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)

We have investigated plasmin mediated proteolysis associated with trophoblast invasion during early stages of pregnancy in the rhesus monkey. In situ hybridization and immunocytochemical localization were used to define the cellular and tissue distribution of urokinase plasminogen activator (uPA), plasminogen activator inhibitor type 1 (PAI-1) and 2 (PAI-2) and urokinase receptor in early monkey placenta and uterus. Our results indicate: (1) uPA is expressed in proliferating and invasive cytotrophoblast located in chorionic villi as well as in extravillous trophoblast associated with uterine arterioles. This raises the possibility that urokinase may play an important role in trophoblast invasion. (2) PAI-1 mRNA is specifically localized in two areas where invasive trophoblast cells encounter maternal tissue directly. The extravillous cytotrophoblast cells at the maternofetal junction express PAI-1 mRNA. The invasive endovascular trophoblast cells within the uterine arterioles also express PAI-1 mRNA. The location sensitive expression of PAI-1 mRNA at the maternofetal junction may imply a protective function of this protease inhibitor that might be induced through interaction with decidual cells. (3) Urokinase receptor antigen has also been found at the maternofetal junction and in endovascular trophoblast cells of the invaded maternal blood vessel. (4) PAI-2 immunoreactivity is found in association with cytotrophoblast cells in anchoring choronic villi suggesting its association with early placentation. In conclusion, we propose that the plasmin/plasminogen activator system may not only regulate extracellular matrix degradation, but also modify migration and invasive behaviour of extravillous trophoblast cells, during early placentation.
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PMID:Expression of urokinase, plasminogen activator inhibitors and urokinase receptor in pregnant rhesus monkey uterus during early placentation. 1073 41

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in patients previously operated on for T1-T2 N-M0 breast cancer. During the trial, blood samples were collected at baseline and on a yearly basis from most of the patients. Evaluation of drug and retinol concentrations by HPLC assay has been performed for all the samples to obtain 4-HPR pharmacokinetic information as well as information on the effect of 4-HPR in lowering retinol plasma levels. The most important criteria for validation and quality control of the HPLC assay are summarized in order to provide a guide and practical recommendations for analytical procedures to be performed during prevention trials. Studies have been performed on subsets of patients participating in the trial in order to identify circulating biomarkers predictive of breast cancer. Evidence has been obtained on a lowering effect of 4-HPR on biologically active IGF-I only in premenopausal women. This was due to a decrease of IGF-I, associated with a trend to an increase in IGF-I binding protein 3 (IGFBP-3). An interim analysis of the ongoing trial indicates that 4-HPR reduces the incidence of contralateral breast cancer only in premenopausal women. Analyses of total and unbound IGF-I are being performed on plasma samples collected at baseline and during intervention from women < or = 50 years old. The relationship between the incidence of a second breast cancer and the changes in IGF-I plasma levels will be assessed in order to validate IGF-I as a surrogate end point of contralateral breast cancer. The preliminary results of other studies on the effects of 4-HPR on tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), and urokinase plasminogen activator (uk-PA) and on the relevance of circulating p53 antibodies with relapse will be also presented.
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PMID:Quality control for HPLC assay and surrogate end point biomarkers from the fenretinide (4-HPR) breast cancer prevention trial. 1076 18

