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)

To characterize the activation state of monocytes during human immunodeficiency virus (HIV) infection, peripheral blood monocytes (PBMs) from patients with acquired immunodeficiency syndrome (n = 10) and from healthy controls (n = 10) were cultured for 4 days. Monocyte culture supernatant (MCS) was collected daily, and levels of urokinase (UK) inhibitor PAI-II, a product of activated monocytes, released into MCS were determined (fibrin plate assay). To examine the activation state of PBMs independently, expression of GM1 ganglioside on PBMs from patients with AIDS (n = 9), patients with AIDS-related complex (ARC) (n = 8), HIV+ asymptomatic patients (n = 6), and HIV- healthy controls (n = 11) was determined (flow cytometry; living cells in suspension). Data are expressed as percent inhibition of UK, or as percent total cells. Patients' MCS collected on days 1-4 of culture contained similar levels of PAI-II because it inhibited UK in similar fashion (70-90%). In contrast, MCS from healthy controls, collected after 2 days, had decreased ability to inhibit UK (15-50%) and thus contained lower levels of PAI-II. Monocyte activation, measured by increased expression of GM1 ganglioside on PBM surfaces, directly correlated with the progression of HIV infection into the development of AIDS, since the order of magnitude of GM1 ganglioside expression on PBMs was AIDS greater than ARC greater than HIV+ asymptomatic = healthy controls. Our data indicate that PBMs from patients with AIDS are constitutively activated and suggest that activation directly correlates with disease progression.
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PMID:Constitutive production of PAI-II and increased surface expression of GM1 ganglioside by peripheral blood monocytes from patients with AIDS: evidence of monocyte activation in vivo. 152 87

Imbalance between intra-alveolar procoagulant activity (PCA) and fibrinolytic activity may lead to fibrin deposition, as described in several pneumopathies, and may eventually contribute to fibrotic changes as observed in Pneumocystis carinii pneumonia (PCP). The aim of our study was to compare these activities in bronchoalveolar lavages of human immunodeficiency virus (HIV)-positive and HIV-negative patients. The material comprised: a) controls (n = 7); b) HIV-positive patients subdivided into PCP (n = 11), bacterial pneumonia (n = 8) and other pneumopathies (n = 22); and c) HIV-negative patients with bacterial pneumonia (n = 8). PCA was significantly increased (p less than 0.05) in all patient groups compared to controls. The urokinase-type plasminogen activator (u-PA) antigen levels were highest during bacterial pneumonia. Regardless of the HIV status, in bacterial pneumonia there was a marked elevation of plasminogen activator inhibitor antigens with little residual fibrinolytic activity. In contrast, the fibrinolytic activity was not decreased in PCP. D-dimer were elevated during PCP compared to controls; the highest levels were found in HIV-negative bacterial pneumonia. These data indicate that transient fibrotic changes seen in PCP may be favoured by increased PCA, but not by a depressed fibrinolytic activity. In bacterial pneumonia PCA is increased and fibrinolysis decreased independently of the HIV status.
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PMID:Procoagulant and fibrinolytic activities in bronchoalveolar fluid of HIV-positive and HIV-negative patients. 156

We have observed that proteins, such as human tissue-type plasminogen activator, pro-urokinase or gp41 of human immunodeficiency virus, which have a high content of rare codons in their respective genes, are not readily expressed in Escherichia coli. Furthermore induction of these heterologous genes leads to growth inhibition and plasmid instability. Supplementation with tRNA(AGA/AGG(Arg)) by cotransfection with the dnaY gene, which supplies this minor tRNA, resulted in high-level production with greatly improved cell viability and plasmid stability.
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PMID:High-level expression of recombinant genes in Escherichia coli is dependent on the availability of the dnaY gene product. 251 92

