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)

The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immunoglobulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the preclinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.
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PMID:Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. 179 69

Although CD4 antigen is expressed on monocytes (MO), its functional role is uncharacterized. In this study, isolated human MO were separated into CD4+ and CD4- MO subsets and assessed for presentation of tetanus toxoid. The CD4- MO subset had decreased antigen presenting cell (APC) capacity as well as increased PGE2 production when compared to the CD4+ MO subset. Addition of a cyclo-oxygenase inhibitor (Indomethacin) did not restore the CD4- MO subset's APC capacity to that of the similarly treated CD4+ MO subset, eliminating differential PGE2 production as the primary cause of differential APC capacity. Production of monokines such as IL-1 and plasminogen activator, which affect APC capacity, was similar in the CD4 MO subsets. However, tumor necrosis factor (TNF) production (IFN gamma plus MDP-induced) of the CD4+ MO subset was slightly greater than that of the CD4- MO. CD4- MO's lower APC capacity is not totally explained by their differential IL-1, TNF, or PGE2 production.
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PMID:Antigen presentation by the CD4 positive monocyte subset. 230 46

Pokeweed-mitogen-induced IgG secretion, Con A suppression and T cell surface markers were measured in 30 chronic progressive multiple sclerosis (MS) patients and 21 healthy controls. Mean IgG secretion was higher in the MS patients than in the controls (2392 +/- 270 vs 1499 +/- 243); Con A suppression was lower (4 +/- 5% vs 24 +/- 4%) and the CD4/CD8 ratio was higher (4.1 +/- 0.4 vs 2.9 +/- 0.4). The above assays were used in vitro to monitor the effects of Wellferon (lymphoblastoid interferon) injections on this group of MS patients. Before treatment the INF-group (n = 14) did not differ from the PLA-group (n = 16). After 1 week of daily injections the level of IgG secreted was dramatically reduced in the INF group (629 +/- 96 ng/ml) compared to the PLA-group (1756 +/- 319 ng/ml). There was no change in either Con A suppression or T cell surface markers. IgG secretion remained lower in the INF-group for the 6 month treatment period. Following cessation of the injections and a 6 month washout period, IgG secretion in the INF-group rose and was equivalent to that observed in the PLA-group. A series of lymphocyte subset mixing experiments implicates the B lymphocyte subset as being directly affected by interferon injections in vitro.
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PMID:Reduction of immunoglobulin G secretion in vitro following long term lymphoblastoid interferon (Wellferon) treatment in multiple sclerosis patients. 295 31

A mathematical model is developed of the compartmentalized sialylation of N-linked oligosaccharides in order to understand and predict the outcome of sialylation reactions. A set of assumptions are presented, including Michaelis-Menten-type dependency of reaction rate on the concentration of the glycoprotein substrate. The resulting model predicts the heterogeneous outcome of a posttranslational oligosaccharide biosynthesis step, a critical aspect that is not accounted for in the modeling of the cotranslational attachment of oligosaccharides to glycosylation sites (Shelikoff et al., Biotech. Bioeng., 50, 73-90, 1996) or general models of the secretion process (Noe and Delenick, J. Cell Sci., 92, 449-459, 1989). In the steady-state for the likely case where the concentration of substrate is much less than the Km of the sialyltransferase, the model predicts that the extent of sialylation, x, will depend upon the enzyme concentration, enzyme kinetic parameters and substrate residence time in the reaction compartment. The value of x predicted by the model using available literature data is consistent with the values of x that have been recently determined for the glycoproteins CD4 (Spellman et al., Biochemistry, 30, 2395-2406, 1991) and t-PA (Spellman et al., J. Biol. Chem., 264, 14100-14111, 1989) secreted by Chinese hamster ovary cells. For the unsaturated case, the model also predicts that x is independent of the concentration of secreted glycoprotein in the Golgi. The general modeling approach outlined in this article may be applicable to other glycosylation reactions and posttranslational modifications.
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PMID:A mathematical model of sialylation of N-linked oligosaccharides in the trans-Golgi network. 918 32

