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

Urokinase (UK), a human urinary plasminogen activator, was modified by the covalent attachment of methoxypolyethylene glycol (PEG) of 5,000 daltons. There were observed changes in substrate specificity and an increase in molecular weight in PEG-modified UK (PEG-UK). We evaluated PEG-UK by ex vivo study using beagles, and found that UK activity in the blood was well maintained over hours after intravenous injection, and that fibrinolysis was more activated compared with native UK by coagulation-fibrinolysis studies.
 ...
PMID:Studies on the effect of PEG-modified urokinase on coagulation-fibrinolysis using beagles. 396 39

Human urokinase (UK) was conjugated with polyethylene glycol-polypropylene glycol (PEG-PPG) and its physicochemical properties were examined. PEG-PPG modification decreased the activity for plasminogen activation, but increased the half-life of this protein when injected intravenously in rabbits. Kinetic analysis of PEG-PPG conjugated UK (PEG-PPG-UK) revealed that the kcat for plasminogen activation decreased 1/5-fold with the increase of Km in comparison with that of UK, although these parameters for cleavage of synthetic substrate (S-2444) did not change. However, the inhibitor constant of PEG-PPG-UK for plasminogen activator inhibitor 1 (PAI 1) was equal to that of UK. Peptide mapping analysis revealed that PEG-PPG binding sites were mainly determined to be Lys 35, 46, 61, 98, 120 and 135 in A-chain and Lys 211, 300, 318, 338, 348, 383 and 404 in B-chain. In addition, the modification rates of A and B-chain were 37.8% and 19.8% on average, respectively.
 ...
PMID:Physicochemical characterization of PEG-PPG conjugated human urokinase. 812 69

Human urokinase (UK) was easily degraded during the incubation at 37 degrees C in a time-dependent manner. The degradation was also observed in the presence of trypsin inhibitors, suggesting that UK was not degraded by exogeneous trypsin-like serine protease but by autolysis. In this cases, the A-chain of UK was selectively degraded. Polyethylene glycol-polypropylene glycol conjugated urokinase (PEG-PPG-UK) was not degraded after prolonged incubation at 37 degrees C. These results demonstrated that PEG-PPG modification completely blocked the degradation of UK by autolysis.
 ...
PMID:Increased stability of PEG-PPG conjugated human urokinase against autolysis. 902 52

Polymer conjugation is of increasing interest in pharmaceutical chemistry for delivering drugs of simple structure or complex compounds such peptides, enzymes and oligonucleotides. For long time drugs, mainly with antitumoral activity, have been coupled to natural or synthetic polymers with the purpose of increasing their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. However only recently complex constructs were devised that exploit the 'enhanced permeability and retention' (EPR) effect for an efficient tumor targeting, the high molecular weight for adsorption or receptor mediated endocytosis and finally a lysosomotropic targeting, taking advantage of acid labile bonds or cathepsin susceptible polypeptide spacers between polymer and drug. New original, very active conjugates of this type, as those based on poly(hydroxyacrylate) polymers, are already in advanced state of development. Labile oligonucleotides, including antisense drugs, were also successfully coupled to polymers in view of an increased cell penetration and stabilization towards nucleases. However, the most active research activity resides in the field of polypeptides and proteins delivery, mainly for the two following reasons: first of all because a great number of therapeutically interesting compounds are now being produced by genetic engineering in large quantity and, secondly, because these products are difficult to administer to patients for several inherent drawbacks. Proteins are in fact easily digested by many endo- and exo-peptidases present in blood or in other body districts; most of them are immunogenic to some extent and, finally, they are rapidly excreted by kidney ultrafiltration. Covalent polymer conjugation at protein surface was demonstrated to reduce or eliminate these problems, since the bound polymer behaves like a shield hindering the approach of proteolytic enzymes, antibodies, or antigen processing cell. Furthermore, the increase of the molecular weight of the conjugate allows to overcome the kidney elimination threshold. Many successful results were already obtained in peptides and proteins, conjugated mainly to water soluble or amphiphilic polymers like poly(ethylene glycol) (PEG), dextrans, or styrenemaleic acid anhydride. Among the most successful are the conjugates of asparaginase, interleukin-2 or -6 and neocarcinostatin, to remind some antitumor agents, adenosine deaminase employed in a genetic desease treatment, superoxide dismutase as scavenger of toxic radicals, hemoglobin as oxygen carrier and urokinase and streptokinase as proteins with antithrombotic activity. In pharmaceutical chemistry the conjugation with polymers is also of great importance for synthetic applications since many enzymes without loss of catalytic activity become soluble in organic solvents where many drug precursors are. The various and often difficult chemical problems encountered in conjugation of so many different products prompted the development of many synthetic procedures, all characterized by high specificity and mild condition of reaction, now known as 'bioconjugation chemistry'. Bioconjugation developed also the design of new tailor-made polymers with the wanted molecular weight, shape, structure and with the functional groups needed for coupling at the wanted positions in the chain.
 ...
PMID:Bioconjugation in pharmaceutical chemistry. 1051 Aug 47