Mechanical loading is important in tissue formation and remodelling, notably in wound repair. The aim of this study was to measure the effects of controlled loading on the release of extracellular matrix protease activities by fibroblasts. Fibroblast populated collagen lattices were subjected to external cyclical loads through a computer controlled unit incorporated into a culture system, a tensioning-Culture Force Monitor. Cyclical loading was compared to untensioned and statically loaded gels (tethered endogenous contraction). Overall changes in a range of protease activities were monitored (chiefly by zymography) as measures of the cyto-mechanical response to these loads. Under static load, 2.5- and 13-fold more matrix metalloproteinase-2 was produced than matrix metalloproteinase-9, at 24 and 48 hours. Total matrix metalloproteinase-9 increased 37 fold on cyclical loading. Total matrix metalloproteinase-3 and urokinase plasminogen activator activities were dramatically reduced on cyclical loading while tissue type plasminogen activator activity was increased. Comparison with cell responses on stiffer substrates (collagen sponges) identified similar matrix metalloproteinase responses to load, but at much reduced levels (4-6 fold matrix metalloproteinase-9 stimulation on loading), showing the importance of matrix compliance to this mechano-response. In conclusion, physiological mechanical loading of fibroblasts in three dimensional collagen lattices elicited complex and substantial changes in matrix modifying proteases. These changes suggest that cells switch between expression of comparable protease activities mainly influencing cell-matrix interactions associated with migration or more generalized extracellular matrix remodelling.
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PMID:Mechanical loading regulates protease production by fibroblasts in three-dimensional collagen substrates. 1088 13

Purified preparations of circulating leukaemic blast cells from patients with acute myeloid (M1-7) or acute lymphoblastic leukaemia, and the myeloid or lymphoid cells from patients with chronic myeloid or lymphocytic forms of leukaemia, were incorporated into clots prepared from fibrinogen and plasminogen. Patterns of lysis were followed and measured by light transmission in a microtitre plate reader. Mature polymorphonuclear and mononuclear cell fractions from normal individuals were studied concurrently for comparison. Blast cells from the myeloid forms of acute leukaemia (M2-4) and 'myeloid' cell fractions from patients with chronic myeloid leukaemia were capable of lysing plasminogen-containing clots; this activity was neutralized by addition of immunoglobulin against urokinase plasminogen activator (u-PA), but not by anti-tissue plasmogen activator (t-PA). Mature polymorphonuclear and mononuclear cells from normal individuals lacked lytic activity, as did the leukaemic cells from patients with acute lymphoblastic or chronic lymphocytic leukaemia. Lysed blast cells showed the presence of free plasminogen activator on sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) with overlay zymography, also neutralized by anti-u-PA, whereas normal polymorphonuclear and mononuclear cells did not. These observations suggest that mechanisms underlying some forms of severe bleeding in acute myeloid leukaemias have a critical fibrinolytic component generated by the blast cells themselves.
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PMID:Myeloid leukaemic cells can lyse fibrin directly. 1112 94

Inflammation and tissue trauma during the surgical procedure reduce the peritoneal fibrinolytic capacity. These conditions promote adhesion formation, and are associated with increased expression of transforming growth factor beta 1 (TGF-beta1). The objective of the present study was to investigate whether TGF-beta1 regulates the expression of fibrinolytic components in peritoneal mesothelial cells. Human peritoneal mesothelial cells (HPMC) were cultured and treated with various concentrations of human recombinant TGF-beta1 (0.1, 1.0 and 10 ng/mL) for 24 h. Levels of tissue- and urokinase plasminogen activator (t-PA and uPA), plasminogen activator inhibitor type-1 (PAI-1) and type-2 (PAI-2) mRNA and protein were assessed by quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) and ELISA, respectively. HPMC expressed these components at the gene and protein level. TGF-beta1 downregulated, dose-dependently t-PA mRNA and protein to about 50% of control values (p = 0.0010), and doubled PAI-1 protein production (p = 0.0008) compared to untreated controls. Although uPA gene expression increased in cells exposed to TGF-beta1, the corresponding protein concentration in conditioned media did not. PAI-2 was not affected, either at the gene or protein level. In conclusion, the results indicate that fibrinolytic capacity of mesothelial cells is reduced by TGF-beta1, suggesting that peritoneal adhesion formation induced by TGF-beta1 may be mediated, in part, through reduction in fibrin degradation capacity at an early stage of peritoneal tissue repair.
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PMID:Differential regulation of mesothelial cell fibrinolysis by transforming growth factor beta 1. 1112 59

