Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addition of proteolytically generated fibronectin fragments (Fn-f) to cultured cartilage tissue causes greatly enhanced release of metalloproteinases (MMPs), such as pro-stromelysin-1 (proSln-1), and suppression of proteoglycan (PG) synthesis, through release of catabolic cytokines, while native fibronectin is ineffective. We have investigated whether enhanced release of proSln-1 was due to up-regulation of pro-Sln-1 mRNA. We report the addition of a 29-kDa (amino-terminal heparin-binding Fn-f) or a 140-kDa (central cell-binding Fn-f) to bovine chondrocytes in monolayer culture causes a dose dependent increase in the expression of pro-Sln-1 mRNA and the greatly enhanced release of pro-Sln-1 protein into the culture media. Up to 700 nM pro-Sln-1 was found in the conditioned media and metabolic labeling showed that it constituted a major portion of newly synthesized protein. A potential activator of pro-Sln-1, urokinase (u-PA), was released at elevated levels in the presence of the Fn-f while other activators, tissue plasminogen activator (t-PA) and plasmin activities were not detected. Addition of these activators to conditioned media did not allow conversion of pro-Sln-1 to active Sln-1. However, aminophenyl mercuric acid activated pro-Sln-1 to a 48-kDa Sln-1 form capable of degrading PG when added to cartilage suspensions. Gelatinase A mRNA was also enhanced, suggesting that the Fn-f may induce MMPs in general. However, the major regulator of Sln-1 activity, tissue inhibitor of MMPs form 1 (TIMP-1), was not induced at the gene level. Thus, a major effect of Fn-f on chondrocytes is to up-regulate pro-Sln-1 expression at the gene level, resulting in pro-Sln-1 as a major protein product.
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PMID:Fibronectin fragments induce the expression of stromelysin-1 mRNA and protein in bovine chondrocytes in monolayer culture. 887 27

Extracellular proteoglycans (PGs) purified from cultured human arterial endothelial cells were tested for their effects on the proliferation of human vascular smooth muscle cells (VSMC). Fractions containing perlecan, the basement membrane heparan sulphate (HS) PG, the large chondrotin sulphate (CS) proteoglycan from connective tissue and other immunoreactive CS did not inhibit the proliferation of human VSMC. Native endothelial extracellular matrix, which was shown to contain the same PGs, demonstrated a pronounced stimulatory effect on the proliferation of human VSMCs. This stimulatory effect was not removed by pre-incubation of the matrix with 1 M NaCl, heparin, platelet extract or plasmin. These experiments demonstrate that PGs produced by human arterial endothelial cells do not inhibit the proliferation of VSMC. These data do not support the hypothesis that human endothelial cells, in vivo, control the activation or proliferation of VSMCs directly by the secretion of a non-proliferative molecule. Instead they support the hypothesis that the endothelial cells counteract intimal hyperplasia of VSMC indirectly by providing a barrier from activating factors in the plasma.
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PMID:The effect of human endothelial cell-derived proteoglycans on human smooth muscle cell growth. 915 95

Melanoma invasion requires migration through the vascular barrier. An early event in this process is the adhesion of metastatic cells to the endothelium. To elucidate the role of TGF-beta in the regulation of this process, human melanoma SK-MEL24 cells were labelled with [5'-(3)H]-thymidine and co-cultured with bovine pulmonary artery endothelial-cell monolayers. Radioactivity was assumed to be proportional to the number of SK-MEL24 cells bound to the endothelium. A low number of melanoma cells adhered to endothelial cells in a time-related manner. Pretreatment for 24 hr with 0.001 to 10 ng/ml TGF-beta1 or TGF-beta2 of both cell types enhanced melanoma-endothelium adhesion in a dose-dependent manner. Both melanoma and endothelial cells expressed RI- and RII-type TGF-beta receptors. The effect of TGF-beta was abolished by co-incubation with the proteoglycan decorin. Conditioned media from melanoma-endothelium co-cultures contained latent TGF-beta and failed to affect cell-cell adhesion. However, activation of TGF-beta by heating the medium or reducing the pH, increased melanoma-endothelium adhesion to an extent similar to that of the TGF-beta administered to the cultures. Zimography demonstrated that both cell types expressed urokinase-type plasminogen activator (uPA). Addition of plasminogen to the co-cultures, which was likely to be activated to plasmin by uPA, resulted in activation of TGF-beta and parallel stimulation of melanoma-endothelium adhesion. In conclusion, TGF-beta may enhance adhesion of melanoma cells to the endothelium, playing a relevant autocrine/paracrine role in the progression of invasive melanoma.
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PMID:Transforming growth factor-beta enhances adhesion of melanoma cells to the endothelium in vitro. 937 35