The RAW264 murine macrophage cell line was used as a model to examine the role of the tat and nef gene products in the transcription regulation of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) in macrophages. Contrary to claims that the activity of the HIV-1 LTR responds poorly in rodent cells to trans activation by the viral tat gene product, cotransfection of RAW264 cells with a tat expression plasmid in transient transfection assays caused a > 20-fold increase in reporter gene expression that was inhibited by mutations in the TAR region. RAW264 cells stably transfected with the tat plasmid displayed similarly elevated HIV-1 LTR-driven reporter gene activity. By contrast to previous reports indicating a negative role for nef in HIV transcription, cotransfection of RAW264 cells with a nef expression plasmid trans activated the HIV-1 LTR driving either a chloramphenicol acetyltransferase or a luciferase reporter gene. The action of nef was specific to the LTR, as expression of nef had no effect on the activity of the simian virus 40, c-fms, urokinase plasminogen activator, or type 5 acid phosphatase promoter. trans-activating activity was also manifested by a frameshift mutant expressing only the first 35 amino acids of the protein. The effects of nef were multiplicative with those of tat gene product and occurred even in the presence of bacterial lipopolysaccharide, which itself activated LTR-directed transcription. Examination of the effects of selected mutations in the LTR revealed that neither the kappa B sites in the direct repeat enhancer nor the TAR region was required as a cis-acting element in nef action. The action of nef was not species restricted; it was able to trans activate in the human monocyte-like cell line Mono Mac 6. The presence of a nef expression cassette in a neomycin phosphotransferase gene expression plasmid greatly reduced the number of G418-resistant colonies generated in stable transfection of RAW264 cells, and many of the colonies that were formed exhibited very slow growth. The frameshift mutant was also active in reducing colony generation. Given the absence of any effect of the frameshift mutation on nef function, its actions on macrophage growth and HIV transcription are discussed in terms of the role of the N-terminal 30 amino acids and of stable secondary structures in the mRNA.
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PMID:Effects of the tat and nef gene products of human immunodeficiency virus type 1 (HIV-1) on transcription controlled by the HIV-1 long terminal repeat and on cell growth in macrophages. 823 Apr 18

NF-kappaB and activator protein 1 (AP-1) are dimeric transcription factors involved in transcriptional regulation in many cells, including neurons. We have examined their activity during mouse cerebellum development, a postnatal process starting just after birth and completed by the fourth postnatal (PN) week. The activity of these factors was analyzed by binding of nuclear extracts to a synthetic oligonucleotide representing the kappaB site of human immunodeficiency virus or the AP-1 site of the urokinase promoter. NF-kappaB activity was observed from 7 PN, was restricted to the developing cerebellum, and was not observed in the early postnatal neocortex and hippocampus. On the other hand, AP-1 activity was not found in cerebellum but was present in both neocortex and hippocampus. Moreover, a kappaB-driven transgene was found to be increasingly expressed in the cerebellum from 5 PN to 10 PN but not in the adult. The regulation of NF-kappaB activation in mouse cerebellum was analyzed by intraperitoneal injection of glutamate receptor antagonists to 9 PN mice, which abolished NF-kappaB-binding activity, suggesting an endogenous loop of glutamate receptor activation. Glutamate receptor agonists, on the other hand, induced NF-kappaB nuclear translocation in the cerebellum of 5 PN mice, which is a stage in which NF-kappaB is not yet endogenously activated. This effect was specific for NF-kappaB and not observed for AP-1. In adult mice, NF-kappaB activity was absent in the cerebellum and was not induced by intraperitoneal injection of glutamate receptor agonists. These data show that NF-kappaB is specifically activated during cerebellum development and indicate an important role of glutamate receptors in this process.
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PMID:Glutamate-dependent activation of NF-kappaB during mouse cerebellum development. 923 17

Pericellular proteolysis initiated by receptor-bound urokinase-type plasminogen activator (uPA) is considered important for directed migration of granulocytes to inflammatory sites. Using flow cytometry and whole-cell binding of radiolabelled-uPA, we found a high level of uPA-receptor (uPAR) expression in granulocytes (3.9 x 104 +/- 0.9 x 104 sites/cell). Modulation of uPAR expression was assessed in the presence of chemoattractant gradients. Our findings demonstrate that interleukin (IL)-8, leukotriene B4(LTB4) and formyl-methionyl-leucyl-phenylalanine (f MLP) caused a dose-dependent upregulation of uPAR on granulocytes in healthy controls. Modulation of uPAR expression is known to regulate chemotactic response. As determined by flow cytometry, uPAR expression by granulocytes from human immunodeficiency virus (HIV)-infected patients was distinctly lower than that of healthy control cells (P < 0.001). However, upregulation of uPAR in response to chemoattractants was similar to that observed in healthy controls. In HIV-infected patients, the uPAR expression on granulocytes correlated (P < 0.001, n = 10) with the number of CD4+ blood cells. In contrast, the expression of IL-8 receptor, CD11b, CD18 and CD62 was not significantly altered in HIV-patients compared with healthy controls.
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PMID:Decreased urokinase receptor expression on granulocytes in HIV-infected patients. 1196 23