Urokinase (UK) type plasminogen activator is a serine protease produced by activated human monocytes. Despite the well-documented roles played by UK in cell-mediated immunity in healthy humans, the roles played by UK in the derangements of cell-mediated immune responses observed in HIV disease remain largely undefined. In these studies the numbers of peripheral blood lymphocytes and monocytes bearing surface UK (UK+) as well as serum levels of UK (flow microfluorimetry and ELISA, respectively) were determined in children with AIDS and in healthy HIV-negative children. The effects of exogenous UK on lymphocyte activation (cell cycle analysis using living cells) and surface marker (CD3, CD4, CD8, and CD19) expression (flow microfluorimetry using fixed cells) were also studied. Data are expressed as percent total cells. Numbers of UK+ lymphocytes in children with AIDS were similar to those observed in healthy children. In contrast, numbers of UK+ peripheral blood monocytes were dramatically decreased (> 70%) in the children with AIDS. However, serum levels of UK were increased (nearly threefold) in these children. When lymphocytes from these children were cultured with soluble UK, numbers of cells in S phase of cell cycle appeared suppressed. Incubation of fixed lymphocytes from either a child with AIDS or from a healthy child with exogenous UK appeared to increase numbers of cells expressing CD3. Incubation with UK had no effect on expression of any other surface marker (CD4, CD8, or CD19) using cells from the child with AIDS. In contrast, incubation with UK appeared to decrease (fivefold) numbers of cells expressing CD19 and increase numbers of cells expressing CD4 and CD8 only when fixed lymphocytes from a healthy HIV-negative child were used. The results suggest important roles for UK in regulation of lymphocyte surface markers in general and in CD3- and CD19-dependent lymphocyte activation pathways specifically. Furthermore, these studies add to a widening body of evidence implicating UK dysregulation in the pathogenesis of HIV disease and may point to pharmacological opportunities involving UK to delay or prevent progression of HIV infection into full-blown AIDS.
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PMID:Altered levels of urokinase on monocytes and in serum of children with AIDS; effects on lymphocyte activation and surface marker expression. 971 59

Human immunodeficiency virus-1 (HIV-1) infection has been shown to result in up-regulation of the urokinase-type plasminogen activator receptor (uPAR/CD87) on leukocytes in vitro and in vivo. The objective of this study was to investigate whether this up-regulation is paralleled by higher serum levels of soluble uPAR (suPAR) in patients with advanced HIV-1 disease and whether the serum level of suPAR is predictive of clinical outcome. Using an enzyme-linked immunosorbent assay, the level of suPAR was measured retrospectively in serum samples from 314 patients with HIV-1 infection. By Kaplan-Meier and Cox regression analyses, the serum suPAR levels were correlated to survival with AIDS-related death as the end point. High levels of serum suPAR (greater than median) were associated with poor overall survival, and Kaplan-Meier analysis on patients stratified by suPAR level demonstrated a continuous increase in mortality rates with higher suPAR levels. After adjustment for accepted prognostic markers-including Centers for Disease Control and Prevention-defined clinical stages, CD4 counts, viral load, beta2-microglobulin, and age-the prognostic strength of suPAR remained highly significant, indicating that the serum suPAR level is a novel, strong, and independent predictor of survival in HIV-1 infection. This report is the first to demonstrate an important association between the plasminogen activator system and disease progression in HIV-1 infection.
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PMID:Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. 1111 Jun 78

We report a novel phospholipase A(2) (PLA(2)), group XII (GXII) PLA(2), distinct from other cysteine-rich groups with a catalytic histidine motif, by its 20-kDa size and distribution of the 14 cysteine residues within the protein. Alternative spliced forms with distinct subcellular localization, designated GXII-1 and GXII-2, were identified by reverse transcription-polymerase chain reaction. Importantly, GXII PLA(2)s, in particular GXII-2 PLA(2), and group V PLA(2), but not group X PLA(2), were selectively expressed in murine type 2 helper T (Th2) clones and in vitro differentiated mouse CD4 Th2 cells as compared with type 1 helper T clones and cells. Stimulation with anti-CD3 appreciably up-regulated expression of GXII PLA(2)s and group V PLA(2) by steady state analysis of the Th2 cells as compared with type 1 helper T cells. These results suggest that group XII and group V PLA(2)s might participate in helper T cell immune response through release of immediate second signals and generation of downstream eicosanoids.
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PMID:A novel group of phospholipase A2s preferentially expressed in type 2 helper T cells. 1127 38

