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)

Wound healing in ligaments is a complex process which leads to functionally impaired scar tissue, even after extended time postinjury. To investigate the potential role of proteinases and inhibitors, as well as potential regulators of their expression, mRNA levels for collagenase, stromelysin, urokinase, PAI-1, and TIMPs 1 to 4 have been assessed by semiquantitative RT-PCR in RNA isolated from rabbit ligaments 3, 6, and 14 weeks postinjury. In addition, mRNA levels for IL-1, TNF, COX-2, and iNOS, potential regulators of proteinase/inhibitor expression, have been assessed. mRNA levels for the proteinases TIMP-1, -2, and -3 and PAI-1 were elevated early in scar tissue, but TIMP-4 mRNA levels exhibited a different pattern. In contrast, mRNA levels for the cytokines iNOS and COX-2 were either unchanged or depressed early after injury. The results indicate that alterations in mRNA levels for proteinases and inhibitors occurring early after injury are likely being influenced by factors other than IL-1, TNF, or products of COX-2 or iNOS.
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PMID:Temporal alterations in mRNA levels for proteinases and inhibitors and their potential regulators in the healing medial collateral ligament. 983 80

Butyrate may have paradoxical effects on epithelial cells of similar origin. This study aimed to examine the hypothesis that one mechanism that dictates a cell's response to butyrate is its state of activation. First, the responses to 24 h exposure to butyrate (1-2 mM) of normal and neoplastic human colonic epithelial cells activated by their isolation and primary culture, and of colon cancer cell lines, LIM1215 and Caco-2, were examined. In primary cultures of normal and cancer cells, butyrate had no effect on alkaline phosphatase activities but significantly suppressed urokinase receptor expression by a mean +/- SEM of 30 +/- 12% and 36 +/- 9%, respectively. Interleukin-8 secretion was suppressed by 44 +/- 7% in normal cells (P < 0.05) but was unchanged in cancer cells. In contrast, the cell lines significantly increased alkaline phosphatase activities by >50%, urokinase receptor expression >2-fold and interleukin-8 secretion >3-fold in response to butyrate. Secondly, the effect of butyrate on Caco-2 cells was examined with or without prior exposure to a specific activating stimulus [tumour necrosis factor alpha (TNF alpha)]. Interleukin-8 secretion increased by 145 +/- 23% and 132 +/- 17% on 24 h exposure to 2 mM butyrate or 0.1 microM TNF alpha alone, respectively. However, in cells pre-treated with TNF alpha, butyrate significantly inhibited secretion by 34 +/- 7% below unstimulated levels. The response to butyrate of urokinase receptor, whose expression was not stimulated by TNF alpha, was unchanged. These effects were mimicked by trichostatin A, an inhibitor of histone deacetylase, suggesting that butyrate's paradoxical effects may have been operating by the same mechanism. In conclusion, some of the paradoxical effects of butyrate do not appear to represent inherent differences between normal and transformed cells. Rather, the response may be determined by the state of activation of the cells.
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PMID:Colonic epithelial cell activation and the paradoxical effects of butyrate. 1022 79

Angiogenesis, the formation of new blood vessels from existing vessels, plays an important role during development. In the adult, it is limited to the female reproductive system and to tissue repair and pathological conditions. Repair associated angiogenesis is usually accompanied by the presence of inflammatory cells, vascular leakage, and fibrin deposition. The temporary fibrin matrix acts, not only as a sealing matrix, but also as a scaffolding for invading leukocytes and endothelial cells during tissue repair. We have used a three-dimensional fibrin matrix to study the outgrowth of human microvascular endothelial cells in capillary-like tubular structures. This process is induced by the simultaneous addition of an angiogenic growth factor (bFGF or VEGF) and the cytokine TNF alpha, and is enhanced by hypoxia. It involves proteolytic activities, in particular cell bound urokinase/plasmin and matrix metalloproteinase activities. Modulation of the fibrin structure markedly affects the extent and stability of capillary tube formation in vitro. Preparation of fibrin at different pH (7.0-7.8) or crosslinking of the fibrin matrix induces differences in fibrin matrix rigidity and structure. This is accompanied by a change in capillary ingrowth. Heparins, in particular low molecular weight heparins, modulate the fibrin structure and by this action affect angiogenesis in vitro. A mutant fibrinogenNieuwegein, which lacks the terminal part of the A alpha chain of fibrin harboring an RGD sequence and the transglutaminase sequence, provided additional evidence that the structure of fibrin is an important determinant for angiogenesis. These findings may have impact on improving wound healing and on influencing angiogenesis in malignancies with a fibrinous stroma.
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PMID:Role of fibrin matrix in angiogenesis. 1146 Apr 96

