in bovine neutrophils. 1041 36

The present study was performed to analyze the relationship between portal hypertension and alterations of the endothelium-derived proteins thrombomodulin, plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1), which were determined in plasma samples of 28 alcoholic cirrhotic patients and 46 controls. Although cirrhotics showed lower levels of PAI-1, but higher thrombomodulin and t-PA levels than controls, no relationship was observed between thrombomodulin, t-PA or PAI-1 and portal pressure. Therefore, the hypothesis that splachnic endothelial damage secondary to portal hypertension leads to altered thrombomodulin, t-PA and PAI-1 levels in alcoholic cirrhosis is not supported by the results of this study.
Alcohol 2000 Feb
PMID:Lack of relationship between plasma thrombomodulin and portal hypertension in alcoholic liver disease. 1071

In this study, we have established a pig model that can combine extensive hemodynamic monitoring with simultaneous repetitive (serial) blood sampling for the study of multiple variables related to the hemostatic system. Sixteen healthy young pigs were studied to evaluate the influence of continuous endotoxin infusion on hemodynamic patterns and activation of coagulation and fibrinolysis. The chief aim of the study was to investigate the applicability of analytical methods primarily developed for use with human plasma samples in quantification of factors and reaction products of the porcine coagulation and fibrinolytic systems, and further, to use these methods to study the longitudinal changes in the plasma levels of these hemostatic variables as a consequence of endotoxin infusion. We found that acute, controlled endotoxemia induced a hemodynamic state of shock and reduced pulmonary gas exchange. Simultaneously, a gradual increase in peripheral blood mononuclear cell tissue factor activity was demonstrated, and increased maximally 5.5-fold 4 hours after onset of endotoxin infusion. Thrombin-antithrombin complexes increased in plasma to maximum levels after 3 hours, accompanied by an ethanol gelation test that was regularly positive after 1 to 2 hours, and fibrin monomer levels that gradually increased maximally 3.8-fold after 6 hours. These changes were followed by gradual decreases of both fibrinogen and factor VII levels, mainly due to consumption. Plasma levels of tissue type plasminogen activator activity peaked at 1.5 hours (11.3-fold increase), whereas the peak of plasminogen activator inhibitor-1 activity (14-fold increase at 4.5 hours) was delayed compared to tissue plasminogen activator and completely extinguished plasma tissue plasminogen activator activity. The sequential activation of coagulation and fibrinolysis established a procoagulant state favoring disseminated intravascular coagulation and microthrombus formation, potentially leading to multiple organ dysfunction.
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PMID:Hemodynamic changes and systemic activation of coagulation and fibrinolysis during controlled endotoxemia in pigs. 1089 51

The poor selectivity of photosensitizers for tumor tissue remains a drawback in photodynamic therapy (PDT) and could be improved by adapted formulations. The cellular uptake, localization and phototoxicity of meta-tetra(hydroxyphenyl)chlorin (mTHPC) encapsulated in submicronic colloidal carriers have been studied in macrophage-like J774 cells and HT 29 human adenocarcinoma cells. Nanocapsules with an external layer made of poly(D,L lactic acid) (PLA NCs), PLA grafted with polyethylene glycol (PLA-PEG NCs), PLA coated with poloxamer 188 (polox PLA NCs) and oil/water nanoemulsion (NE) have been examined. The cellular uptake by J774, as determined by microspectroflorimetry, is reduced with mTHPC encapsulated into surface-modified NCs--PLA-PEG and polox PLA--compared with naked PLA, indicating a possible limitation of the clearance of such carriers by the reticuloendothelial system. Encapsulation also modifies the interaction between mTHPC and HT29 cells. Compared with the manufacturer's solution (PEG, ethanol, water), the cellular uptake is strongly reduced. However, the HT29 phototoxicity is much less affected and a protecting effect against plasma proteins is observed. Fluorescence microscopy reveals a specific punctate fluorescence pattern with PLA-PEG and polox PLA NCs in contrast to a more diffuse distribution with NE and solution, indicating that photodamage targeting could be different. These findings suggest that photosensitizers encapsulated into surface-modified nanocapsules could be a promising approach for improving PDT efficacy and this has to be confirmed in vivo.
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PMID:A comparative study of the cellular uptake, localization and phototoxicity of meta-tetra(hydroxyphenyl) chlorin encapsulated in surface-modified submicronic oil/water carriers in HT29 tumor cells. 1094 81

In contrast to a reduced risk of coronary heart disease (CHD) with light to moderate alcohol consumption, heavy alcohol intake and binge drinking are associated with increased cardiovascular mortality. Alcohol has an acute and profound effect on fibrinolysis that may be relevant to the pathogenesis of CHD. The short-term effects of a low (two glasses, 250 mL, 20 g ethanol) and a high (six glasses, 750 mL, 60 g ethanol) intake of red wine were studied in male volunteers and compared to the intake of mineral water. To find a threshold for inhibition of fibrinolysis and to study a binge effect, a second experiment was performed comparing the intake of four (500 mL, 40 g ethanol) and eight (1000 mL, 80 g ethanol) glasses of red wine with mineral water. Plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), plasmin-antiplasmin (PAP) complexes and clot lysis time were measured. In contrast to the circadian rhythm with an enhanced fibrinolysis in the evening that was found in the mineral water group, an intake above four glasses of wine inhibited fibrinolysis significantly. After the intake of two glasses no significant disturbance of the circadian rhythm was observed. Five hours after the consumption of six glasses of wine, a dramatic increase occurred of PAI-1 antigen (77 +/- 42 microg L-1 vs. - 5 +/- 10 microg L-1 in the mineral water controls; P < 0.001) and PAI-1 activity (27 +/- 15 U mL-1 vs. - 2 +/- 3 U mL-1 in mineral water controls; P < 0.001). Despite a rise in t-PA antigen, t-PA activity dropped (- 0.5 +/- 0.2 U mL-1 vs. - 0.1 +/- 0.2 in controls; P < 0.001) as did PAP complexes (- 103 +/- 55 microg L-1 vs. - 26 +/- 57 microg L-1 in controls; P < 0.01). After the consumption of eight glasses of wine, the clot lysis assay indicated continued inhibition of fibrinolysis the following morning. Drinking a large amount of alcohol in the evening results in an acute inhibition of fibrinolysis, persisting the following morning. This may predispose to accelerated atherosclerosis and set the stage for thrombotic coronary events, explaining the higher cardiovascular mortality risk in binge drinkers.
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PMID:Acute inhibitory effect of alcohol on fibrinolysis. 1116 56


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