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

---

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

Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the processes of peripheral tissue remodeling and fibrinolysis through the regulation of plasminogen activation. We found that cultured human astrocytes efficiently released PAI-1, and that both mRNA expression and protein release of PAI-1 were suppressed by pretreatment of the cells with daunorubicin. To examine the role of PAI-1 in the nervous system, neuronally differentiated PC-12 cells (PC-12 neurons) were maintained in a PAI-1-deficient culture medium derived from daunorubicin-pretreated astrocytes. The deficiency of PAI-1 in the medium caused a significant reduction in Bcl-2 and Bcl-XL mRNAs and an increase in Bcl-XS and Bax mRNAs in PC-12 neurons at 3 h. The changes in balance between mRNA expressions of the anti- and pro-apoptotic Bcl-2 family proteins caused caspase-3 activation following the release of cytochrome c from mitochondria. Apoptotic morphological change and DNA fragmentation were also observed in the neuronal cells at 24 h. Addition of exogenous PAI-1 protein to the inhibitor-deficient medium blocked the apoptotic changes in PC-12 neurons. However, addition of PAI-1 antibodies to control medium caused similar apoptotic changes in PC-12 neurons. During the apoptotic processes, plasminogen activator (PA) activity in the PAI-1-deficient medium was as low as the control level. The present data suggest that PAI-1 has physiological functions other than its role as PA inhibitor for the survival of neurons.
...
PMID:Deficient release of plasminogen activator inhibitor-1 from astrocytes triggers apoptosis in neuronal cells. 1145 96

The effects of tumor necrosis factor (TNF)-alpha on the plasminogen activator (PA)/plasmin system in human dental pulp (HDP) cells were examined. TNF-alpha treatment induced a significantly high level of PA activity in the conditioned medium of HDP cells in a time- and dose-dependent manner, compared with untreated control cells. Western-blot analysis revealed that tissue type (t)PA protein in conditioned medium was increased by TNF-alpha when compared with control medium. Furthermore the tPA mRNA level had increased in HDP cells treated with TNF-alpha, as determined by reverse transcription-polymerase chain reaction, but urokinase PA and PA inhibitor-1 mRNA levels did not increase. We examined the effects of TNF-alpha against activities of matrix metalloproteinases (MMPs) using zymography. TNF-alpha stimulated MMP-2 activity in conditioned medium and stimulated MMP-9 activity with addition of plasminogen into conditioned medium. The present results suggested that TNF-alpha stimulates PA activity via an enhancement of tPA gene expression in HDP cells and MMP-2 activity, and further that tPA-activated TNF-alpha stimulated MMP-9.
...
PMID:Stimulation of plasminogen activator activity and matrix metalloproteinases of human dental pulp-derived cells by tumor necrosis factor-alpha. 1148 46

The effect of wound fluids collected from acute well-healing wounds and chronic nonhealing venous leg ulcers on the plasminogen activation system of keratinocyte and fibroblast cell cultures was studied in a simplified wound-healing model. Acute wound fluid was collected from donor sites of split skin grafts at different time points representing the progressive healing of the wound. Urokinase-type plasminogen activator, tissue-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor 1 expression were studied. The methods used were immunocapture assay and immunocytochemistry. The results indicated that the later the acute wound fluid was collected, the greater the urokinase-type plasminogen activator and the lower the plasminogen inhibitor-1 level in treated cells. In contrast, the level of urokinase-type plasminogen activator receptor remained stable irrespective of wound fluid treatment. Immunostaining for urokinase-type plasminogen activator of acute wound fluid-treated cells showed a disseminated punctate pattern over the cell surface, but with chronic wound fluid, urokinase-type plasminogen activator was localized to focal contacts. Our findings support the view that in the acute wound environment the plasminogen activator system is proteolytically active and that in chronic leg ulcers urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor may also be organized for cell adhesion and migration.
...
PMID:Differential effects of acute and chronic wound fluids on urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and tissue-type plasminogen activator in cultured human keratinocytes and fibroblasts. 1167 40

A number of experimental and clinical studies have recently underlined the importance, in acute myocardial infarction, of platelet adhesion and aggregation after plaque rupture. During clot resolution, platelet-rich thrombi are relatively resistant to fibrinolytic agents, mainly due to the release of plasminogen inhibitor-1 by platelets which are activated as a result of the increase in thrombin generation induced by plasminogen activator therapy despite heparin administration. Platelet glycoprotein (GP) IIb/IIIa integrin receptor blockers prevent platelet aggregation by blocking the final pathway of platelet activation. Thus, they also prevent the formation of an intraluminal white thrombus without affecting adhesion. Animal and human studies have shown that the potent inhibition of platelet GP IIb/IIIa receptors can lead to modest reperfusion rates even without exogenous fibrinolytic therapy. This suggests that combining the "dethrombotic" effects of a GP IIb/IIIa antagonist with lower fibrynolytic doses may result in a synergistic effect. Preclinical studies including patients with myocardial infarction have shown that such combined treatment increases the incidence, speed and durability of reperfusion. It has also been proved to be useful in improving the microcirculatory coronary flow and in facilitating subsequent percutaneous coronary interventions. In the phase III GUSTO V trial, abciximab combined with 5 + 5 U of reteplase and low-dose weight-adjusted heparin led to a 30-day mortality rate that was similar to that obtained with full-dose reteplase (10 + 10 U) and standard heparin therapy, without causing a significant increase in the incidence of intracranial hemorrhage. The results of this trial offer a rationale for alternative reperfusion therapy, although further analyses, including a 1-year follow-up, are needed to define the patient groups that are most likely to benefit from such a new regimen.
...
PMID:[New strategies in the treatment of acute myocardial infarction]. 1172 6

