Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) activation is regulated by Ca2+, phospholipids, diacylglycerol (DAG) and fatty acids. Phorbol myristate acetate (PMA) which mimics the effect of DAG on PKC induces transcriptional activation of the urokinase-type plasminogen activator (u-PA) gene in LLC-PK1 cells. We examined in the present work the relationships between PKC activity, fatty acids, and u-PA synthesis in this cell line. We showed that H7, an inhibitor of PKC, inhibited the PMA-induced u-PA synthesis by LLC-PK1 cells. PMA-induced u-PA synthesis was enhanced by eicosatetraynoic acid (ETYA), a competitive inhibitor of both the lipoxygenase and cyclooxygenase pathways and inhibited by nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway. Three other unrelated lipoxygenase inhibitors (phenidone 100 microM, BW755 50 microM and diethylcarbamazine 50 microM) had no effect on u-PA biosynthesis. Two polyunsaturated fatty acids other than ETYA, arachidonic acid and linoleic acid, also potentiated the PMA effect and a lipoxygenase derivative, 12 hydroxyeicosatetraenoic acid (12 HETE), did not modify the basal and PMA-stimulated u-PA syntheses. PKC activity purified from cytosol of LLC-PK1 cells was stimulated by addition of 16 nM PMA in vitro and this effect was blunted by simultaneous addition of 5 microM NDGA. By Northern blot analysis using a pig u-PA cDNA probe we found that PMA increased the steady state level of u-PA mRNA after 2 h of incubation and that NDGA inhibited this effect. These data suggest that NDGA inhibits PMA-stimulated PKC activity in intact cells leading to a decrease of u-PA mRNA level and u-PA biosynthesis in PMA-stimulated LLC-PK1 cells. Polyunsaturated fatty acids have opposite effects.
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PMID:Nordihydroguaiaretic acid inhibits urokinase synthesis by phorbol myristate acetate-stimulated LLC-PK1 cells. 212 15

Human diploid fibroblasts were cultured on microcarriers made from DEAE-dextran, denatured collagen, DEAE-dextran linked to denatured collagen, and glass. Cells grown on these four substrates were examined for the production of proteolytic enzymes and arachidonic acid metabolites. Culture fluids from cells grown on the DEAE-dextran microcarriers contained the highest amounts of proteolytic enzyme activity. Both plasminogen-independent and plasminogen-dependent fibrinolytic activities were present and the plasminogen-dependent activity seemed to result from the presence of both urokinase and tissue plasminogen activator. Culture fluid from the cells grown on the glass microcarriers contained the least amount of protease activity, and nearly all of the plasminogen-activator activity seemed to be of the urokinase type. Protease activity in the culture fluids of cells grown on the other two substrates were intermediate. With regard to arachidonic acid metabolites, cells grown on the DEAE-dextran microcarriers produced the highest amounts of cyclooxygenase products but very low levels of lipoxygenase metabolites. Cells grown on the other three substrates produced comparable amounts of various cyclooxygenase products (lower than that produced by cells on the DEAE-dextran substrate). Cells grown on the glass microcarriers also produced detectable amounts of two lipoxygenase metabolites--leukotriene B4 and leukotriene C4. Inasmuch as both proteolytic enzymes and arachidonic acid metabolites regulate basic cell properties, the differential amounts of these metabolites observed in the culture fluids on the various substrates may contribute to the biological differences that exist on these substrates.
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PMID:Proteolytic enzymes and arachidonic acid metabolites produced by MRC-5 cells on various microcarrier substrates. 309 7

The release of plasminogen activators (PA) from human isolated glomeruli has been studied by a sensitive radioenzymatic assay using 125I-fibrin coated tubes and plasminogen. The glomerular fibrinolytic activity (GFA) was detectable after 15 minutes of incubation. Then it increased with time, the glomerular protein concentration, and with the plasminogen concentration (P less than 0.001 for all). CaCl2 (1 mM) increased the GFA (9.7 +/- 0.9 versus 4.9 +/- 0.4 micrograms fibrin/mg/30 min, P less than 0.05). The GFA was also enhanced when pH increased. Arachidonic acid (AA, 1 to 20 micrograms/ml) increased the GFA in a saturable manner. Inhibitors of cyclooxygenase (aspirin) or of lipoxygenase (nordihydroguaiaretic acid) did not modify the basal and AA-stimulated GFA. Other polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), eicosatrienoic acid (ETA), eicosatetraynoic acid (ETYA), or dihomo-gamma-linoleic acid (DHL), also stimulated the GFA whereas linoleic acid and oleic acid did not. Polyunsaturated fatty acids also stimulated the fibrinolytic activity of glomerular supernatants. Specific antibodies to t-PA, and to a lesser extent to u-PA, decreased this fibrinolytic activity whether or not AA was added. Furthermore, AA and EPA were found to increase the activity of purified u-PA and t-PA. We conclude that human glomeruli release both t-PA and u-PA, and that this release is increased by calcium and alkaline pH. The polyunsaturated fatty acids enhanced the GFA, mainly by a stimulatory effect of PA activity rather than an increased release of PA from glomerular cells.
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PMID:Polyunsaturated fatty acids increase fibrinolytic activity of human isolated glomeruli. 309 75

