UNIPROT:P00750 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in plasminogen activator are associated with the reproductive tissue remodelling that occurs during growth. Given the trophic effects of relaxin on the pig uterus and cervix, the present study was designed to examine the impact of relaxin on urokinase and tissue-type plasminogen activator (uPA and tPA) protein and activity in the uterus and cervix of prepubertal pigs. After relaxin administration in vivo to induce growth of the immature uterus and cervix, plasminogen activator activity was measured in uterine flushes and uterine and cervical tissue using a chromogenic substrate assay. Immunoreactive uPA and tPA protein in uterine flushes and uterine and cervical tissue was detected by western blotting. Urokinase plasminogen activator activity was significantly higher (P < 0.05) in uterine flushes from relaxin-treated animals than in controls. However, there was no change in uterine flush tPA activity or protein in response to in vivo relaxin treatment. There was no evidence for acid-labile inhibitors of plasminogen activator in uterine flushes of any of the animals. Cell-associated uterine tissue uPA and tPA activity, as well as protein, were similar in relaxin-treated and control prepubertal pigs. In the cervix, cell-associated tPA activity decreased significantly (P < 0.05) in relaxin-treated animals, while cervical uPA activity was unchanged. These results support the view that at least one means by which relaxin promotes pig uterine growth is by increasing uterine secretion of uPA. In addition, these studies suggest that relaxin administration in vivo to prepubertal gilts has tissue-specific effects with respect to plasminogen activator.
...
PMID:Regulation of urokinase- and tissue-type plasminogen activator by relaxin in the uterus and cervix of the prepubertal gilt. 987 63

Stroke remains the leading cause of neurological disability and the third leading cause of death worldwide, consuming a large share of total healthcare expenditures. In this review, we discuss the cost effectiveness of stroke prevention for various risk factor-modification programmes and pharmacological interventions with aspirin (acetylsalicylic acid), ticlopidine and warfarin. Cost considerations and potential cost savings resulting from acute treatment are discussed for parenterally administered anticoagulants, such as heparin and nadroparin, and for intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; r-tPA). Patients with multiple risk factors for stroke require more aggressive prevention strategies which are associated with a greater risk of complications. The rates of complications, particularly intracerebral haemorrhage, should be kept low to achieve cost benefits for warfarin and alteplase. Reduced hospital length of stay is the key factor in the implementation of cost-effective stroke therapies. The analysis of future clinical trials of new stroke therapies should also include economic parameters, such as length of hospital stay and intensity of resource usage, to help guide formulary and therapeutic decision.
...
PMID:Cost considerations in the pharmacological prevention and treatment of stroke. 1016 30

Extracellular matrix (ECM) not only provides a structural support for the organism, but also actively conducts cell-to-cell signal transduction and regulates cell proliferation, migration, development and metabolism. The targeted ECM degradation generated by plasminogen activator (PA) and regulated by plasminogen activator inhibitor (PAI) is, therefore, an event that affects a wide variety of physiological and pathological processes. The ovary is the best model to study the regulation and function of extracellular proteolysis mediated by multicomponents like the PA system. Studies carried out over the past 10 years in a number of laboratories have elucidated some of the biochemical events related to the function and regulation of the PA system in the ovary: hormone-induced proteolytic activity provided by tissue-type PA(tPA) and modulated by PAI-1 in the preovulatory follicles is responsible for a controlled and directed proteolysis leading to rupture of selected follicles during ovulation, whereas the coordinated expression of urokinase-type PA (uPA) and PAI-1 in the early growing follicle may be important in ECM degradation during cell proliferation and migration; the PA system may also play a role in the control of corpus luteum (CL) development through an autocrine or paracrine mechanism. Increase in tPA and PAI-1 expression in CL at a later stage is well correlated with a sharp decrease in CL progesterone production, while the increase in uPA mRNA levels and activity in the early stage of CL development is correlated with an increase in progesterone secretion.
...
PMID:Regulation of the plasminogen activator system in the ovary. 1021 45

