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)

The lung-colonizing ability of low-metastatic Lewis lung carcinoma cells (P-29) was enhanced by their in vitro treatment with butyric acid and its sodium salt, sodium butyrate. Of the short chain fatty acids tested, butyric acid was the most effective in enhancing the lung-colonizing ability of P-29 cells; propionic acid and valeric acid were slightly effective, but acetic acid and caproic acid were ineffective. The enhancing effect of butyric acid on the lung-colonizing ability of P-29 cells was reversible, indicating that the result was the consequence of epigenetic alterations. Treatment of P-29 cells with butyric acid resulted in enhancement of secretion of plasminogen activator, cellular cathepsin B activity, and cellular adhesiveness. The phenotypes of cells treated with butyric acid were compared with those of cells treated with dimethyl sulfoxide, which was reported to enhance the lung-colonizing ability of P-29 cells. Significant differences were found in the phenotypes, especially that of cellular adhesiveness; that is, butyric acid enhanced mainly homotypic aggregation of the cells, while dimethyl sulfoxide enhanced mainly heterotypic adhesion, such as adhesion to monolayers of endothelial cells. In addition, butyric acid reversibly caused hyperacetylation of core histones in P-29 cells, while dimethyl sulfoxide did not.
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PMID:Effect of butyric acid on lung-colonizing ability of cloned low-metastatic Lewis lung carcinoma cells. 394 96

The antiestrogenic character and potency of 4-(N,N-diethylaminoethoxy)-4'-methoxy-alpha-(p-hydroxyphenyl)-alpha' -ethylstilbene (H1285) and its binding to estrogen receptor and to estrogen-noncompetible antiestrogen binding sites have been studied in MCF-7 human breast cancer cells. H1285 has an affinity for the estrogen receptor (Kd 0.23 nM) which is comparable to that of estradiol (Kd 0.25 nM), and the binding of these two compounds to estrogen receptor is mutually competitive. On high salt sucrose gradients, the sedimentation profiles of nuclear receptor complexes with H1285 and estradiol are different. While the sedimentation profile of the complex with estradiol varies with the buffer composition, being 4.1S in phosphate:thioglycerol: glycerol and predominantly 5.5S in Tris:EDTA buffered gradients, the H1285 receptor complex shows the same sedimentation (5.5S) regardless of the buffer composition. H1285 also binds to estrogen-noncompetable antiestrogen binding sites that are distinct from the estrogen receptor with a low affinity, only 15% that of the antiestrogen tamoxifen. The biological character and potency of H1285 were examined by determining its effects on cell proliferation, cellular progesterone receptor levels, and plasminogen activator activity. In MCF-7 cells, H1285 was a 30- to 100-fold more potent inhibitor of cell proliferation than was the antiestrogen tamoxifen, and it was approximately equipotent with the higher affinity antiestrogen trans-hydroxytamoxifen. H1285 evoked very minimal increases in cellular progesterone receptor levels, and no increase in plasminogen activator activity over a broad range of concentrations (10(-10)-10(-6)M), and it suppressed plasminogen activator activity stimulated by estradiol. Therefore, by the criteria we have used, we conclude that H1285 is a potent and very effective antiestrogen in MCF-7 cells. The ability of estradiol to reverse the suppression of cell proliferation by H1285, and the high affinity of H1285 for estrogen receptor and its low affinity for estrogen-noncompetible antiestrogen binding sites suggest that H1285 exerts its antiestrogenic effects via interaction with the estrogen receptor of these breast cancer cells.
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PMID:Antiestrogenic potency and binding characteristics of the triphenylethylene H1285 in MCF-7 human breast cancer cells. 404 Aug 7

We have investigated the factors governing the plasminogen-dependent fibrinolysis catalyzed by the serine proteinase, plasminogen activator (EC 3.4.21.-), under physiologic conditions. We found that live rabbit fibroblasts digested much less fibrin than predicted by cell-free assay of the secreted plasminogen activator. The reduced catalytic activity of plasminogen activator expressed by cells growing on fibrin was regulated by the salt concentration of culture medium. The plasminogen activators of cells from several mammalian species were inhibited by physiologic salt concentrations (0.15 M NaCl) in cell-free assays. CaCl2 and KCl, but not D-glucose, were also effective inhibitors. The catalytic activity of purified human urokinase and of plasmin was unaffected by increased ionic strength. Plasminogen activators secreted both spontaneously and in response to stimulation by the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate, were inhibited by 0.15 M NaCl. Physiologic salt concentration appeared to function by interacting with plasminogen activator, or plasminogen, and a third component, possibly a reversible inhibitor. One consequence of this regulation of plasminogen activator under physiologic conditions is the limitation of plasminogen-dependent fibrin degradation by living cells.
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PMID:Expression of the catalytic activity of plasminogen activator under physiologic conditions. 645 62

