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)

Iron and iron metabolism are critical in a variety of physiologic and pathophysiologic processes, including lung injury and repair. The plasmin/plasminogen activator (PA) system is involved in the extensive remodeling process that follows acute lung injury, and alveolar epithelial cells play a key role in this repair process. Herein we report that decreased intracellular iron availability markedly suppresses cell-surface plasmin generation by A549 human carcinoma-derived pulmonary epithelial cells. This effect is mediated by concomitant downregulation of urokinase-type PA and upregulation of PA inhibitor-type 1 expression. Northern analyses, runoff transcription assays, and messenger RNA half-life experiments using actinomycin demonstrate that transcriptional and post-transcriptional mechanisms are operative. Given these potent in vitro effects on the plasmin/PA system, we speculate that adequate intracellular iron stores are important for successful repair of acute lung injury.
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PMID:Decreased intracellular iron availability suppresses epithelial cell surface plasmin generation. Transcriptional and post-transcriptional effects on u-PA and PAI-1 expression. 1042 12

The causative agent of plague, Yersinia pestis, is regarded as being noninvasive for epithelial cells and lacks the major adhesins and invasins of its enteropathogenic relatives Yersinia enterocolitica and Yersinia pseudotuberculosis. However, there are studies indicating that Y. pestis invades and causes systemic infection from ingestive and aerogenic routes of infection. Accordingly, we developed a gentamicin protection assay and reexamined invasiveness of Y. pestis for HeLa cells. By optimizing this assay, we discovered that Y. pestis is highly invasive. Several factors, including the presence of fetal bovine serum, the configuration of the tissue culture plate, the temperature at which the bacteria are grown, and the presence of the plasminogen activator protease Pla-encoding plasmid pPCP1, were found to influence invasiveness strongly. Suboptimal combinations of these factors may have contributed to negative findings by previous studies attempting to demonstrate invasion by Y. pestis. Invasion of HeLa cells was strongly inhibited by cytochalasin D and modestly inhibited by colchicine, indicating strong and modest respective requirements for microfilaments and microtubules. We found no significant effect of the iron status of yersiniae or of the pigmentation locus on invasion and likewise no significant effect of the Yops regulon. However, an unidentified thermally induced property (possibly the Y. pestis-specific capsular protein Caf1) did inhibit invasiveness significantly, and the plasmid pPCP1, unique to Y. pestis, was essential for highly efficient invasion. pPCP1 encodes an invasion-promoting factor and not just an adhesin, because Y. pestis lacking this plasmid still adhered to HeLa cells. These studies have enlarged our picture of Y. pestis biology and revealed the importance of properties that are unique to Y. pestis.
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PMID:Invasion of epithelial cells by Yersinia pestis: evidence for a Y. pestis-specific invasin. 1089 51

tert-Butyl hydroperoxide (TBHP) mobilizes arachidonic acid (AA) from membrane phospholipids in rat hepatocytes under cytotoxic conditions, thus leading to an increase in intracellular AA, which precedes cell death. In the present work, the involvement of lipid peroxidation, thiol status, and reactive oxygen species (ROS) in the intracellular AA accumulation induced by 0.5 mM TBHP was studied in rat hepatocytes. Cells treated with TBHP maintained viability and energy status at 10 min. However, TBHP depleted GSH, as well as inducing lipid peroxidation and ROS formation, detected by dichlorofluorescein (DCF) fluorescence. TBHP also significantly increased (32.5%) the intracellular [14C]-AA from [14C]-AA-labelled hepatocytes. The phospholipase A(2) (PLA(2)) inhibitor, mepacrine, completely inhibited the [14C]-AA response. The addition of antioxidants to the cell suspensions affected the TBHP-induced lipid response differently. The [14C]-AA accumulation correlated directly with ROS and negatively with endogenous GSH. No correlation between [14C]-AA and lipid peroxidation was found. Promethazine prevented lipid peroxidation and did not affect the [14C]-AA increase. We conclude that TBHP stimulates the release of [14C]-AA from membrane phospholipids through a PLA(2)-mediated mechanism. Endogenous GSH and ROS play a major role in this effect, while lipid peroxidation-related events are unlikely to be involved. Results suggest that specific ROS generated in iron-dependent reactions, different from lipid peroxyl radicals, are involved in PLA(2) activation, this process being important in TBHP-induced hepatocyte injury.
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PMID:tert-Butyl hydroperoxide-induced lipid signaling in hepatocytes: involvement of glutathione and free radicals. 1155 15