Plasminogen activator inhibitor type 1 (PAI-1), a risk marker of atherosclerosis, is highly expressed in adipose tissue from obese subjects. PAI-1 is also considered as an acute phase protein. Recently, adipose tissue has been described as a source of inflammatory cytokines. Therefore, our aim was to study the relationships between PAI-1, and IL-6, TNF, TNF receptors (TNFRSF1s) and TGFbeta1, in plasma and adipose tissue from obese (n = 60) and lean (n = 28) subjects. Study has been extended to plasminogen activators (t-PA and u-PA). Compared to lean subjects, obese subjects exhibited higher plasma levels of all the studied parameters (except for TGFbeta1) whereas in adipose tissue only PAI-1, t-PA and TGFbeta antigen levels differed. In the obese population, plasma PAI-1 levels were weakly associated with circulating TNF, and this relationship disappeared after adjustment for plasma t-PA. Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFbeta, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability. TNF and IL-6 were the main contributors to t-PA variability in plasma and in adipose tissue, respectively. Our results argue on the relevance of TNFRSF1s in the regulation of PAI-1 expression by adipose tissue. Association between t-PA, which is mainly produced by endothelial cells, and IL-6 or TNF suggest that inflammation might be involved in angiogenesis in adipose tissue.
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PMID:Relationships between fibrinolytic and inflammatory parameters in human adipose tissue: strong contribution of TNFalpha receptors to PAI-1 levels. 1235 79

Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF-kappa B, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies.
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PMID:Anticancer potential of curcumin: preclinical and clinical studies. 1268 Feb 38

In breast cancers, clinical symptoms of inflammation localised around the tumour at the time of diagnosis have been considered to have poor prognosis significance. In this study, the biological mechanisms responsible for the deleterious action of monocytes in cancer were investigated. The incubation of the breast-cancer-derived MDA-MB231 cells with monocytes resulted in an increase in factors involved in cell invasion (i.e. both cancer cells and monocytes-associated urokinase and Tissue Factor, and PAI-1 and MMP-9 secretion). Moreover, the functions of monocytes were also modified. Incubation of monocytes with MDA-MB231 cancer cells resulted in a downregulation in the secretion of the antiproliferative cytokine Oncostatin M, while the apoptotic factor TNF alpha was dramatically increased. However, MDA-MB231 cancer cells have been shown to be resistant towards the apoptotic action of TNF alpha. These findings demonstrate that incubation of MDA-MB231 cancer cells with monocytes induced a crosstalk, which resulted in an increased expression of factors involved in cancer cell invasiveness and in a modification of monocytes function against cancer cells, while inflammatory effects were increased.
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PMID:Cooperation between monocytes and breast cancer cells promotes factors involved in cancer aggressiveness. 1269 85

Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore be involved in astrocyte inflammation. In this study, we explored the effect of the MLK inhibitors CEP-1347 and CEP-11004 on the activation of murine astrocytes by either TNF plus IL-1 or by a complete cytokine mix containing additional IFN-gamma. The compounds blocked NO-, PG-, and IL-6 release with a median inhibitory concentration of approximately 100 nM. This activity correlated with a block of the JNK and the p38 pathways activated in complete cytokine mix-treated astrocytes. Although CEP-1347 did not affect the activation of NF-kappaB, it blocked the expression of cyclooxygenase-2 and inducible NO synthase at the transcriptional level. Quantitative transcript profiling of 17 inflammation-linked genes revealed a specific modulation pattern of astrocyte activation by MLK inhibition, for instance, characterized by up-regulation of the anti-stress factors inhibitor of apoptosis protein-2 and activated transcription factor 4, no effect on manganese superoxide dismutase and caspase-11, and down-regulation of major inflammatory players like TNF, GM-CSF, urokinase-type plasminogen activator, and IL-6. In conclusion, MLK inhibitors like CEP-1347 are highly potent astrocyte immune modulators with a novel spectrum of activity.
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PMID:Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347. 1529 95