Current research suggests that the appearance of endometrial integrins and pinopode appearance signal the opening of the receptive phase of the endometrium. These integrins may be activated by the interleukin-1 system (IL-1). IL-1beta, expressed by the blastocyst, induces vascular endothelial growth factor (VEGF) which, in turn, promotes angiogenesis and integrin expression in endometrial cells. The IL-1 system also triggers the expression of gamma interferon (IFN-gamma) from T lymphocytes. Decidual natural killer (NK) lymphocytes interact with invading trophoblast to generate leukaemia inhibitory factor (LIF). LIF induces uPA and gelatinase, enzymes which play a crucial role in trophoblastic invasion. Progesterone is a potent inhibitor of LIF, while oestrogen is a potent inducer. Oestrogen in serum reflects follicular IL-1beta level and correlates with the outcome of embryo transfer after in vitro fertilization (IVF). Progesterone induces nitric oxide (NO) synthesis in the decidua, and NO promotes local vasodilatation and uterine quiescenceMeasurement of placental protein 14 (PP14, glycodelin-A) in serum may be of value as a screening test for implantation potential. However, human chorionic gonadotrophin (hCG) remains the most reliable predictor of successful implantation and pregnancy viability. An ovulation + 14 hCG level < 50 IU/l is often predictive of a non-viable outcome, while an ovulation + 21 hCG of < 200 IU/l always indicates a non-viable pregnancy. hCG secretion by invading trophoblast appears to be negatively modulated by endothelin-1 (ET-1) and prostaglandin F(2alpha)(PGF2alpha), while tissue growth factors and collagenases are positive modulators of hCG expression.ProalphaC, an inhibin pro-monomer, may have some value in monitoring corpus luteum function. Inhibin A, activin A and follistatin all rises throughout pregnancy and peak at 36 weeks of gestation. Relaxin is another ovarian hormone that may have a role in predicting implantation. Relaxin induces placental protein 14 (PP14, glycodelin-A) expression in a receptive endometrium, and measurement of serum PP14 may be of value as a screening test for implantation potential.
 ...
PMID:Endocrinology of the peri-implantation period. 1102

We report the design and synthesis of enzyme-responsive nanofibers. The fibers are composed of self-assembled hydrophobic beta-sheet peptides incorporating protease-sensitive domains, fluorescent reporters, and hydrophilic poly(ethylene glycol) (PEG) units. Using urokinase plasminogen activator (uPA) as a model system, nanofibers were developed to release fluorescent fragments upon uPA incubation. These protease-sensitive nanofibers may have considerable biomedical applications as diagnostic sensors or for protease-assisted drug deliveries.
 ...
PMID:Protease-sensitive fluorescent nanofibers. 1791 58

Transplantation of islets of Langerhans (islets) is a promising technique for treating insulin-dependent diabetes mellitus (type I). One unresolved issue is early graft loss due to inflammation triggered by blood coagulating on the surface of islets after transplantation into the portal vein. Here, we describe a versatile method for modifying the surface of islets with an ultrathin membrane carrying the fibrinolytic enzyme urokinase or the anticoagulant heparin. The surface of islets was modified with a poly(ethylene glycol)--phospholipid conjugate bearing a biotin group (biotin-PEG-lipids, PEG MW: 5000). Biotin-PEG-lipids were anchored to the cell membranes of islets, and the PEG-lipid layer on the islets was further covered by streptavidin and biotin-bovine serum albumin conjugate using a layer-by-layer method. The surface was further activated with oxidized dextran. Urokinase was anchored to the islets through Schiff base formation. Heparin was anchored to the islets through polyion complex formation between anionic heparin and a cationic protamine coating on the islets. No practical islet volume increase was observed after surface modification, and the modifications did not impair insulin release in response to glucose stimulation. The anchored urokinase retained high fibrinolytic activity, which could help to improve graft survival by preventing thrombosis on the islet surface.
 ...
PMID:Islets surface modification prevents blood-mediated inflammatory responses. 1853 7