The proteinase inhibitor, type-1 plasminogen activator inhibitor (PAI-1), is a major regulator of the plasminogen activator system involved in plasmin formation and fibrinolysis. The present study explores the effects of intracellular iron on the expression of PAI-1 and associated cell-surface plasmin activity in human lung fibroblasts; and reports the presence of a novel iron-responsive protein. ELISA revealed a dose-dependent increase in PAI-1 antigen levels expressed in the conditioned medium of cells treated with deferoxamine, in the three cell lines studied. A concomitant increase in mRNA levels was also observed by Northern analyses. Presaturation with ferric citrate quenched the effect of deferoxamine. Experiments with transcription and translation inhibitors on TIG 3-20 cells demonstrated that intracellular iron modulated PAI-1 expression at the post-transcriptional level with the requirement of de-novo protein synthesis. Electrophoretic mobility shift assay and UV crosslinking assays revealed the presence of an approximately 81-kDa nuclear protein that interacted with the 3'-UTR of PAI-1 mRNA in an iron-sensitive manner. Finally, we demonstrated that the increased PAI-1 is functional in suppressing cell-surface plasmin activity, a process that can affect wound healing and tissue remodeling.
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PMID:Post-transcriptional regulation of plasminogen activator inhibitor-1 by intracellular iron in cultured human lung fibroblasts--interaction of an 81-kDa nuclear protein with the 3'-UTR. 1586 97

Poly(lactic acid) (PLA)-supported dibenzoylmethane (dbm) and corresponding metal complexes have potential applications as biomaterials and catalysts. Using hydroxyl-functionalized dbm (i.e., dbmOH) as the initiator and Sn(oct)2 as the catalyst, lactide ring-opening polymerizations were unexpectedly slow (6 h), and PDIs broadened when molecular weights >10 000 were targeted. Because interactions between the dbm ligand and Sn(oct)2 may be responsible for the diminished catalyst activity and molecular weight control, iron(III) was employed as a protecting group to form Fe(dbmOH)3. Shorter reaction times (10 min) were noted with this trifunctional metalloinitiator and Sn(oct)2, and higher molecular weights were achievable. Moreover, it was discovered that Fe(dbmOH)3 serves not only as an initiator but also as a catalyst and activating group for the polymerization. Even without the tin catalyst, iron-centered polymers with low PDIs (<1.1) were obtained within 10 min ( approximately 70% monomer conversion). The resulting Fe(dbmPLA)3 stars were demetalated by acid treatment to generate dbmPLA for subsequent coordination to other metals. To explore the scope of iron beta-diketonate complexes as catalysts, additional studies were performed with dbmOH and benzyl alcohol initiators using either iron tris(dbm) or iron tris(acac) (acac = acetylacetonate) as the catalyst. Here too, PLA products were obtained, and the iron catalysts were readily separated by treatment with aqueous HCl.
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PMID:Iron tris(dibenzoylmethane)-centered polylactide stars: multiple roles for the metal complex in lactide ring-opening polymerization. 1624 97

In this work, we describe an experimental investigation on the colloidal stability of suspensions of three kinds of particles, including magnetite, poly(lactic acid) (PLA), and composite core/shell colloids formed by a magnetite core surrounded by a PLA shell. The experiments were performed with dilute suspensions, so that recording the optical absorbance with time gives a suitable indication of the aggregation and sedimentation of the suspensions. The method allowed us to distinguish very accurately between the different surface and magnetic forces responsible for the structures acquired by particle aggregates. Thus, the pure PLA suspensions are very sensitive to ionic strength and almost unaffected by pH changes. On the contrary, the stability of magnetite systems is mainly controlled by pH. The effect of vertical magnetic fields on the stability of magnetite and magnetite/PLA suspensions is also investigated. The PLA shell reduces the magnetic responsiveness of magnetite, but it is demonstrated that the mixed particles can also form structures induced by the field, despite their lower magnetization, and they can be considered in magnetically targeted biomedical applications.
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PMID:Colloidal stability of magnetite/poly(lactic acid) core/shell nanoparticles. 1651 88

In this work, magnetite (Fe(3)O(4)) nanoparticles with an average size 10 nm modified by sodium oleate were prepared by the modified controlled chemical coprecipitation method, which can be well dispersed in water and linked well with protein molecules because of the presence of -COOH on their surface. Then magnetic poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) microspheres containing interferon alpha-2b (IFN-a-2b) were prepared by the modified water-in-oil-in-water solvent evaporation procedure. X-ray powder diffraction analysis, particle size analysis, transmission electron microscopy, scanning electron microscopy, and vibrating-sample magnetometer (VSM) analysis were carried out to examine phase composition, surface and interior morphology, size and size distribution, and magnetic properties of the magnetic microspheres. Also the effects of some important parameters on the magnetic biodegradable microspheres were investigated, such as magnetite dosage in the preparation system, stirring rate of the suspension medium, and concentration of the external aqueous phase. And the antiviral activity of IFN-a-2b encapsulated in the magnetic polymeric microspheres was evaluated by the vesicular stomatitis virus (VSV) cytopathicity inhibition assay. The results showed that the properties of IFN-loaded magnetic PLGA and PLA microspheres were better than the conventional protein-loaded polymeric microspheres, such as perfect magnetic properties, higher protein encapsulation efficiency, and less effect on the antiviral activity of protein. These indicated that the magnetic PLA and PLGA microspheres containing IFN-a-2b exhibited strong potential as targeted-drug delivery vehicles, which could be rapidly localized to the immunization-related tissues easily by an external magnetic field.
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PMID:Preparation and characterization of interferon-loaded magnetic biodegradable microspheres. 1843 13