P388D1 is a murine macrophage cell line which spontaneously secretes plasminogen activator (PA; activated function) and lysozyme (LYS; constitutive function). Compounds which decrease PA secretion without affecting LYS secretion have potential as "down-regulators" of macrophage function and, hence, of the immune system. Glucocorticoids (e.g., dexamethasone, IC50 less than 0.01 microM) and auranofin (IC50 = 1 microM) are positive in this model. In contrast, cyclooxygenase inhibitors (indomethacin, ibuprofen and piroxicam, all at 1 microM) boost PA secretion; lipoxygenase inhibitors (REV-5901, NDGA and piriprost, all at 10 microM) have little or no effect. Dexamethasone, but not auranofin, induces a urokinase-inhibitory activity which elutes between 0.13 and 0.19 M NaCl upon anion exchange HPLC (TSK-DEAE-5-PW). Fibrin overlay following SDS-PAGE of the HPLC peak reveals a urokinase-inhibitory band at approximately 90 Kd.
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PMID:Pharmacological modulation of plasminogen activator secretion by P388D1 cell line. 312 May 14

This hypothesis proposes that the essential fatty acids (EFAs), linoleic acid (LA) and gamma-linolenic acid (GLA), play important roles in cancer treatment. Oxidation of LA by lipoxidase especially increases tumour cell death, whilst GLA inhibits urokinase-type plasminogen activator (uPA) activity. Increased uPA activity is: firstly, responsible for cancer invasion and metastasis and secondly, responsible for proteolysis of lipoxidase which favours a decrease in cancer cell death. Addition of LA and GLA to available therapeutic regimens may be worth considering in cancer treatment.
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PMID:Can linoleic acid and gamma-linolenic acid be important in cancer treatment? 773 15

Malignant cells show increased urokinase (UK) activity and decreased peroxidation of essential fatty acids (EFA). In order to explore this phenomenon the effect of UK on the lipoxidase activity was spectrophotometrically investigated. Decreased lipoxidase activity was obtained with increased UK concentrations (r = -1.000, p < 0.0001). This proteolytic effect of UK on lipoxidase was eliminated with the addition of the UK inhibitor leupeptin. These results suggest that the increase in UK activity in malignant cells may decrease the lipoxidase activity and thus peroxidation of EFA. The effectiveness of a given EFA in killing cancer cells would therefore depend on the modulation of the lipoxidase activity by the UK-type plasminogen activator.
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PMID:Modulation of lipoxidase activity by urokinase-type plasminogen activator. 782 32

In previous studies conducted in rats and in women, we have shown that oral contraceptive (OC) administration induced a platelet hyperaggregation simultaneously with an increased platelet lipid biosynthesis which might be related to lipid peroxidation. In the present study, we specifically studied the arachidonic acid and the fibrinolytic pathways in relation to the fatty acid composition in female rats treated for 6 weeks with OC (ethinyl estradiol plus lynestrenol). We found that platelets of treated animals were not only hyper-responsive to thrombin and ADP, but also to sodium arachidonate. In addition, the results of the thrombin-induced release of labeled arachidonic acid pre-incorporated into platelet membrane phospholipids showed an increased biosynthesis of lipoxygenase and cyclooxygenase metabolites after OC treatment. These data indicated a stimulated platelet arachidonate metabolism in OC animals compared to controls which was further confirmed by the increased thrombin-induced production of thromboxane B2 (TXB2) as measured with a radioimmunoassay. The platelet thrombin-stimulated TXB2 biosynthesis was inhibited in vitro in the presence of 500 mu M aspirin and 1 mM vitamin E; the erythrocytes from OC animals compared with controls presented an enhanced in vitro susceptibility to free radical-induced hemolysis. These data indicated that a free radical mediated-process might occur. This hypothesis is confirmed by an increase of plasma lipid peroxidation parameters (conjugated dienes, lipid peroxides, thiobarbituric acid reactive substances). After OC-treatment, a decrease in plasma and platelet long chain polyunsaturated fatty acids, particularly (n-3), is in keeping with this idea. Furthermore, the results of the peritoneal macrophage-dependent fibrinolytic activity indicated that OC induced a drastic decrease in urokinase plasminogen activator activity which might further contribute to the platelet hyperactivity. Altogether these data suggest that besides the reported increase in clotting factors, platelet hyperactivity, possibly through a stimulated free radical-induced arachidonic acid metabolism, might be involved in the known high thrombogenic risk observed in OC users.
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PMID:Enhanced platelet thromboxane synthesis and reduced macrophage-dependent fibrinolytic activity related to oxidative stress in oral contraceptive-treated female rats. 912 95