Serine proteases, such as thrombin and tissue-type plasminogen activator, play an important role in brain injury after intracerebral hemorrhage and other neurologic disorders. Plasminogen activator inhibitor-1 is one of the serine protease inhibitors, or serpins. The balance between serine proteases and serpins may affect the outcome of intracerebral hemorrhage. The purpose of this study was to determine whether plasminogen activator inhibitor-1 and tissue-type plasminogen activator are upregulated after intracerebral hemorrhage and the role that thrombin plays in that induction. Plasminogen activator inhibitor-1 protein levels were upregulated after intracerebral hemorrhage. Brain plasminogen activator inhibitor-1 content also increased after thrombin infusion in a dose-dependent manner. Hirudin, a specific thrombin inhibitor, blocked the upregulation of plasminogen activator inhibitor-1 after intracerebral hemorrhage. Time courses showed that plasminogen activator inhibitor-1 levels around the hematoma peaked at the first day. Plasminogen activator inhibitor-1-positive cells were detected in the perihematomal area and the ipsilateral basal ganglia after thrombin infusion, but not in the contralateral hemisphere. Plasminogen activator inhibitor-1 messenger RNA levels were increased at 24 hours after intracerebral hemorrhage and after thrombin infusion. However, tissue-type plasminogen activator protein levels were the same in the control, whole-blood, and thrombin-infusion groups. In conclusion, intracerebral hemorrhage and thrombin infusion stimulate plasminogen activator inhibitor-1 but not tissue-type plasminogen activator production in the brain. The upregulation of plasminogen activator inhibitor-1 may be neuroprotective by limiting thrombin or other serine protease-induced toxicity.
...
PMID:Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage. 1180 94

Fibrinolysis is controlled by the plasminogen activator system. The proteolytic activity of this system is mediated by plasmin, which is generated from plasminogen by one of two plasminogen activators. Plasminogen activator inhibitor-1 (PAI-1) inhibits this process. Individuals with reduced fibrinolytic activity are at increased risk for ischemic cardiovascular events, and reduced fibrinolysis may underlie some of the pathological consequences of reduced nitric oxide (NO) availability. Within the vasculature, angiotensin II stimulates the release of PAI-1, thereby reducing fibrinolytic activity. Thus, the plasminogen activator system is largely controlled by the renin-angiotensin system (RAS). In accordance with this finding, treatment with angiotensin converting enzyme (ACE) inhibitors is associated with substantial reductions in the incidence of ischemic cardiovascular events. Links between the RAS, fibrinolytic balance, and cardiovascular pathology are further supported by evidence from transgenic and knockout animal models. This article discusses the role of the plasminogen activator system in cardiovascular pathology, and the potential for alleviating that pathology by manipulation of the RAS.
...
PMID:Angiotensin and vascular fibrinolytic balance. 1182 73

Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of both tissue- and urokinase-type plasminogen activators (t-PA, u-PA). PAI-1 also regulates the attachment of cells to the adhesive glycoprotein vitronectin (VN). PAI-1 gene expression has been observed in various cell types, and many regulatory factors have been identified to play a role in PAI-1 gene transcription. The complete picture of how the PAI-1 gene is expressed when cells adhere to a culture plate has not been fully elucidated. We found that in anchorage-dependent cells, PAI-1 gene was up-regulated when cells were beginning to attach to a culture dish and was down-regulated when cells had attached completely. The PAI-1 gene expression was induced only in adhered cells but not in non-adhered cells. The regulation of PAI-1 protein was also found in both culture medium and cell lysate when cells were attached to a culture dish. Our experiment indicates that vitronectin and fibronectin, as components of ECM, may be the factors involved in the regulation of PAI-1 gene expression. PAI-1, as an inhibitor of the interaction between vitronectin and integrin alphavbeta3, may also be a regulator of its own expression.
...
PMID:Cell adhesion regulates the plasminogen activator inhibitor-1 gene expression in anchorage-dependent cells. 1182 81