In a number of cases, thrombolytic therapy fails to re-open occluded blood vessels, possibly due to the occurrence of thrombi resistant to lysis. We investigated in vitro how the lysis of hardly lysable model thrombi depends on the choice of the plasminogen activator (PA) and is accelerated by ultrasonic irradiation. Lysis of compacted crosslinked human plasma clots was measured after addition of nine different PAs to the surrounding plasma and the effect of 3 MHz ultrasound on the speed of lysis was assessed. Fibrin-specific PAs showed bell-shaped dose-response curves of varying width and height. PAs with improved fibrin-specificity (staphylokinase, the TNK variant of tissue-type PA [tPA], and the PA from the saliva of the Desmodus rotundus bat) induced rapid lysis in concentration ranges (80-, 260-, and 3,500-fold ranges, respectively) much wider than that for tPA (a 35-fold range). However, in terms of speed of lysis, these three PAs exceeded tPA only slightly. Reteplase and single-chain urokinase were comparable to tPA, whereas two-chain urokinase, anistreplase, and streptokinase were inferior to tPA. In the case of fibrin-specific PAs, ultrasonic treatment accelerated lysis about 1.5-fold. For streptokinase no acceleration was observed. The effect of ultrasound correlated with the presence of plasminogen in the outer plasma, suggesting that it was mediated by facilitating the transport of plasminogen to the surface of the clot. In conclusion, PAs with improved fibrin-specificity induce rapid lysis of plasminogen-poor compacted plasma clots in much wider concentration ranges than tPA. This offers a possibility of using single-or double-bolus administration regimens for such PAs. However, it is not likely that administration of these PAs will directly cause a dramatic increase in the rate of re-opening of the occluded arteries since they are only moderately superior to tPA in terms of maximal speed of lysis. Application of high-frequency ultrasound as an adjunct to thrombolytic therapy may increase the treatment efficiency, particularly in conjunction with fibrin-specific PAs.
...
PMID:Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: comparison of nine plasminogen activators in vitro. 1023 48

Antithrombotic and clotting factors have long been targets for drug discovery, necessitating the development of blood assays to determine the efficacy of lead compounds prior to animal testing. We have developed a reconstituted blood clot lysis assay which eliminates the need for on-site donors. The assay uses whole blood stored at 4 degrees C obtained from a local blood bank, diluted 1:10 in phosphate buffer. This blood was supplemented with 125I-labeled fibrinogen and the release of radioactive fibrinopeptides from formed clots was measured. The whole blood used in this assay, which had been stored at 4 degrees C for several days, no longer formed solid or retracting clots. Thus, platelets 5-7 days ex vivo (165 x 10(6) platelets) were added to the whole blood in the presence of thrombin (0.80 IU/ml) to form clots. Solid clots formed within 2 min of thrombin addition and began retracting shortly thereafter. In the absence of any thrombolytic agent, clots fully retracted within 2.5 h and remained stable. Thrombin-stimulated clot formation was completely inhibited by heparin. Clots could be lysed in a dose-dependent fashion in the presence of tissue-type plasminogen activator. Clot lysis could be completely inhibited in a dose-dependent fashion with plasminogen activator inhibitor type 1. To demonstrate the utility of this assay as a screen for thrombolytic agents, a 14-amino-acid PAI-1-inhibitory peptide relieved the PAI-1 effect on tPA in a dose-dependent fashion. These data describe an assay for the screening of potential pro-fibrinolytic agents that target PAI-1 inhibition in a human plasma-based system that is versatile, cost-effective, and physiologically relevant and does not rely on the availability of on-site blood donors.
...
PMID:A reconstituted dilute blood clot lysis assay for the medium throughput screening of thrombolytic compounds. 1032 61