Mass spectrometry is a powerful proteomic tool enabling researchers to survey the global proteome of a cell. This technique has only recently been employed to investigate cell-material interactions. We had previously identified material scarcity and limited adherent cells as challenges facing mass spectrometric analysis of cell-material interactions. U937 adherent to tissue culture poly(styrene) was used as a model system for identifying proteins expressed by adherent monocytes and analyzed by HPLC coupled offline to MALDI-ToF/ToF (LC-MALDI). We identified 645 proteins from two cation fractions of crude U937 monocyte cell lysate. Forty three proteins of interest from the 645 were chosen based on literature searches for relevance to monocyte-material inflammation and wound healing. Proteins such as 40S ribosomal protein S19 and tyrosyl tRNA synthetase highlight the ability of LC-MALDI to identify proteins relevant to monocyte-material interactions that are currently unexplored. We used PEG-based semi-interpenetrating polymer networks and PEG-only hydrogels to investigate surface dependent effects on the Src family kinase Hck and plasminogen activator inhibitor-2 (PAI-2) using the pyrazolo pyrimidine small molecule inhibitor PP2 and exogenous urokinase plasminogen activator addition, respectively. Hck is well researched in cell adhesion while PAI-2 is virtually unknown in cell-material interactions. U937 on TCPS and PEG-only hydrogels secreted similar levels of inflammatory cytokines and gelatinase MMP-9. MCP-1 secretion from monocytes on PEG-only hydrogels was Hck independent in contrast to Hck-dependent MCP-1 secretion in U937 on TCPS. Overall, U937 adherent to sIPNs secrete low levels of soluble gelatinase MMP-9, IL-1beta, TNF-alpha, IL-6, and MCP-1 independent of Hck and PAI-2. This work demonstrates significant changes in surface dependent expression of proteins from monocytes adherent to PEG-based materials compared to TCPS.
 ...
PMID:Identification of regulatory Hck and PAI-2 proteins in the monocyte response to PEG-containing matrices. 1944 25

Gold nanorods exhibit strong absorbance of light in the near infrared region, which penetrates deeply into tissues. Since the absorbed light energy is converted into heat, gold nanorods are expected to act as a contrast agent for in vivo bioimaging and as a thermal converter for photothermal therapy. To construct a gold nanorod targeted delivery system for tumor a peptide substrate for urokinase-type plasminogen activator (uPA), expressed specifically on malignant tumors, was inserted between the PEG chain and the surface of the gold nanorods. In other words, we constructed PEG-peptide-modified gold nanorods. After mixing the gold nanorods with uPA, the PEG chain was released from the surface of the gold and subsequently nanorod aggregation took place. The formation of the aggregation was monitored as a decrease in light absorption at 900 nm. Tumor homogenate induced a significant decrease in this absorption. Larger amount of the PEG-peptide-modified gold nanorods bound to cells expressing uPA in vitro compared with control gold nanorods, which had scrambled sequence of the peptide. The PEG-peptide-modified gold nanorods showed higher accumulation in tumor than the control after they were injected intravenously into tumor-bearing mice, however, the density of the peptide on the surface of the gold nanorods was a key factor of their biodistributions. This targeted delivery system, which responds to uPA activity, is expected to be a powerful tool for tumor bioimaging and photothermal tumor therapy.
 ...
PMID:Controlled release of PEG chain from gold nanorods: targeted delivery to tumor. 2047 43

Transplantation of islets of Langerhans is a promising method for treating patients with insulin-dependent diabetes mellitus. The major obstacle in clinical settings is early graft loss due to inflammation triggered by blood coagulation and complement activation on the surface of the islets after intraportal transplantation. We propose a versatile method for modifying the surface of islets with the fibrinolytic enzyme urokinase and the soluble domain of the anticoagulant enzyme thrombomodulin. The surfaces of islets were modified with a poly(ethylene glycol)-phospholipid conjugate bearing a maleimide group (Mal-PEG-lipid; PEG MW = 5000 kDa). The Mal-PEG-lipid anchored to the cell membranes of islets, resulting in the presentation of functional maleimide groups on the islet surface. The surface was further treated with thiolated urokinase and thrombomodulin that conjugated by thiol/maleimide bonding. No practical islet volume increase was observed after surface modification, and the modifications did not impair insulin release in response to glucose stimulation. Furthermore, the activity of the immobilized urokinase and thrombomodulin was maintained. These modifications could help to improve graft survival by preventing thrombus formation on the surface of transplanted islets.
 ...
PMID:Co-immobilization of urokinase and thrombomodulin on islet surfaces by poly(ethylene glycol)-conjugated phospholipid. 2110 76


1 2 3 Next >>