Every inflammatory process, including that in the course of bronchial asthma may disturb the balance in blood coagulation and fibrinolysis system. The aim of the present study was to evaluate fibrinolysis in patients with bronchial asthma. The study group consisted of 41 patients with bronchial asthma, hitherto untreated (25 women, 16 men, at mean age 37.37 +/- 12.4 years) and 22 healthy adults (control group). In these subjects, the following parameters were established: euglobulin lysis time (ELT), the concentration of tissue plasminogen activator antigen (t-PA Ag), the concentration of urokinase plasminogen activator antigen (u-PA Ag), the activity of plasminogen activator inhibitor type 1 (PAI-1), the concentration of plasmin-antiplasmin complex (PAP) and fibrinogen/fibrin degradation products (FDP). It was found that patients with bronchial asthma had statistically significantly higher mean values of FDP (9.25 +/- 6.7 micrograms/ml vs. 5.0 +/- 5.9 micrograms/ml; p < 0.001), ELT (123.5 +/- 42.7 min vs. 97.4 +/- 27.1 min; p < 0.001), t-PA Ag (8.36 +/- 3.66 ng/ml vs. 5.5 +/- 3.71 ng/ml; p < 0.01) and PAP complexes (250.3 +/- 95.8 ng/ml vs. 193.4 +/- 60.7 ng/ml; p < 0.02). Mean u-PA Ag concentration in patients with bronchial asthma was significantly lower than in control group (0.24 +/- 0.16 ng/ml vs. 0.53 +/- 0.18 ng/ml; p < 0.01). No statistically significant differences were observed as to PAI-1 activity between patients with bronchial asthma and healthy subjects. The results of the present study suggest that increased concentrations of t-PA Ag, PAP and FDP complexes are the evidence for greater activity of fibrinolysis system in subjects with bronchial asthma.
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PMID:Fibrinolysis system in patients with bronchial asthma. 1120 94

Cellular proteases are those proteases that are localized in the cytoplasm and on the cell surface, but not those secreted into the extracellular matrix. Proteases localized on the cell surface play a specific role in the invasion process of malignant tumor cells. These are activated by a relatively complicated cascade in which different cathepsins, the plasminogen activator system, plasmin, and the matrix metalloproteinases, including the membrane-type matrix metalloproteinases, play a major role. This article places emphasis on the biologic function and oncologic significance of cathepsins B and L, as well as on the urokinase plasminogen activator and the membrane-type matrix metalloproteinases localized on the cell surface. Recent investigations on these factors revealed that they are dependent on each other, such that the upregulation or downregulation also causes alterations in the regulation of the other factors. This fact alone elucidates the complexity of this system. Moreover, there is growing evidence that other proteases hitherto known to have other functions, e.g. as signal proteases in the immunologic system, may be important for invasion provesses. To provide an example of this, we describe the invasive potential of aminopeptidase N (APN/CD13). These recent results, which shed light on the role of further proteases in invasion processes, clearly show the complexity of this proteolytic system. Against this biologic background, it seems not to be promising to establish single proteases as distinct parameters for the prognosis of the metastatic potential of malignant tumors.
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PMID:[Cellular proteases and invasion]. 1121 51

