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)

Prospective characterization of pharmacodynamics of tissue-type plasminogen activator (t-PA) is needed for diverse clinical applications. Accordingly, we used physiologically based, computer simulation of participating biochemical reactions in response to concentrations of circulating t-PA seen with infusions of 1 to 7 hr duration in 45 patients. Predicted values were compared with those from a "training set" obtained in six patients given t-PA for coronary thrombosis and six receiving therapy for peripheral arterial occlusion. Subsequently, results of simulation were compared prospectively with observations from a "test set" of 33 consecutive patients given low doses of t-PA for as long as 7 hr or higher doses for 1 to 2 hr and with data from 101 patients given t-PA in the European Cooperative Trial. Fits between observed and predicted values were close. Based on observations in the training set, the alpha 2-macroglobulin reaction with circulating plasmin and ongoing synthesis of plasminogen were incorporated in the simulations. Fibrinogenolysis in vitro was documented despite supplementation of samples with aprotinin, particularly when concentrations of t-PA were high. This phenomenon can lead to overestimation of fibrinogen depletion and was found to be obviated by the use of PPACK, a novel serine protease inhibitor. Results indicate that the simulation approach developed permits economic, prospective evaluation of regimens of t-PA suitable for diverse conditions and delineation of the impact of individual constituents and reactions on pharmacodynamics of t-PA and on the risk of induction of a systemic lytic state.
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PMID:Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation. 308 27

Maspin is a novel serine protease inhibitor (serpin) with tumor suppressive potential in breast and prostate cancer, acting at the level of tumor invasion and metastasis. It was subsequently demonstrated that maspin inhibits tumor invasion, at least in part, by inhibiting cell motility. Interestingly, in cell-free solutions, maspin does not inhibit several serine proteases including tissue-type plasminogen activator and urokinase-type plasminogen activator (uPA). Despite the recent biochemical evidence that maspin specifically inhibits tissue-type plasminogen activator that is associated with fibrinogen or poly-L-lysine, the molecular mechanism underlying the tumor-suppressive effect of maspin remains elusive. The goal of this study was to investigate the effect of maspin on cell surface-associated uPA. In our experimental system, we chose prostate carcinoma DU145 cells because these cells mediate plasminogen activation primarily by uPA, as shown by two different colorimetric enzyme activity assays. Purified recombinant maspin produced in baculovirus-infected Spodoptera frugiperda Sf9 insect cells [rMaspin(i)] binds specifically to the surface of DU145 cells, inhibits the DU145 cell surface-bound uPA, and forms a stable complex with the uPA in DU145 cell lysate. The inhibitory effect of rMaspin(i) on cell surface-bound uPA was similar to that of an uPA-neutralizing antibody and was reversed by a polyclonal antibody against the reactive site loop sequence of maspin. The Ki value for rMaspin(i) in cell surface-mediated plasminogen activation was 20 nM, which was comparable to the Ki values for plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2, respectively. Furthermore, the proteolytic inhibitory effect of rMaspin(i) was quantitatively consistent with its inhibitory effect on the motility of DU145 cells in vitro. Our data demonstrate an important role for the prostate carcinoma cell surface in mediating the inhibitory interaction between rMaspin(i) and uPA. Thus, future maspin-based therapeutic strategies may prove useful in blocking the invasion and metastasis of uPA-positive prostate carcinoma.
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PMID:The surface of prostate carcinoma DU145 cells mediates the inhibition of urokinase-type plasminogen activator by maspin. 1098 85

Maspin is a novel serine protease inhibitor with tumor suppressive activity, inhibiting tumor invasion and metastasis. To date, the underlying molecular mechanism of maspin remains elusive. Recombinant maspin has been shown to specifically inhibit cell surface-associated urokinase-type plasminogen activator (uPA) and fibrinogen-bound tissue-type plasminogen activator. However, the role of endogenous maspin in plasminogen activation is totally unknown. To address this issue, we generated stable maspin-expressing transfectants using prostate carcinoma cells DU145 as the parental cell line. We report here that endogenous maspin exerts pleiotropic inhibitory effects on the pericellular uPA system. Maspin expression led to a significantly reduced level of cell surface-bound uPA and uPA receptor proteins without altering the steady-state levels of the respective mRNAs. Treatment with receptor-associated protein (RAP), a specific inhibitor of low-density lipoprotein receptor-related protein, lead to a significantly increased level of secreted uPA and cell surface uPAR in maspin transfectants but not in the mock control cells. A combination of enzymatic and molecular analyses revealed that maspin inhibits the cell surface-mediated plasminogen activation by forming an SDS-resistant complex with cell surface-bound uPA. In addition, maspin expression led to a dramatic reduction in the release of active uPA, both high molecular weight and the low molecular weight, into the conditioned culture medium. Consistently, the conditioned medium of maspin transfectant clones had a significantly reduced activity in converting plasminogen to plasmin. The inhibitory effect of maspin on pericellular uPA correlates with significantly decreased cell invasion potential and motility in vitro. The maspin-neutralizing antibody (Abs4A) reversed the subdued invasive potential of maspin transfectant cells in a dose-dependent manner. In summary, this study provides the first evidence that endogenous maspin is a potent inhibitor of pericellular uPA. Furthermore, our results support a current hypothesis that maspin blocks tumor invasion and motility by inhibiting localized pericellular proteolysis.
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PMID:Pleiotrophic inhibition of pericellular urokinase-type plasminogen activator system by endogenous tumor suppressive maspin. 1175 84