The endothelium participates in haemostasis, inflammation, blood pressure regulation and other physiological systems. Consequently, endothelial dysfunction has been related to hypertension, thrombosis and atherosclerosis. Both von Willebrand factor (vWF) and tissue-type plasminogen activator (t-PA) are synthesized by the endothelium and their plasma levels increased during endothelium activation or injury. So far, they are well-known markers of endothelial cell function. Many circumstances activate or damage the endothelium, such as viruses, bacterium and inflammation. Circulating vWF and t-PA were studied in 92 unselected human immunodeficiency virus-1 (HIV-1)-infected patients [27 patients with and 65 patients without acquired immunodeficiency syndrome (AIDS)] and correlated with plasma levels of pro-inflammatory cytokines (tumour necrosis factor-alpha, interleukin-6), viral load, CD4 T-cell count and infectious status. HIV-1-infected patients had significantly higher plasma levels of vWF (152 versus 90%), tumour necrosis factor-alpha (31.3 versus 9.0 pg/ml) and interleukin-6 (3.5 versus 1.9 pg/ml) but not t-PA (5.9 versus 4.2 ng/ml) than the control group. These two endothelial markers correlated significantly with viral load and interleukin-6 levels in HIV-1-infected patients. The highest levels of vWF and t-PA were found in patients with AIDS. In conclusion, endothelial cell perturbation is present in HIV infection and may be a consequence of different mechanisms such as viral load, cytokines and advanced diseases.
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PMID:Viral load and disease progression as responsible for endothelial activation and/or injury in human immunodeficiency virus-1-infected patients. 1254 23

Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Whereas PAI-1 is not expressed in normal kidneys, it is strongly induced in glomerular diseases and thus could promote the local accumulation of fibrin. To study the role of PAI-1 in the development of inflammatory glomerular injury, passive antiglomerular basement membrane (GBM) glomerulonephritis (GN) was induced in PAI-1 knockout mice and in wild-type mice of the same genetic background. Unexpectedly, PAI-1 deficiency was associated with an early and severe exacerbation of glomerular injury: Infiltration by CD4 T cells, proportion of fibrinous crescents, and renal function impairment were significantly more pronounced in PAI-1 -/- mice. Interestingly, activation of transforming growth factor (TGF)- beta, which is known to be dependent on the PA/plasmin system in vitro, was dramatically enhanced in the kidneys in the absence of PAI-1. Moreover, administration of neutralizing antibodies against TGF-beta significantly attenuated the disease in PAI-1 -/- mice. This suggests that the poor outcome of GN in PAI-1 -/- mice is consecutive to an uncontrolled activation of TGF-beta and confers PAI-1 with a new, immunomodulatory role.
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PMID:Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta. 1289 66

The in vivo local reaction of as-polymerized poly-L-lactide composed of 96% L-lactide and 4% D-lactide (PLA96) was investigated by histology at 2, 13 and 26 weeks after subcutaneous implantation in rats. In order to simulate possible end stage reactions the PLA96 was also predegraded in vitro until approximately 50% weight loss. The local reaction of predegraded PLA (PLA96(168)) was compared to the local reaction of polyethylene (PE) and non-predegraded PLA (PLA96). For PE and PLA96 a mild local reaction was observed at all time points consisting of a minimal layer of macrophage like cells with incidentally multinucleated giant cells at the implant interface, surrounded by a mild connective tissue capsule. For PLA96 at weeks 13 and 26 some minimal alterations in terms of degradation and ingrowth of cells was noted. The in vitro incubation (90 degrees C for 168 h) of PLA96(168) resulted for the thin 0.2 mm samples in complete degradation. Predegraded 0.5, 1.0 and 2.0 mm PLA96(168) samples were implanted and evaluated. The 1.0 and 2.0 mm samples could be evaluated for all time points investigated, but some 0.5 mm PLA96(168) samples were already completely resorbed at week 2 after implantation. In general, responses found for the predegraded PLA96(168) at weeks 2, 13 and 26 were similar with a pronounced macrophage infiltrate containing birefringent material, encapsulation of polymer fragments, and the presence of a debris area consisting of polymer and cellular remnants. In lymph nodes foamy macrophages with birefringent material were only observed in lymph nodes draining sites with predegraded PLA96(168). Immunohistochemistry was performed for further characterization of the cellular infiltrate. At the implant interface of the non-degrading PE and PLA96, ED1 and OX6 (MHC class II) positive cells were identified. In the capsule macrophage like cells expressed all three macrophage markers ED1, ED2, and ED3. CD4 and CD8 positive cells, indicating T helper and T supressor/cytotoxic cells, respectively, could be observed in low numbers, CD4 more than CD8. Both CD4 and CD8 were occasionally observed within the degrading PLA96(168) implant. Polymorphonuclear neutrophilic granulocytes were mainly observed at 2 weeks after implantation. We showed that predegradation could be used as a means to study late tissue reactions to polymers. Complete degradation may be studied with relatively thin implants, but this may lead to rather optimistic interpretation of resorption periods. When materials are intended to be used for screws and/or plates for bone fixation, implants of at least 1.0-2.0 mm thickness should be used as these may show a more realistic representation of the resorption characteristics of the material under investigation.
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PMID:Tissue response to partially in vitro predegraded poly-L-lactide implants. 1557 52


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