Transforming growth factor-beta (TGF-beta) is normally secreted in a latent form, and plasmin-mediated proteolytic cleavage of latency-associated peptide (LAP), a component of latent TGF-beta complex that makes the complex inactive, activates latent TGF-beta. In the present study, we investigated the possible involvement of calpain, one of the cysteine proteases, in the activation of latent TGF-beta. When recombinant latent TGF-beta was incubated with calpain (1-10 u/ml) in a test tube, calpain cleaved LAP and released mature TGF-beta from the latent complex. When calpain was applied to cultured bovine capillary endothelial (BCE) cells, a low concentration of calpain (0.05-0.1 u/ml) inhibited the migration and proliferation of the cells, and these inhibitory effects were abrogated by anti-TGF-beta antibody as well as by calpain inhibitor peptide, but not by alpha2-antiplasmin, a specific inhibitor of plasmin. Active TGF-beta was detected in the conditioned medium of BCE cells collected in the presence of calpain. Chemical cross-linking of (125)I-calpain to BCE cells followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis indicated that calpain bound to the cell surface through chondroitinase ABC-sensitive proteoglycan. In addition, treatment of the BCE cells with chondroitinase ABC abrogated the inhibitory effect of calpain on the migration of these cells. Our data thus suggest that calpain is able to activate latent TGF-beta through a mechanism independent of plasmin. This activation is efficient in the presence of cells, and calpain binds to the cell surface via proteoglycan and activates latent TGF-beta, which is targeted to the same surface.
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PMID:Cell-associated activation of latent transforming growth factor-beta by calpain. 942 5

The effect of the plasminogen activator Pla of Yersinia pestis on the adhesiveness of bacteria to the mammalian extracellular matrix was determined. Y. pestis KIM D27 harbors the 9.5-kb plasmid pPCP1, encoding Pla and pesticin; the strain efficiently adhered to the reconstituted basement membrane preparation Matrigel, to the extracellular matrix prepared from human lung NCI-H292 epithelial cells, as well as to immobilized laminin. The isogenic strain Y. pestis KIM D34 lacking pPCP1 exhibited lower adhesiveness to both matrix preparations and to laminin. Both strains showed weak adherence to type I, IV, and V collagens as well as to human plasma and cellular fibronectin. The Pla-expressing recombinant Escherichia coli LE392(pC4006) exhibited specific adhesiveness to both extracellular matrix preparations as well as to laminin. The Pla-expressing strains showed a low-affinity adherence to another basement membrane component, heparan sulfate proteoglycan, but not to chondroitin sulfate proteoglycan. The degradation of radiolabeled laminin, heparan sulfate proteoglycan, or human lung extracellular matrix by the Pla-expressing recombinant E. coli required the presence of plasminogen, and degradation was inhibited by the plasmin inhibitors aprotinin and alpha2-antiplasmin. Our results indicate a function of Pla in enhancing bacterial adhesion to extracellular matrices. Y. pestis also exhibits a low level of Pla-independent adhesiveness to extracellular matrices.
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PMID:Expression of plasminogen activator pla of Yersinia pestis enhances bacterial attachment to the mammalian extracellular matrix. 982 51

Tumor necrosis factor-alpha (TNF-alpha)-stimulated gene-6 (TSG-6) is up-regulated by various cytokines and growth factors. TSG-6 binds to hyaluronan in inflamed synovial tissue and forms a complex with a serine protease inter-alpha-trypsin inhibitor (IalphaI), increasing the protease inhibitory effect of IalphaI >100-fold. The TSG-6/IalphaI complex then blocks serine proteases, including the plasminogen-plasmin activation, probably the most important component in the activation processes of matrix metalloproteinases. To gain insight into the mechanisms of TSG-6 action in arthritis, we have used an autoimmune murine model (proteoglycan-induced arthritis) for systemic, and a monoarticular form of arthritis (antigen-induced arthritis) for local treatment of arthritis with recombinant mouse TSG-6 (rmTSG-6). Intravenous injection of rmTSG-6 induced a dramatic reduction of edema in acutely inflamed joints by immobilizing CD44-bound hyaluronan and, in long-term treatment, protected cartilage from degradation and blocked subchondral and periosteal bone erosion in inflamed joints. The intra-articular injection of a single dose (100 microg) of rmTSG-6 exhibited a strong chondroprotective effect for up to 5 to 7 days, preventing cartilage proteoglycan from metalloproteinase-induced degradation. In contrast, rmTSG-6 did not postpone the onset, nor reduce the incidence of arthritis. We were unable to detect any significant differences between control and rmTSG-6-treated animals when various serum markers (including pro- and anti-inflammatory cytokines, auto- and heteroantibody productions) or antigen-specific T-cell responses were compared, nor when the expressions of numerous cell surface receptors or adhesion molecules were measured. TSG-6 seems to play a critical negative regulatory feed-back function in inflammation, especially in arthritic processes.
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PMID:Anti-inflammatory and chondroprotective effect of TSG-6 (tumor necrosis factor-alpha-stimulated gene-6) in murine models of experimental arthritis. 1169 32