We have earlier reported that the redox-active antioxidant, vitamin C (ascorbic acid), activates the lipid signaling enzyme, phospholipase D (PLD), at pharmacological doses (mM) in the bovine lung microvascular endothelial cells (BLMVECs). However, the activation of phospholipase A(2) (PLA(2)), another signaling phospholipase, and the modulation of PLD activation by PLA(2) in the ECs treated with vitamin C at pharmacological doses have not been reported to date. Therefore, this study aimed at the regulation of PLD activation by PLA(2) in the cultured BLMVECs exposed to vitamin C at pharmacological concentrations. The results revealed that vitamin C (3-10 mM) significantly activated PLA(2) starting at 30 min; however, the activation of PLD resulted only at 120 min of treatment of cells under identical conditions. Further studies were conducted utilizing specific pharmacological agents to understand the mechanism(s) of activation of PLA(2) and PLD in BLMVECs treated with vitamin C (5 mM) for 120 min. Antioxidants, calcium chelators, iron chelators, and PLA(2) inhibitors offered attenuation of the vitamin C-induced activation of both PLA(2) and PLD in the cells. Vitamin C was also observed to significantly induce the formation and release of the cyclooxygenase (COX)- and lipoxygenase (LOX)-catalyzed arachidonic acid (AA) metabolites and to activate the AA LOX in BLMVECs. The inhibitors of PLA(2), COX, and LOX were observed to effectively and significantly attenuate the vitamin C-induced PLD activation in BLMVECs. For the first time, the results of the present study revealed that the vitamin C-induced activation of PLD in vascular ECs was regulated by the upstream activation of PLA(2), COX, and LOX through the formation of AA metabolites involving oxidative stress, calcium, and iron.
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PMID:Redox-active antioxidant modulation of lipid signaling in vascular endothelial cells: vitamin C induces activation of phospholipase D through phospholipase A2, lipoxygenase, and cyclooxygenase. 1849 33

There are a number of therapies available to recanalize occluded arteries. However, even though proven beneficial, these approaches are not without significant shortcomings. Previous research showed that by encapsulating therapeutic thrombolytic enzymes in liposomic formulations, the reperfusion times in vivo were significantly lower than for administration of free thrombolytic. Like liposomes, biodegradable, diblock polymers of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) have been shown to have therapeutic benefit as delivery vehicles for a variety of drug delivery concepts. We report on new formulations based on tissue plasminogen activator (tPA) encapsulated in magnetic, PLA-PEG microcarriers. We studied the tPA encapsulation efficiency, loading, and release after varying the molecular weight of polymer, carrier size, tPA solution composition, and use of ultrasound to enhance release. We loaded 3.3-9.4wt% tPA and 12-17wt% magnetite into the carriers, depending on the exact formulation. The release of tPA was complete 20min after reconstitution. Ultrasound insonation failed to enhance tPA release rates in smaller carriers but significantly enhanced release in larger carriers. With these formulations, we should be able to achieve lytic concentrations if we can magnetically concentrate 5mg of carrier within about 11ml of blood volume near the clot.
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PMID:Encapsulation and release of plasminogen activator from biodegradable magnetic microcarriers. 1864 39

Acute liver failure (ALF) can be complicated by lung dysfunction. The aim of this study was to test the hypothesis that inhibition of oxidative stress through iron chelation with desferrioxamine (DFX) attenuates pulmonary injury caused by ALF. 14 adult female domestic pigs were subjected to surgical devascularisation of the liver and were randomised to a study group (DFX group, n = 7), which received post-operative intravenous infusion of DFX (14.5 mg x kg(-1) x h(-1) for the first 6 h post-operatively and 2.4 mg x kg(-1) x h(-1) until completion of 24 h), and a control group (n = 7). Post-operative lung damage was evaluated by histological and bronchoalveolar lavage fluid (BALF) analysis. DFX resulted in reduced BALF protein levels and tissue phospholipase (PL)A(2) activity. Plasma malondialdehyde and BALF nitrate and nitrite concentrations were lower, while catalase activity in the lung was higher after DFX treatment. PLA(2), platelet-activating factor acetylhydrolase and total cell counts in BALF did not differ between groups. Histological examination revealed reduced alveolar collapse, pneumonocyte necrosis and total lung injury in the DFX-treated animals. DFX reduced systemic and pulmonary oxidative stress during ALF. The limited activity of PLA(2) and the attenuation of pneumonocyte necrosis could represent beneficial mechanisms by which DFX improves alveolar-capillary membrane permeability and prevents alveolar space collapse.
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PMID:Desferrioxamine attenuates minor lung injury following surgical acute liver failure. 1904 11


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