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At least 199 records · Page 11Linked to original sources

PubMed2001

EtMIC4: a microneme protein from Eimeria tenella that contains tandem arrays of epidermal growth factor-like repeats and thrombospondin type-I repeats.

Micronemes are specialised secretory organelles that release their proteins by a stimulus-coupled exocytosis that occurs when apicomplexan parasites make contact with target host cells. These proteins play crucial roles in motility and invasion, most likely by mediating adhesion between parasite and host cell surfaces and facilitating the transmission of dynamic forces generated by the parasite actinomyosin cytoskeleton. Members of the TRAP family of microneme proteins are characterised by having extracellular domains containing one or more types of cysteine-rich, adhesive modules, highly-conserved transmembrane regions and cytosolic tails that contain one or more tyrosines, stretches of acidic residues and a single tryptophan. In this paper, we describe a novel member of the TRAP family, EtMIC4, a 218 kDa microneme protein from Eimeria tenella. EtMIC4 contains 31 epidermal growth factor (EGF) modules, 12 thrombospondin type-1 (TSP-1) modules and a highly acidic, proline and glycine-rich region in its extracellular region, plus the conserved transmembrane and cytosolic tail. Like EtMIC1, another TRAP family member from E. tenella, EtMIC4 is expressed in sporozoites and all the merozoite stages of the parasite, suggesting that this parasite has a strong requirement for TSP-1 modules. Unlike the other microneme proteins so far studied in E. tenella, EtMIC4 appears to be found constitutively on the sporozoite surface as well as within the micronemes.

Amino Acid Sequence↗

PubMed2002

Cytokine traps: multi-component, high-affinity blockers of cytokine action.

Cytokines can initiate and perpetuate human diseases, and are among the best-validated of therapeutic targets. Cytokines can be blocked by the use of soluble receptors; however, the use of this approach for cytokines such as interleukin (IL)-1, IL-4, IL-6 and IL-13 that use multi-component receptor systems is limited because monomeric soluble receptors generally exhibit low affinity or function as agonists. We describe here a generally applicable method to create very high-affinity blockers called 'cytokine traps' consisting of fusions between the constant region of IgG and the extracellular domains of two distinct cytokine receptor components involved in binding the cytokine. Traps potently block cytokines in vitro and in vivo and represent a substantial advance in creating novel therapeutic candidates for cytokine-driven diseases.

Animals↗

PubMed1996

Morphogenesis of the lung: control of embryonic and fetal branching.

Lung development differs in the embryo and fetus with regard to branching pattern and organization of the epithelial cells. The surrounding mesodermal component, the capsule, has long been known to play a role in branching. As a result of recent analyses of distribution of components of the extracellular matrix coupled with interference with their expression, we are beginning to understand how branching is controlled. Insoluble macromolecules of the basal lamina and deeper extracellular matrix may act as physical barriers or traps to sequester soluble components. The soluble growth factors activate genes regulating cell proliferation.

Animals↗

PubMed2006

Fluorescence labelling of phosphatase activity in digestive glands of carnivorous plants.

A new ELF (enzyme labelled fluorescence) assay was applied to detect phosphatase activity in glandular structures of 47 carnivorous plant species, especially Lentibulariaceae, in order to understand their digestive activities. We address the following questions: (1) Are phosphatases produced by the plants and/or by inhabitants of the traps? (2) Which type of hairs/glands is involved in the production of phosphatases? (3) Is this phosphatase production a common feature among carnivorous plants or is it restricted to evolutionarily advanced species? Our results showed activity of the phosphatases in glandular structures of the majority of the plants tested, both from the greenhouse and from sterile culture. In addition, extracellular phosphatases can also be produced by trap inhabitants. In Utricularia, activity of phosphatase was detected in internal glands of 27 species from both primitive and advanced sections and different ecological groups. Further positive reactions were found in Genlisea, Pinguicula, Aldrovanda, Dionaea, Drosera, Drosophyllum, Nepenthes, and Cephalotus. In Utricularia and Genlisea, enzymatic secretion was independent of stimulation by prey. Byblis and Roridula are usually considered as "proto-carnivores", lacking digestive enzymes. However, we found high activity of phosphatases in both species. Thus, they should be classified as true carnivores. We suggest that the inflorescence of Byblis and some Pinguicula species might also be an additional "carnivorous organ", which can trap a prey, digest it, and finally absorb available nutrients.