A novel human plasma protein was found in the eluate from the dextran sulfate column, which was used for the treatment of the patients with hypercholesteremia to reduce plasma low density lipoprotein. The results of sequence analysis revealed that this protein was a homologue of heavy chains of inter-alpha-trypsin inhibitor (ITI) family, and it was termed IHRP (ITI family heavy chain related protein). IHRP was identified as an acute-phase protein in animals, and slightly increased concentrations in human plasmas were observed in the patients with inflammatory disorders. IHRP bound to actin and inhibited its polymerization, and IHRP suppressed the phagocytosis and chemotaxis of polymorphonuclear cells. These results suggest that IHRP may function as an anti-inflammatory protein. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which was also found in human plasma. It is consisted of three epidermal growth factor domains, one kringle domain and one serine protease domain from its amino terminus. The amino acid sequence of PHBP is homologous to that of hepatocyte growth factor activator. Purified 75-kDa single chain pro-form of PHBP was auto-activated (auto-cleaved) to 50-kDa heavy chain and 25-kDa light chain, both of them are bridged by a disulfied bond. PHBP digested alpha-chain and beta-chain of fibrinogen to prevent coagulation and cleaved single chain urokinase type plasminogen activator (scuPA) to the active hetero dimer form (tcuPA). The auto-activation of PHBP was accelerated in the presence of dextran sulfate or phosphatidylethanolamine as well as factor XII of the coagulation system. C1 inhibitor of the complement system was identified as the main inhibitor of PHBP in human plasma. Partial hepatectomy and administration of carbon tetrachloride or galactosamine caused the conversion of pro-PHBP to the active form in mouse but administrations of turpentine and mercury chloride did not, suggesting the hepatic injury specific activation of PHBP. These results indicate that PHBP participates not only in the fibrinolytic system but also in the degradation cascade of extracellular matrix (ECM), i.e., PHBP activates scuPA to tcuPA, tcuPA activates matrix metalloproteases (MMPs) and activated MMPs degrade ECM for the tissue remodeling after hepatic injury.
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PMID:Novel human plasma proteins, IHRP (acute phase protein) and PHBP (serine protease), which bind to glycosaminoglycans. 1532 Jul 89

A novel serine protease with fibrinolytic activity named CSP was purified from the culture supernatant of the fungus Cordyceps sinensis, a kind of Chinese herbal medicine. Analysis of the purified enzyme by SDS-PAGE indicated that CSP was a single polypeptide chain with an apparent molecular weight of 31 kDa, and N-terminal sequencing revealed that the first ten amino acid residues of the enzyme were Ala-Leu-Ala-Thr-Gln-His-Gly-Ala-Pro-Trp-. When casein was used as a substrate, the proteolytic activity of CSP reached its maximum at pH 7.0 and 40 degrees C. The effect of chemical agents on the enzyme activity indicated that CSP is a serine protease with a free cysteine residue near the active site. It hydrolysed fibrinogen, fibrin and casein with a high efficiency, while hydrolysing bovine serum albumin (BSA) and human serum albumin (HSA) to a lesser extent. CSP was found to be a plasmin-like protease, but not a plasminogen activator, and it preferentially cleaved the A alpha chain of fibrinogen and the alpha-chain of fibrin. Therefore, the extracellular protein CSP may represent a potential new therapeutic agent for the treatment of thrombosis.
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PMID:A novel extracellular protease with fibrinolytic activity from the culture supernatant of Cordyceps sinensis: purification and characterization. 1766 28

Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As haemostatic processes play an important role in wound healing, this study focused on the effects of maggot secretions on coagulation and fibrinolysis. The results showed that maggot secretions enhance plasminogen activator-induced formation of plasmin and fibrinolysis in a dose- and time-dependent manner. By contrast, coagulation was not affected by secretions. Biochemical studies indicated that a novel serine protease within secretions, designated Sericase, cleaved plasminogen to several fragments. Recombinant Sericase degraded plasminogen leading amongst others to the formation of the mini-plasminogen like fragment Val454-plasminogen. In addition, the presence of a non-proteolytic cofactor in secretions was discovered, which plays a role in the enhancement of plasminogen activator-induced fibrinolysis by Sericase. We conclude from our in vitro studies that the novel serine protease Sericase, with the aid of a non-proteolytic cofactor, enhances plasminogen activator-induced fibrinolysis.
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PMID:A novel serine protease secreted by medicinal maggots enhances plasminogen activator-induced fibrinolysis. 2464 46