Cultures of cartilage explants have long been used to study the effects of modulators of extracellular matrix degradation. We present a simple and rapid assay system, based on culture of rabbit cartilage explants, which permits study of the effects of protease inhibitors on proteoglycan degradation (caused by either aggrecanases or matrix metalloproteinases [MMPs]), and on collagen degradation. The assay is based on the ability of interleukin-1 to stimulate both aggrecanase activity and synthesis of inactive MMPs, which are then activated by p-aminophenylmercuric acetate for the study of MMP-mediated proteoglycan degradation or by plasmin for the study of collagen degradation. Proteoglycan degradation is quantified as percent release of radioactivity from cartilage explants previously labeled with (35)SO4(2-). Collagen degradation is calculated as percent release of collagen, measured by colorimetric assay of hydroxyproline.
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PMID:Assays of proteoglycan and collagen degradation in cultures of rabbit cartilage explants. 1528 May 98

Spinal cord scar tissue presents a combined physical and molecular barrier to axon regeneration. Theoretically, spinal cord injuries (SCIs) can be rendered more permissive to axon growth by either suppressing synthesis of misaligned, fibrotic scar tissue and associated axon growth inhibitors, or enzymatically degrading them. We have previously shown that acute infusion of human recombinant decorin core protein into discreet stab injuries of the rat dorsal column pathways effected a major suppression of inflammation, astrogliosis, and multiple axon growth inhibitory chondroitin sulfate proteoglycans, which combined to promote rapid axon growth across the injury site. The high efficiency of chondroitin sulfate proteoglycan (CSPG) core protein suppression (approximately 90%) suggested that decorin may promote CSPG degradation in addition to suppressing CSPG synthesis. As the serine protease plasmin can degrade axon growth inhibitory CSPGs (neurocan and phosphacan) and its zymogen, plasmininogen is synthesized by microglia, we have investigated whether decorin treatment of acute SCIs and cultured adult spinal cord microglia can increase plasminogen/ plasmin synthesis. Infusion of hr-decorin over the first 8 days post-SCI induced 10- and 17-fold increases in plasminogen and plasmin protein levels, respectively, within sites of injury and a threefold increase in microglial plasminogen mRNA in vitro. In addition to potentially degrading multiple axon growth inhibitory components of the glial scar, plasmin is known to play major roles in activating neurotrophins and promoting central nervous system (CNS) plasticity. The wider implications of decorin induction of plasmin in the injured spinal cord for axon regeneration, and recovery of function at acute and chronic time points post-SCI are reviewed.
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PMID:Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by adult microglia in vitro. 1662 25

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. They are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. MMPs are excreted by a variety of connective tissue and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. Matrix metalloproteinases are considered as promising targets for the treatment of cancer due to their strong involvement in malignant pathologies. Clinical/preclinical studies on MMP inhibition in tumor models brought positive results raising the idea that the development of strategies to inhibit MMPs may be proved to be a powerful tool to fight against cancer. However, the presence of an inherent flexibility in the MMP active-site limits dramatically the accurate modeling of MMP-inhibitor complexes. The interest in the application of quantitative structure-activity relationships (QSARs) has steadily increased in recent decades and we hope it may be useful in elucidating the mechanisms of chemical-biological interactions for this enzyme. In the present review, an attempt has been made to explore the in-depth knowledge from the classification of this enzyme to the clinical trials of their inhibitors. A total number of 92 QSAR models (44 published and 48 new formulated QSAR models) have also been presented to understand the chemical-biological interactions. QSAR results on the inhibition of various compound series against MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 reveal a number of interesting points. The most important of these are hydrophobicity and molar refractivity, which are the most important determinants of the activity.
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PMID:Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. 1727 14

Suramin is an anti-neoplastic drug. Its actions include the inhibition of binding of urokinase-type plasminogen activator (uPA) to its receptor, an event which may prevent cartilage breakdown. The aim of this work was to determine the effect of suramin on cartilage resorption. Cartilage expiants, stimulated with interleukin-1alpha, tumour necrosis factor-alpha or retinoic acid were incubated with suramin. Release of incorporated (35)S-sulphate from pre-labelled expiants was used as a measure of proteoglycan breakdown and toluidine blue staining was used to visualise proteoglycan loss.Suramin inhibited the resorption of cytokine and retinoic acid-stimulated bovine nasal cartilage at concentrations between 100-1000 microM. These findings were confirmed by histochemistry. Though reversibility studies indicated that suramin toxicity could not be excluded above 100 muM, retention of suramin in the expiants may have contributed to this. There was no significant effect on lactate production up to 500 muM. The observed inhibition of cartilage resorption may reflect actions of suramin on the PA/plasmin system or on cytokine action.
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PMID:The effect of suramin on the resorption of bovine nasal cartilage. 1765 41


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