Animals↗

PubMed1985

Potentiation of antimetabolite action by uridylate trapping.

Uridylate-trapping analogs of D-galactose or D-glucose divert the uridylate moiety of UDPglucose and/or UTP to UDP-sugar analogs that accumulate while the pools of UTP and of related pyrimidine nucleotides are depleted. The uridylate-trapping action of sugar analogs is determined by the enzyme pattern of the target tissue. D-Galactose analogs are preferentially metabolized by hepatoma cells and hepatocytes. TA3-mammary tumor cells are susceptible to the action of D-glucosamine and other D-glucose analogs. A high rate of de novo pyrimidine synthesis and/or an active salvage of extracellular uridine compensate for the uridylate-trapping action of sugar analogs and prevent depletion of UTP pools. Accordingly, synergistic actions are induced by combining sugar analogs, such as D-galactosamine or D-glucosamine, with inhibitors of de novo pyrimidine synthesis, such as lapachol or 6-azauridine. Uridylate-trapping by D-galactosamine, acting on hepatocytes, shifts the balance between uridine consumption and uridine release by the liver and results in a fall of uridine and cytidine concentrations in blood plasma (20). Cultured hepatocytes produce uridine and cytidine. Combination of 5-fluorouridine with sugar analogs results in the formation of fluorinated UDP-sugar analogs in hepatoma cells or in mammary tumor cells. Formation of FUDP-sugar analogs transiently removes intracellular FUTP, but FUDP can be released subsequently in glycosyltransferase reactions (22). Pretreatment of hepatoma cells or of TA3-mammary tumor cells with an uridylate-trapping sugar analog in combination with an inhibitor of de novo pyrimidine synthesis enhances the uptake of 5-fluorouridine, its incorporation into RNA, and its growth inhibitory effect. The chemotherapeutic action of 5-fluorouridine in rats and mice, carrying the AS-30D and the TA3 ascites tumor, respectively, is significantly improved by pretreatment with an amino sugar together with 6-azauridine.

Amino Sugars↗

PubMed1997

Reduction of histone cytotoxicity by the Alzheimer beta-amyloid peptide precursor.

In a search for Alzheimer beta-amyloid peptide precursor ligands, Potempska et al. (Arch. Biochem. Biophys. (1993) 304, 448) found that histones bind with high affinity and specificity to the secreted precursor. Because exogenous histones can be cytotoxic, we compared the effects of histones on the viability of cells which produce little beta-amyloid peptide precursor (U-937) to those on cells that produce twenty times as much precursor (COS-7). Addition of purified histones caused necrosis of U-937 cells (histone H4, LD50 = 1.5 microM). Extracellular A beta precursor in the submicromolar range prevented histone-induced U-937 cell necrosis. Cell-surface precursor also reduced histone toxicity: COS-7 cells were less sensitive to the toxic effects of histone H4 (LD50 = 5.4 microM). COS-7 cells in which the expression of an APP mRNA-directed ribozyme reduced the synthesis of the protein by up to 80% were more sensitive to histone H4 (LD50 = 3.2 microM) than cells that expressed the vector alone. Histone H4 binds to cell-associated A beta precursor. Cells expressing the A beta precursor-directed ribozyme bound less 125I-labeled histone H4 than those expressing the vector alone. In the limited extracellular space of tissues in vivo, both secreted and cell-surface A beta precursor protein may play significant roles in trapping chromatin or histones and removing them from the extracellular milieu.

Amyloid beta-Protein Precursor↗

PubMed2002

Molecular rearrangements of the extracellular vestibule in NMDAR channels during gating.