Atherosclerosis is still an important disease. It accounts for 39% of deaths in the U.K. and 12 million U.S citizens have atherosclerosis-associated disease. Atherosclerosis may exert clinical effects by slow narrowing, producing stable angina or dramatic rupture, producing acute coronary syndromes such as unstable angina or myocardial infarction and death. Macrophages are abundant in ruptured atherosclerotic plaques. Macrophages are innate immune effectors, i.e. they are activated without antigenic specificity. This may make them liable to indiscriminate tissue damage, since they are less selective than lymphocytes. Macrophages are recruited and activated by many signals and have an impressive armamentarium of molecules to promote tissue damage. Macrophage recruitment by abnormal endothelium over developing atherosclerotic plaques, is aided by endothelial expression of adhesion molecules (ICAM-1, VCAM, ELAM). Use of knockout mice has implicated the chemoattractant cytokine (chemokine) MCP-1 in attracting macrophage recruitment in atherosclerosis. Macrophage-activation stimuli associated with atherosclerotic risk factors include oxidised low density lipoprotein (oxLDL, "bad cholesterol"), advanced glycosylation end products (AGEs) of diabetes, angiotensin II and endothelin. Substantial work has clarified macrophage activation by OxLDL via macrophage scavenger receptors (MSRs), especially MSRA and CD36. Activated macrophages express effector molecules that kill cells and degrade extracellular matrix. These include Fas-L and nitric oxide (NO). Macrophage NO is derived from the high output inducible nitric oxide synthase (iNOS) pathway and upregulates vascular smooth muscle (VSMC) cell surface Fas, priming them for apoptosis. Activated macrophages express surface Fas-L, similar to cytotoxic T-lymphocytes and natural killer cells. Since VSMCs promote plaque stability, VSMC apoptosis may promote plaque rupture. Macrophages express multiple metalloproteinases (e.g. stromelysin) and serine proteases (e.g. urokinase) that degrade the extracellular matrix, weakening the plaque and making it rupture prone. Macrophages secrete numerous other effectors including reactive oxygen species, eicosanoids, tumour necrosis factor alpha and interleukin-1. Macrophage-derived transforming growth factor beta promotes fibrosis. Existing cardiovascular treatments including angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, aspirin, cholesterol reduction agents especially statins may inhibit macrophages. The interaction of NO-donors with macrophages and apoptosis is complex and bifunctional. Traditional anti-inflammatory agents such as glucocorticoids and cyclophosphamide have very serious side effects and are probably inappropriate. Novel anti-inflammatory agents e.g. new immunosuppressives and anti-TNF therapy may have an improved cost-benefit ratio.
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PMID:Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. 1563 83

We have previously developed TNF prodrugs comprised of a N-terminal scFv targeting, a TNF effector and a C-terminal TNFR1-derived inhibitor module linked to TNF via a MMP-2 motif containing peptide, allowing activation by MMP-2-expressing tumor cells. To overcome the known heterogeneity of matrix metalloprotease expression, we developed TNF prodrugs that become processed by other tumor and/or stroma-associated proteases. These TNF prodrugs comprise either an uPA-selective or a dual uPA-MMP-2-specific linker which displayed efficient, target-dependent and cleavage sequence-specific activation by the corresponding tumor cell-expressed proteases. Selective pharmacologic inhibition of endogenous uPA and MMP-2 confirm independent prodrug processing by these two model proteases and indicate the functional superiority of a prodrug containing a multi-specific protease linker. Processing optimised TNF prodrugs should increase the proportion of active therapeutic within the targeted tissue and thus potentially enhance tumor response rate.
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PMID:Target-selective activation of a TNF prodrug by urokinase-type plasminogen activator (uPA) mediated proteolytic processing at the cell surface. 1663 12

In the present work we used a murine mammary cancer model of two related adenocarcinomas with different lung metastasizing abilities, to compare their global gene expression profiles. Clontech Atlas mouse cDNA microarrays of primary cultured tumor cells were employed to identify genes that are modulated in the more metastatic variant MM3 relative to its parental tumor M3. A total of 88 from 1,176 genes were differentially expressed in MM3 primary cultures, most of them (n=86) were upregulated. Genes were grouped according to their functions as associated with signal transduction and transcription regulation (e.g. Stat1 and Zfp 92), with cell adhesion and motility (cadherin 1, fibronectin), with invasion and angiogenesis (uPA, 72 kDa MMP2), with the regulation of cell proliferation and cell death (cyclins G and A2, TNF), and also included growth factors and receptors, oncogenes and tumor suppressors genes (p107, TGFbeta2, TBR-I, PDGFR). Only 2 genes, TTF1 and fibronectin (FN), showed a significant downregulation. Notably FN expression, loss of which has been associated with a malignant phenotype, was reduced about 19-fold in the more metastatic MM3 cells. Previously known differences in expression patterns associated with the metastatic capacity of MM3 and M3 adenocarcinomas, including downregulation of FN or upregulated expression of TGFbeta and proteases, were confirmed by the array data. The fact that FN was one of the only two genes significantly down-regulated out of the 1,176 genes analyzed stresses the hypothesis that FN may behave as an important metastasis suppressor gene in mammary cancer.
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PMID:Fibronectin is distinctly downregulated in murine mammary adenocarcinoma cells with high metastatic potential. 1708 68


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