A stronger positive association between fibrinogen or tissue-type plasminogen activator antigen (tPA-ag) and fasting insulin is observed in women than in men. We investigated whether this effect could be explained by a difference in smoking habits. The relations between markers for insulin resistance [fasting insulin and insulin resistance as estimated by the homeostasis model assessment (HOMA-IR)] and fibrinogen and tPA-ag were examined cross-sectionally in 4976 (582 for tPA-ag) subjects from the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome) study. The modifying effect of smoking habits were evaluated. Seventeen percent of women and 27% of men were smokers. Fibrinogen concentrations were higher in smokers than in non-smokers, in men only. Female smokers had lower concentrations of tPA-ag than non-smokers. In both women and men, fibrinogen was positively associated with fasting insulin [women: beta = 0.33 mg/U (95% confidence interval: 0.29, 0.37); men: beta = 0.15 mg/U (0.11, 0.19)] and with HOMA-IR [women: beta = 0.17 microg/microU mol/l (0.15, 0.19): men: beta = 0.06 (0.04, 0.08)]. For tPA-ag these associations were for insulin beta = 0.76 mg/U (0.54, 0.98) and beta = 0.89 mg/U (0.67, 1.11), and for HOMA-IR beta = 0.47 microg/microU mol/l (0.33, 0.61) and beta = 0.45 microg/microU mol/l (0.33, 0.57), women and men respectively. The associations of fibrinogen and tPA-ag with insulin and HOMA-IR were sharply reduced in male smokers compared to male non-smokers, however the strength of the associations in male non-smokers did not reach that in women. Fibrinogen and tPA-ag are independently related with markers of insulin resistance, with the relation with fibrinogen being stronger in women than in men. The strong modifying effect of smoking habits does not completely explain this gender difference.
...
PMID:Gender differences in the relation between fibrinogen, tissue-type plasminogen activator antigen and markers of insulin resistance: effects of smoking. D.E.S.I.R. Study Group. Data from an Epidemiological Study on Insulin Resistance Syndrome. 1049 72

The plasminogen activating system plays a key role in the cascade of tumour-associated proteolysis leading to extracellular matrix degradation and stromal invasion. Changes in the expression of this system, consisting of urokinase- and tissue-type plasminogen activators (uPA and tPA, respectively), plasminogen activator inhibitors (PAI-1, PAI-2) and uPA receptor, have been associated with tumour aggressiveness in a variety of solid malignant tumours. This paper describes a study of squamous intraepithelial lesions (SILs, n=36), squamous cell carcinomas (SCCs, n=42), and normal mucosa (n=5) of the uterine cervix by in situ hybridization with (35)S-labelled RNA probes. uPA transcripts were absent from normal mucosa and non-invasive lesions, but present in atypical epithelial cells of all microinvasive carcinomas ( n=19) and in some of the more advanced invasive carcinomas (n=11). PAI-1 transcripts were found in stromal cells of most tissue samples with, however, significantly increased levels in invasive SCC compared with SIL, microinvasive SCC, and normal mucosa. uPA-positive invasive carcinomas often displayed additional PAI-1 expression by tumour cells. At variance with uPA, tPA transcripts were found in atypical epithelial cells of low- and high-grade SILs. In the majority of SCCs tested (27/29 cases), the HPV 16 E6/E7 oncogene and uPA transcription were correlated. uPA and PAI-1 expression indicates invasive growth when expressed by atypical epithelial cells of squamous cervical lesions. Moreover, the presence of uPA transcripts is indicative of early invasive growth. uPA and tPA seem to have different functions in the development of invasive properties in uterine cervical squamous epithelium.
...
PMID:Urokinase gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix. 1054 82

The study investigated the formation of perforated synapses in rat hippocampal cell cultures. Perforated synapses are defined by their discontinuous postsynaptic densities (PSDs) and are believed to occur in parallel with changes in synaptic activity and possibly also synaptic efficacy. Several in vivo studies have demonstrated an increase in the frequency of perforated synapses induced by development and environmental stimulation as well as long-term potentiation (LTP). Also in in vitro brain slices, LTP was associated with an elevated number of perforated spine synapses. Our study demonstrated for the first time that the formation of perforated synapses can be induced by a short-term increase in spontaneous neural activity in a hippocampal cell culture model. Stimulation with the GABAA-antagonist picrotoxin (PTX) induced a significant increase in the percentage of perforated synapses. This strong increase was blocked when APV was added together with PTX, indicating that the formation of perforated synapses depended on the activation of NMDA receptors. We also showed that inhibition of the tissue type plasminogen activator (tPA-stop/PAI-1) significantly interfered with the activity-induced increase in perforated synapses. This implies that the proteolytic activities of tPA might be involved in steps which are downstream from the NMDA receptor-mediated synaptic plasticity leading to structural changes at synaptic contacts. In contrast, even long-term inhibition of electrical network activity by tetrodotoxin had no effect on the number of perforated synapses, but almost completely abolished the formation of spine synapses. These results indicate that a short-term increase in neural activity via NMDA receptors and a proteolytic cascade involving tPA lead to the formation of perforated synapses.
...
PMID:Activity-dependent formation of perforated synapses in cultured hippocampal neurons. 1059 50