Many N-methyl-D-aspartate receptor (NMDAR) channel blockers that have therapeutic potential can be trapped in the closed state. Using a combination of the substituted cysteine accessibility method and open channel blockers, we found that the M3 segment forms the core of the extracellular vestibule, including a deep site for trapping blockers. The M3 segment, as well as more superficial parts of the extracellular vestibule, undergo extensive remodeling during channel closure, but do not define the activation gate, which is located deeper in the pore. Rather, the pore walls lining the extracellular vestibule constrict during channel closure. This movement is essential for coupling ligand binding to activation gate opening and accounts for the different mechanisms of open channel block, including trapping.

Aminacrine↗

PubMed1992

Spin-trapping of free radicals during phthalocyanine photosensitization of lymphoma cells in vitro.

Spin-trapping and electron spin resonance (ESR) spectroscopy were used to detect free radicals generated during light exposure of lymphoma cells sensitized in vitro by metallotetrasulfophthalocyanines (Al-PcS4 and Zn-PcS4). 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) and alpha-phenyl-beta-tert-butylnitrone (PBN) were used as spin-trapping agents. Hydroxyl radical spin-adducts were detected under conditions of both extracellular and intracellular photosensitization. In addition, organic radicals of different origin and/or variable yields were trapped, depending on the photosensitization conditions and the spin-trap used. For comparison, analogous experiments were carried out with another tumor-localizing photosensitizer, Photofrin II.

Burkitt Lymphoma↗

PubMed2005

Complement dependent trapping of infectious HIV in human lymphoid tissues.

OBJECTIVES: HIV-1 bound extracellularly to follicular dendritic cells (FDC) in germinal centers (GC) of lymphoid tissues (LT) represents the largest viral reservoir in HIV-infected individuals; however there is no direct evidence as to whether HIV trapped in human GC remains infectious. In the GC, complement receptors and Fc gamma receptors have been suggested to participate in trapping of HIV; therefore, the relative contribution of complement- and Fc gamma receptors in binding HIV on LT was investigated and the infectivity of this virus was tested. DESIGN: As it is difficult to isolate FDC without contaminations of productively infected cells, HIV was detached from LT of HIV positive individuals using antibodies blocking complement- and Fc gamma receptors. Isolated virus was tested in an infectivity assay. METHODS: HIV detached from LT was quantified by HIV p24 ELISA, PCR and in an in vitro infectivity assay. Presence and accessibility of viral envelope proteins, complement factors and immunoglobulins on the surface of detached viral particles were evaluated through viral capture by respective antibodies. RESULTS: Although both C3d-fragments and IgG molecules were identified on the surface of HIV detached from LT, trapping of HIV was mediated solely by CR2-C3d interactions, whereas contribution of Fc gamma receptors was not detectable. Infectivity assays with HIV stripped from LT of HIV positive individuals revealed that in four out of ten patients HIV particles were infectious. CONCLUSIONS: These findings indicate that in the GC infectious virus is trapped on CR2-expressing FDC (or B cells). Reduction of this pool of HIV could be a therapeutic goal.

Cells, Cultured↗

PubMed2004

Characterization of covalently inhibited extracellular lipase from Streptomyces rimosus by matrix-assisted laser desorption/ionization time-of-flight and matrix-assisted laser desorption/ionization quadrupole ion trap reflectron time-of-flight mass spectrometry: localization of the active site serine.