Several papers concerning abnormalities of blood coagulation and fibrinolysis during hyperthyroidism, have been published. Increased von Willebrand Factor (vWF) activity and high fibrinogen levels have been reported. However, there is controversy concerning the presence of a hypercoagulable state in hyperthyroidism. We investigated various hemostatic parameters in 41 hyperthyroid patients and compared them to 20 euthyroid controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX and X activities, vWF, antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1), as well as common lipid variables, were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with control subjects, fibrinogen, factor IX, vWF, AT III and PAI-1 were significantly increased in patients (p<0.05, p<0.0001, p<0.05, p<0.01 and p<0.0001; respectively), whereas factor X and t-PA were decreased (p<0.05). We showed that free T4 (FT3) levels were correlated with factor VIII activity (r=0.35, p<0.05). FT4, FT3 and TSH did not correlate with fibrinogen, vWF, AT III, t-PA, or PAI-1. AT III was inversely correlated with factor VII activity (r=-0.48, p<0.01). Protein C and S were correlated with vWF levels (r=0.58, p<0.0001; r=0.55, p<0.0001, respectively). Protein C was inversely correlated with t-PA (r=-0.39, p<0.01). There was a negative correlation between triglycerides, LDL-C and F X (r=-0.45, p<0.05; r=-64, p<0.01, respectively). Mean platelet volume (MPV) was correlated with anti-thyroid peroxidase (TPO) antibodies (in Graves'disease) and F IX activity (r=0.57, p<0.05 and r=0.39, p<0.05; respectively). We found important differences in the coagulatory /fibrinolytic parameters between the hyperthyroid patients and healthy controls. Hyperthyroid patients may experience vascular endothelial dysfunction and decreased fibrinolytic activity in blood. This endothelial activation may represent a situation with a higher thromboembolic potential.
...
PMID:Blood coagulation and fibrinolysis in patients with hyperthyroidism. 1203 Jun 6

To determine whether there is a correlation between fibrinolytic activity and dyslipidemia, we performed a study of 72 subjects (20 patients with hypercholesterolemia, 20 with hypertriglyceridemia, 12 with isolated low high-density lipoprotein (HDL)-cholesterol (mean age 47.7 +/- 6.3, body mass index 24.7 +/- 0.4) and 20 healthy controls. Plasminogen activator inhibitor-1 (PAI-1), tissue-plasminogen activator activity and plasmin-antiplasmin complexes (PAP) were detected at baseline and after venous occlusion test. We also measured at baseline lipidic pattern, soluble E and P selectins (sE-sel, sP-sel), prothrombin factor 1+2 (F1+2), lipoprotein(a), factor VII, plasma insulin, fibrinogen, homocysteine, and thrombin activable fibrinolysis inhibitor (TAFI) activity. Fibrinolysis was significantly reduced in hypertriglyceridemic patients compared with hypercholesterolemic patients and control subjects (PAP, p < 0.01 and p < 0.001) and was associated with increased PAI-1 (at baseline and after venous occlusion test, p < 0.001). sP-sel, F1 +2 and TAFI were not significantly different compared with controls, while hypercholesterolemic subjects showed a significant increase in these parameters (p < 0.001), which were related to decreased PAP only at the upper low-density lipoprotein (LDL)-cholesterol levels (>160 mg/dl) (p < 0.001, r = -0.76). Moreover, there was no significant difference in PAI-1 activity (at baseline and after venous occlusion test) compared with controls. In conclusion, endothelial dysfunction was the main mechanism of decreased fibrinolysis in subjects with hypertriglyceridemia and low HDL-cholesterol, while enhanced thrombin generation and TAFI activity were the main determinants in hypercholesterolemia.
...
PMID:Different mechanisms of fibrinolysis impairment among dyslipidemic subjects. 1206 44

Plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator in plasma, is a well established risk factor in thrombotic diseases. Reduction of active PAI-1 levels may lead to a decreased tendency of thrombosis. Compounds that can suppress pharmacologically active PAI-1 levels are therefore considered as putative drugs. In the present study, we describe the PAI-1 neutralizing properties and mechanism of a newly selected compound (i.e. fendosal, HP129) in comparison to four previously reported compounds (i. e. AR-H029953XX, XR1853, XR5118 and the peptide TVASS) using different assays. The inhibitory effect of these compounds on active PAl-1 was analyzed by a plasmin-coupled chromogenic assay (Coaset t-PA), direct chromogenic assays (t-PA, u-PA) and quantification of complex formation by ELISA, SDS-PAGE and surface plasmon resonance. Comparative evaluation of the obtained IC50 values reveals large differences [i.e. IC50 of 15 microM (HP129) vs. >1000 microM (XR5118) determined at 37 degrees C using SDS-PAGE] between the compounds studied. Importantly, the relative potency of the various compounds is also dependent on the method used (10 to 170-fold differences in IC50 values). Characterization of the PAI-1 forms (i.e. active, non-reactive and substrate) generated upon inactivation reveals that the newly described compound HP129 induces a unique pathway (i.e. active to non-reactive conversion via a substrate-behaving intermediate) of inactivation compared to the other compounds. Taken together, these data strongly suggest that the various compounds act through different mechanisms. In addition, the results stress the necessity for a careful selection of the method used for the evaluation of PAI-1 inhibitors, preferably requiring a panel of screening methods.
...
PMID:Characterization and comparative evaluation of a novel PAI-1 inhibitor. 1215 54


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

---