The intracellular localization of the serine protease plasminogen activator was analyzed in homogenates of bovine brain cortex using differential fractionation procedures. The distribution of the enzyme was clearly different from that of cytosol and mitochondrial markers, and was similar to that of plasma membrane proteins and of the muscarinic acetylcholine receptor, which is a specific marker for the synaptic membrane. The specific activity of plasminogen activator was increased in fractions enriched in intact synaptosomes. Most of the enzyme in intact synaptosomes was found to be firmly associated with the synaptosomal membrane, and could be solubilized by high concentrations of salt or by non-ionic detergent. Purified synaptic vesicles, however, did not contain large amounts of plasminogen activator. Bovine brain synaptosomes were shown to contain two species of the enzyme, having apparent molecular weights of 80,000 and 55,000. The presence of plasminogen activator in the synaptosomal membrane may indicate its possible involvement in the functioning of nerve terminals.
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PMID:Plasminogen activator is enriched in the synaptosomal plasma membranes. 675 70

Endothelial cells were obtained from the aortae of newborn calves and cloned. High plasminogen activator (PA) activity was detected in the supernatant medium and the cell lysates of confluent cultures. The PA activity in the growth medium increased steadily during 12 hrs of incubation, indicating active enzyme secretion by these cells. Sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis of the concentrated medium demonstrated the presence of four plasminogen activators with apparent molecular weights of 77,000 (+/- 3000), 43,000 (+/- 2000), 26,000 (+/- 1500) and 14,500 (+/- 1500) respectively. The 43,000, 26,000 and 14,500 molecular weight forms could be converted to radioactive derivatives by active site labeling with 3H diisopropyl fluorophosphate (3H DFP) while the 77,000 Dalton form took up only traces of this radioactively labeled compound. The 43,000 molecular weight form was partially purified by means of salt precipitation and gel filtration. This enzyme preparation activated plasminogen by proteolytic cleavage with maximum activity at pH 7.5-8.5 and demonstrated a specific activity of 80,000 CA (Committee on Thrombolytic Agents) units/mg protein when tested on 125I-fibrin in the presence of plasminogen. This PA was rapidly and irreversibly inhibited by diisopropyl fluorophosphate (DFP), suggesting that it was a serine protease. The partially purified enzyme was extremely labile at temperatures from 0-60 degrees C, but could be stabilized by lowering the pH to 3 or by the addition of albumin.
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PMID:Secretion of plasminogen activators by cultured bovine endothelial cells: partial purification, characterization and evidence for multiple forms. 719 62

The platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa, fibrinogen receptor) represents the final common pathway for platelet aggregation. Inhibition of GPIIb/IIIa with antibodies or peptides containing the RGD sequence has been reported to prevent arterial thrombosis. We examined DMP 728 [(cyclic[D-2-amino-butyryl-N2-methyl-L-arginyl-glycyl-L-aspartyl-3-(a min o- methyl-benzoic acid], methanesulfonic acid salt], a cyclic peptidomimetic, GPIIb/IIIa receptor antagonist, for prevention of thrombosis and rethrombosis in a canine model of carotid artery thrombosis. Dogs were anesthetized, and both carotid arteries were instrumented with an electrode, a flow probe, and a stenosis. A 300-microA current was applied to the intimal surface in the right carotid artery (RCA, control) through the electrode; time to occlusive thrombus formation and thrombus mass was noted. The RCA served as the control vessel; the left carotid artery (LCA) served as the test vessel after DMP 728 administration (0.1 or 1. mg/kg, intravenously, i.v.). As compared with controls, occlusive thrombus formation was reduced by both doses of DMP 728 (control 100% n = 12; 0.1 mg/kg i.v. 17%, p < 0.05, n = 6; 1.0 mg/kg i.v. 0%, p < 0.05, n = 6), time to occlusion was increased (p < 0.05), and thrombus weight was reduced (p < 0.05). Ex vivo platelet aggregation was inhibited in all groups. In a second group of animals, a carotid artery thrombus was formed and lysed with anisoylated plasminogen activator complex (APSAC; 0.05 U/kg intraarterially, i.a.) with or without DMP 728.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antithrombotic effects of DMP 728, a platelet GPIIb/IIIa receptor antagonist, in a canine model of arterial thrombosis. 751 23