A chemical modification approach combined with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry was used to identify the active site serine residue of an extracellular lipase from Streptomyces rimosus R6-554W. The lipase, purified from a high-level overexpressing strain, was covalently modified by incubation with 3,4-dichloroisocoumarin, a general mechanism-based serine protease inhibitor. MALDI time-of-flight (TOF) mass spectrometry was used to probe the nature of the intact inhibitor-modified lipase and to clarify the mechanism of lipase inhibition by 3,4-dichloroisocoumarin. The stoichiometry of the inhibition reaction revealed that specifically one molecule of inhibitor was bound to the lipase. The MALDI matrix 2,6-dihydroxyacetophenone facilitated the formation of highly abundant [M + 2H](2+) ions with good resolution compared to other matrices in a linear TOF instrument. This allowed the detection of two different inhibitor-modified lipase species. Exact localization of the modified amino acid residue was accomplished by tryptic digestion followed by low-energy collision-induced dissociation peptide sequencing of the detected 2-(carboxychloromethyl)benzoylated peptide by means of a MALDI quadrupole ion trap reflectron TOF instrument. The high sequence coverage obtained by this approach allowed the confirmation of the site specificity of the inhibition reaction and the unambiguous identification of the serine at position 10 as the nucleophilic amino acid residue in the active site of the enzyme. This result is in agreement with the previously obtained data from multiple sequence alignment of S. rimosus lipase with different esterases, which indicated that this enzyme exhibits a characteristic Gly-Asp-Ser-(Leu) motif located close to the N-terminus and is harboring the catalytically active serine residue. Therefore, this study experimentally proves the classification of the S. rimosus lipase as GDS(L) lipolytic enzyme.

Amino Acid Sequence↗

PubMed1994

Antioxidant potential of anaerobic human plasma: role of serum albumin and thiols as scavengers of carbon radicals.

Extracellular fluids contain low-molecular-weight antioxidants that are actively involved in the defense against reactive oxygen species. The antioxidant activity of these compounds is largely due to their ability to trap oxygen radicals. Less known is the ability of extracellular antioxidants to scavenge carbon-centered free radicals (C-radicals). These radicals can be involved in the damage under hypoxic/anoxic conditions as well as in ischemia/reperfusion injury. We studied the reactivity of some plasma antioxidants toward a water-soluble C-radical generated by the azocompound 2,2'-azobis(2-amidinopropane) hydrochloride (AAP) under anaerobic conditions. The AAP C-radical in plasma was trapped by the spin trap 3,5-dibromo-4-nitrosobenzene-sulfonic acid (DBNBS) and produced a DBNBS radical. The scavenging properties of urate, cysteine, glutathione, natural amino acids, and serum albumin were assessed by the inhibition of the intensity of DBNBS radical. The antioxidant activity of ascorbate and that of vitamin E was measured directly by the formation of their free radicals. Urate, vitamin E and non-SH amino acids were ineffective and ascorbate was a poor scavenger of AAP C-radical. At variance, cysteine and glutathione (0.1-1.0 mM) were effective scavengers of AAP C-radicals and, importantly, protected plasma ascorbate from oxidation under both aerobic or anaerobic conditions. Our data show that ascorbate in aerobic plasma can reduce vitamin E radical and the oxidized ascorbate may be recycled by a thiol antioxidant cycle. Low-molecular-weight antioxidants accounted only partially for plasma scavenging activity of C-radicals. Plasma strongly reduced the intensity of DBNBS radical and, after dialysis, its activity was reduced by approximately 10%. Serum albumin showed an antioxidant activity comparable to dialyzed plasma. Also the cysteine residue of serum albumin was an efficient scavenger of C-radicals as shown by approximately 20% decrease in the protein scavenging activity after thiol alkylation. These results suggest that elevation in the concentration of total reduced thiols in plasma may improve its antioxidant activity under hypoxic/anoxic conditions. This may be particularly useful since other important antioxidant mechanisms such as urate, ascorbate, and vitamin E appear to be inefficient.

Aerobiosis↗

PubMed2005

Right time, right place: the organization of membrane proximal signaling.

The basic mechanisms of lymphocyte activation are well established, with stimulation via the antigen receptor inducing a rapid wave of tyrosine phosphorylation that requires the coordinated action of multiple protein tyrosine kinase families. This in turn leads to the generation of second messengers like Ca(2+), diacylglycerol (DAG) and inositoltrisphosphate (IP(3)) as well as the activation of effector molecules like Ras and the mitogen-activated protein kinases (MAPKs) and ultimately in activation of the transcription factors NFAT, AP-1, and NF-kappaB, resulting in gene transcription. Researchers, hoping to interconnect these events, have identified a multitude of proteins, among which is a relatively new group, the transmembrane adaptor proteins (TRAPs). TRAPs are unique in that they lack extracellular ligands and possess neither enzymatic nor transcriptional activity, but rather serve as scaffolds providing docking sites for other proteins and thereby serving to coordinate signals proximal to the membrane. Our study of these novel molecules is shedding new insights into the positive and negative regulatory mechanisms which fine tune antigen receptor signaling.