NF-kappaB is an inducible transcription factor involved in the immune response, inflammation, and viral transcription. To address how the two NF-kappaB and three Sp1 binding sites of the human immunodeficiency virus (HIV) long terminal repeat (LTR) control multiple activator assembly and transcription, we first observed and compared unique conformations between the crystallographic structure of the NF-kappaB p50.p65 heterodimer bound to the uPA-kappaB target site to that of the p50.p65.HIV-kappaB complex. Next, cooperativity between two NF-kappaB molecules bound to tandem HIV-kappaB sequences was measured as well as that of NF-kappaB and transcription factor Sp1 when bound to adjacent sites. The cooperativity of hybrid HIV-LTR enhancers was measured with the 3' kappaB site converted to uPA-kappaB or to interferon beta gene enhancer kappaB. The hybrids were defective in transcriptional activator assembly and less active transcriptionally. These functional differences correlate with observed conformational differences and demonstrate that distinct kappaB DNA sequences function as allosteric regulators in a gene-specific manner.
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PMID:The kappa B DNA sequence from the HIV long terminal repeat functions as an allosteric regulator of HIV transcription. 1197 Sep 49

The binding of urokinase-type plasminogen activator (uPA) to its glycosyl-phosphatidyl-inositol (GPI) anchored receptor (uPAR) mediates a variety of functions in terms of vascular homeostasis, inflammation and tissue repair. Both uPA and uPAR, as well as their soluble forms detectable in plasma and other body fluids, represent markers of cancer development and metastasis, and they have been recently described as predictors of human immunodeficiency virus (HIV) disease progression, independent of CD4+ T cell counts and viremia. A direct link between the uPA/uPAR system and HIV infection was earlier proposed in terms of cleavage of gp120 envelope by uPA. More recently, a negative regulatory effect on both acutely and chronically infected cells has been linked to the noncatalytic portion of uPA, also referred to as the amino-terminal fragment (ATF). ATF has also been described as a major CD8+ T cell soluble HIV suppressor factor. In chronically infected promonocytic U1 cells this inhibitory effect is exerted at the very late stages of the virus life cycle, involving virion budding and entrapment in intracytoplasmic vacuoles, whereas its mechanism of action in acutely infected cells remains to be defined. Since uPAR is a GPI-anchored receptor it requires association with a signaling-transducing component and different partners, which include CD11b/CD18 integrin and a G-protein coupled receptor homologous to that for the bacterial chemotactic peptide formyl-methionyl-leucyl-phenylalanine. Which signaling coreceptor(s) is(are) responsible for uPA-dependent anti-HIV effect remains currently undefined.
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PMID:The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection. 1296 Feb 38

Human immunodeficiency virus (HIV) dementia (HIVD) is associated with an increase in the number of activated monocytes within the central nervous system (CNS), a pathological feature that may be more remarkable in the setting of superimposed substance abuse. Monocytes may transport HIV to the brain, and, moreover, activated and/or infected monocytes have been shown to release a number of potent neurotoxins. Although the mechanisms responsible for the increase in the CNS ingress of monocytes are multiple, blood-brain barrier (BBB)-degrading matrix metalloproteinases (MMPs) are likely to play an important role. The current study investigates the effects of the HIV-1-encoded protein Tat, and the drug of abuse methamphetamine, on MMP release from brain derived cells. The release of urokinase plasminogen activator (uPA), an activator of MMPs, was also investigated. Mixed human neuron/astrocyte cultures were stimulated with Tat or methamphetamine, and supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) and/or gelatin substrate zymography. Results showed that Tat and methamphetamine increased the release of MMP-1 from these cultures. Tat also increased supernatant levels of active MMP-2. In addition, both Tat and methamphetamine stimulated the release of the MMP activator uPA, and in a manner that was sensitive to inhibition with pertussis toxin. Together, these results suggest that in HIVD, Tat and methamphetamine may contribute to CNS inflammation by stimulating increased release and/or activation of matrix-degrading proteinases through mechanisms that include Gi/Go-coupled signaling. These results also suggest a potential mechanism for acceleration of HIVD with methamphetamine use.
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PMID:Human immunodeficiency virus type 1 Tat and methamphetamine affect the release and activation of matrix-degrading proteinases. 1498 25

High blood levels of the soluble urokinase receptor (suPAR) strongly predict increased mortality in human immunodeficiency virus-1 (HIV-1)-infected patients. This study investigated the plasma concentration of suPAR in 29 treatment-naive HIV-1-infected patients during 5 years treatment with highly active antiretroviral therapy (HAART). Plasma suPAR decreased after introducing HAART, most pronounced during the first treatment year. The change in plasma suPAR was independent of changes in viral replication and CD4+ cells but it was strongly correlated with plasma levels of the soluble TNF receptor II. Compared with healthy individuals, plasma suPAR and sTN-FrII was increased in untreated patients. After initiating HAART, plasma sTNFrII remained increased whereas plasma suPAR decreased to a level comparable with healthy individuals. The present data indicate that the circulating suPAR level is linked to inflammation in untreated as well as HAART-treated HIV-1-infected patients.
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PMID:Soluble urokinase receptor levels in plasma during 5 years of highly active antiretroviral therapy in HIV-1-infected patients. 1509 49


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