The effect of plasmin substrates D-valyl-L-leucyl-lysine-p-nitroanilide (S-2251) and H-D-norleucyl-hexahydrotyrosyl-lysine-p-nitro-anilide (Spectrozyme-PL) on the rate of activation of native human plasminogen in physiological salt solution is studied. Plasminogen activation by two-chain urokinase-type plasminogen activator (urokinase), two-chain tissue-type plasminogen activator (tc-tPA) or trypsin, but not by single chain tPA (sc-tPA) is increased 5- to 10-fold by both substrates, as determined by electrophoretic and spectrophotometric kinetic analysis. The amidolytic activity of sc-tPA, on the other hand, is inhibited by the plasmin substrates in a non-competitive manner (K1 of 6.4 . 10(-4) M for S-2251 and 2.9 . 10(-4) M for Spectrozyme-PL), whereas urokinase and tc-tPA activities are not affected. It is concluded that plasmin substrates containing a lysine residue have a general capacity to enhance plasminogen activation presumably by inducing a conformational change in the native zymogen in a manner similar to 6-aminohexanoate, while the same substrates are inhibitory both on the amidolytic activity of sc-tPA and the activation of native and des1-77-plasminogen by sc-tPA.
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PMID:Dual effect of synthetic plasmin substrates on plasminogen activation. 769 14

Savoxepine-loaded poly(DL-lactic acid) (PLA) nanoparticles were prepared using an emulsion technique involving a salting-out process which avoids surfactants and chlorinated solvents. After their formation, the nanoparticles were purified by cross-flow microfiltration and subsequently freeze-dried. The drug loading and the drug entrapment efficacy were improved by using savoxepine base rather than the methanesulfonate salt and by modifying the pH of the aqueous phase. A drug entrapment efficacy as high as 95% was obtained with a 9% drug loading. The overall yield of the procedure can rise up to 93%. In vitro release studies have demonstrated that by varying the mean size of the nanoparticles and their drug loading, the release of the drug from the nanoparticles can be modulated to last from several hours to more than 30 days, thus allowing the preparation of an injectable extended-release dosage form.
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PMID:In vitro extended-release properties of drug-loaded poly(DL-lactic acid) nanoparticles produced by a salting-out procedure. 790 25

Plasminogen-activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of tissue-type plasminogen activator, is an unusual member of the serine protease inhibitor (serpin) superfamily in that it spontaneously converts to a latent form lacking activity. This latent form can be reactivated by denaturation and refolding, but the activation is usually incomplete and often leads to aggregation of the protein. In this study we have developed a high-level expression system that leads to the accumulation of PAI-1 at 30-50% total microbial protein. We have developed a single-step purification protocol which can be completed in a few hours, yielding approximately 20 mg purified recombinant PAI-1/litre culture. The purified PAI-1 was 80-100% active and was stable upon incubation at 37 degrees C with a half-life of approximately 48 h. At 20 degrees C, PAI-1 activity was stable for a week and at 4 degrees C it retained its activity completely for up to two months. Freezing caused significant loss of activity. The stability of PAI-1 activity was found to be dependent on pH and ionic strength, being most stable at pH 5.6 and at an ionic strength of 1 M salt. We show that by a combination of high-level expression and rapid purification under optimum conditions, it is possible to produce active and stable PAI-1 in high yield.
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PMID:Purification and characterization of active and stable recombinant plasminogen-activator inhibitor accumulated at high levels in Escherichia coli. 807 33

In order to define the possible effects of heparin on the fibrinolytic system under physiological conditions, we studied the interactions of this drug with plasminogen and its activators at various ionic strengths. As reported in recent literature, heparin stimulated the activation of Lys-plasminogen by high molecular weight (HMW) and low molecular weight (LMW) two-chain urokinase-type plasminogen activator (u-PA) and two-chain tissue-type plasminogen activator (t-PA) 10- to 17-fold. Our results showed, however, that this stimulation only occurred at low ionic strength and was negligible at a physiological salt concentration. Direct binding studies were performed using heparin-agarose column chromatography. The interaction between heparin and Lys-plasminogen appeared to be salt sensitive, which explains at least in part why heparin did not stimulate plasminogen activation at 0.15 M NaCl. The binding of u-PA and t-PA to heparin-agarose was less salt sensitive. Results were consistent with heparin binding sites on both LMW u-PA and the amino-terminal part of HMW u-PA. Single-chain t-PA bound more avidly than two-chain t-PA. The interactions between heparin and plasminogen activators can occur under physiological conditions and may modulate the fibrinolytic system.
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PMID:Interaction of plasminogen activators and plasminogen with heparin: effect of ionic strength. 812 48


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