Although there is considerable interest in the role of neutrophils and platelets in acute cerebral ischemia-reperfusion, there are very little data related to the effect of systemic thrombolytic therapy on these blood elements. In the present study a rabbit model was used to examine the effects of cerebral ischemia, tissue-plasminogen activator therapy, or both on neutrophil and platelet peripheral counts and activity, the latter studied by stimulated neutrophil and platelet impedance aggregation and neutrophil oxygen-free radical chemiluminescence. New Zealand white rabbits (n = 25) were randomized to receive either tissue-plasminogen activator (6.3 mg/kg IV; 20% bolus, remainder as a 2-hour infusion) or vehicle (0.9% saline) 3 hours following either autologous clot embolization or sham carotid artery isolation. Thus, four groups were examined: sham (n = 4), tPA only (n = 4), stroke only (n = 8), and stroke plus tPA (n = 9). Two hours after completion of thrombolytic therapy or vehicle infusion, the experiments were terminated, that is, 7 hours following autologous clot embolization or sham instrumentation. Blood was sampled from the thoracic aorta, and neutrophil and platelet peripheral counts and activity were determined prior to embolization and 0.5, 2.0, 4.0, and 7.0 hours following autologous clot embolization. No significant difference in platelet counts, either over time or between groups, was noted. In contrast to the platelet counts, the neutruphil count significantly increased over time, rising approximately 2.5-fold from baseline in all four groups (p < 0.001). No significant increase in neutrophil accumulation (myeloperoxidase assay; 10 (7) PMNs/g tissue; mean +/- SEM) was noted within infarcted regions of either the stroke (1.26 +/- 0.07; n = 5) or stroke plus tissue-plasminogen activator (1.26 +/- 0.09; n = 5) groups when compared to either viable brain regions within the ischemic hemisphere (1.29 +/- 0.03; n = 4) or in sham controls (1.36 +/- 0.35; n = 4). Neutrophil activity (aggregation, oxygen-free radical release) in both groups undergoing autologous clot embolization demonstrated a trend toward higher values when compared to the two sham-operated groups. Tissue-plasrninogen activator administration did not significantly affect ex vivo neutrophil activity. In contrast, platelet aggregation was significantly reduced by the administration of tPA with (p = 0.001) or without (p < 0.01) autologous clot embolization. Thus, in the present rabbit model platelet but not neutrophil activity is modulated by the administration of tissue-plasminogen activator, while autologous clot embolization results in a trend toward acute neutrophil activation.
...
PMID:Neutrophil and Platelet Activity and Quantification Following Delayed tPA Therapy in a Rabbit Model of Thromboembolic Stroke. 1060 28

This experimental study evaluated the effect of intrathecal injection of tissue-type plasminogen activator followed by cisternal drainage in the ultra-early stage of aneurysmal subarachnoid haemorrhage to prevent vasospasm. Twenty Japanese white rabbits were divided into five groups. Either tPA (groups A, B, and E) or saline (groups C and D) was injected intrathecally 1 hour (groups A, B, C, and D) or 21 hours (group E) after the intrathecal injection of blood. Cerebrospinal fluid was drained 2, 4, and 6 hours after the intrathecal injection of blood (groups A, C, and E). On day 4, the angiographic caliber of the basilar artery in each group was as follows (mean +/- SD): A, 85.9 +/- 5.0%; B, 74.6 +/- 5.3%; C, 69.1 +/- 2.7%; D, 64.0 +/- 4.9%; E, 80.2 +/- 2.7% (compared with baseline). In the two groups in which CSF was drained (groups A and C), fibrinolysis with tPA significantly suppressed vasospasm. In the two groups treated with tPA (groups A and B), cisternal drainage significantly suppressed vasospasm. In the two groups treated with saline (groups C and D), however, cisternal drainage did not suppress vasospasm. Examination of the series of CSF samples (groups A and C) showed that fibrinolysis with tPA effectively cleared clots early. In the two groups treated with tPA and CSF drainage (groups A and E), early removal of subarachnoid clots reduced the degree of vasospasm. Early fibrinolysis with tPA and early removal of subarachnoid clots by drainage is effective for preventing vasospasm.
...
PMID:Experimental study of intracisternal administration of tissue-type plasminogen activator followed by cerebrospinal fluid drainage in the ultra-early stage of subarachnoid haemorrhage. 1067 5

<< Previous 1 2 3 4 5 6 7 8 9 10