The interleukin-1 (IL-1) system plays an integral role in local intercellular interactions during implantation. In addition, the plasminogen activator system, especially urokinase plasminogen activator (u-PA), plasminogen activator inhibitor (PAI-1), and u-PA receptor (u-PAR), are crucial during embryo implantation. Decidualization and implantation are complex processes dependent upon several proteases, including u-PA, and IL-1 is known to affect PA activity in several cell types. We investigated the role of IL-1beta in regulating u-PA, PAI-1, u-PAR, and soluble u-PAR messenger ribonucleic acid (mRNA) expression in cultured human endometrial stromal cells using quantitative competitive PCR. For confirmation of the mRNA data, we measured PAI-1 and u-PAR protein by enzyme-linked immunosorbent assay. Confluent stromal cell cultures treated with progesterone and estradiol for 9 days were stimulated with IL-1beta, and IL-1beta plus IL-1beta antibody for an additional 24 h. Total RNA was extracted, reverse transcribed, and coamplified using quantitative and competitive PCR with internal standards. IL-1beta increased PAI-1, u-PAR, and soluble u-PAR expression in a dose-dependent manner, and this result was reversed by anti-IL-1beta antibody treatment. u-PA mRNA expression was not dependent on IL-1beta. These results suggest that IL-1 may be important in regulating PAI-1 and u-PAR during stromal cell decidualization before implantation.
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PMID:Interleukin-1beta regulates urokinase plasminogen activator (u-PA), u-PA receptor, soluble u-PA receptor, and plasminogen activator inhibitor-1 messenger ribonucleic acid expression in cultured human endometrial stromal cells. 1123 29

To study the in vivo effect of all-trans-retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) on the expression of tissue factor (TF) and the other hemostatic disturbance, a series of parameters were measured either in bone marrow blasts or plasma from acute promyelocytic leukemia (APL) patients. The plasma parameters were measured by ELISA or chromogenic studies. The TF transcription was assessed using reverse transcription-polymerase chain reaction (RT-PCR) technique. The results indicated that the blast cell procoagulant activity (PCA), TF antigen of APL cell lysate, as well as the transcription of APL TF mRNA elevated at diagnosis, were reduced after ATRA or As(2)O(3) therapy. The plasma level of P-selectin, TF, thrombin-antithrombin complex (TAT), soluble fibrinmonomer complex, thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), plasmin-antiplasmin complex, tissue plasminogen activator (t-PA) activity, urokinase plasminogen activator (u-PA) and its receptor (u-PAR), and D-dimer (D-D) significantly increased. Fibrinogen (Fg), antigen level of protein C (PC), plasminogen (PLG) activity, alpha(2)-plasminogen inhibitor activity (alpha(2)-PI), and plasminogen activator inhibitor (PAI) activity were decreased at diagnosis. The protein C activity (PC:A) and protein S (PS) remained unchanged. All the parameters were restored to normal ranges after complete remission (CR) except elevation of TF and TAT in both groups, as well as PC:A, PS, and t-PA in the ATRA group. In conclusion, there existed activation of platelets and consumption of anticoagulants as well as activation of coagulation and fibrinolytic system before treatment. Both ATRA and As(2)O(3) therapy downregulated the expression of TF mRNA, decreased the PCA and TF level in APL cells, significantly inhibited coagulation activation, corrected secondary hyperfibrinolysis and the other hemostatic abnormalities, and thus greatly improved the bleeding symptom in early stage of the treatment.
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PMID:Effects of all-trans-retinoic acid and arsenic trioxide on the hemostatic disturbance associated with acute promyelocytic leukemia. 1136 12

The low density lipoprotein receptor-related protein-deleted in tumor (LRP1B, initially referred to as LRP-DIT) was cloned and characterized as a candidate tumor suppressor. It is a new member of the low density lipoprotein receptor gene family. Its overall domain structure and large size (approximately 600 kDa) are similar to LRP and suggest that it is a multifunctional cell surface receptor. Herein, we characterize a series of ligands for the receptor using cell lines that stably express it as a domain IV minireceptor (mLRP1B4). Ligands of LRP including receptor-associated protein, urokinase plasminogen activator, tissue-type plasminogen activator, and plasminogen activator inhibitor type-1 each demonstrate binding, internalization, and degradation via mLRP1B4. Interestingly, the kinetics of ligand endocytosis is distinctly different from that of LRP, with LRP1B exhibiting a markedly diminished internalization rate. In addition, tissue expression analysis reveals that the LRP1B gene is expressed in brain, thyroid, and salivary gland. These studies thus extend the physiological roles of members of the LDL receptor family.
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PMID:The putative tumor suppressor LRP1B, a novel member of the low density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein. 1138 78


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