Cell Membrane↗

PubMed2003

Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents.

Ion-trapping theory predicts that alkalinization of tumor extracellular pH will enhance the anti-tumor activity of weak-base chemotherapeutics. We have previously demonstrated that chronic and acute treatment of tumor-bearing mice with sodium bicarbonate results in tumor-specific alkalinization of extracellular pH. Furthermore, bicarbonate pretreatment enhances the anti-tumor activity of doxorubicin and mitoxantrone in two different mouse tumor models. Previous work has indicated subtle, yet significant differences between the pH sensitivities of the biodistribution and anti-tumor efficacies of doxorubicin and mitoxantrone in vitro. The present study demonstrates that systemic alkalinization selectively enhances tumor uptake of radiolabeled mitoxantrone, but not doxorubicin. Results using these two drugs are quantitatively and qualitatively very different, and can be explained on the basis of differences in the octanol-water partition coefficients of their charged forms. These results suggest that inducing metabolic alkalosis in patients would have a positive effect on response to mitoxantrone therapy. However, the therapeutic index would not increase if sodium bicarbonate also caused increased retention of mitoxantrone in susceptible normal tissues in the host. The major dose-limiting organ systems for mitoxantrone are heart, liver, bone marrow, spleen and blood cells. Bicarbonate was found to have no significant effect on the distribution of mitoxantrone to any of these tissues except for spleen. However, neither spleen weights nor lymphocyte counts were adversely affected by NaHCO(3) pretreatment, indicating that this co-therapy does not enhance myelosuppression due to mitoxantrone therapy. These findings suggest that metabolic alkalosis would produce a net gain in mitoxantrone therapeutic index.

Animals↗

PubMed2002

Bacteroides fragilis adherence to Caco-2 cells.

The ability of ten Bacteroides fragilis strains isolated from intestinal and non-intestinal infections, normal flora and environment to adhere to human colon carcinoma cells, Caco-2, was examined. The adherence capacity varied among the strains tested from strongly adherent (76-100%) to non- or weakly adherent (0-25%). Negative staining with Indian ink showed that all the strains were capsulated, although strain 1032 (strongly adherent and originated from bacteremia) had the highest rate of capsulated cells in the culture. All strains studied presented an electron-dense layer and no fimbrial structures in their surface after PTA negative staining. The analysis of the strains with ruthenium red showed the presence of an acidic polysaccharide and also surface vesicles in all of them. The strain 1032 presented an aggregative adherence pattern toward Caco-2 cells monolayers. It could be seen trapped by elongated microvilli and surrounded by extracellular material in the scanning electron microscope. Treatment with sodium periodate (100 mM/1 h) reduced significantly its adherence capacity and also the expression of an electron-dense layer and of the capsule, detected with PTA and Indian ink staining, respectively. We suggest that the capsular polysaccharide might mediate the adherence of the B. fragilis to Caco-2 cells.

Journal Article↗

PubMed1991

Nitric and nitrous oxide reductases are active under aerobic conditions in cells of Thiosphaera pantotropha.

Use of Clark-type electrodes has shown that, in cells of Thiosphaera pantotropha, the nitrous oxide reductase is active in the presence of O2, and that the two gases involved (N2O, O2) are reduced simultaneously, but with mutual inhibition. Reduction of nitrate, or nitrite, to N2O under aerobic conditions involves NO as an intermediate, as judged by trapping experiments with the ferric form of extracellular horse heart cytochrome c and the demonstration that the cells possess a nitric oxide reductase activity. The overall conversion of nitrate to N2, the process of denitrification, under aerobic conditions, is thus not prevented by reaction of NO with O2 and depends upon a nitrous oxide reductase system which differs from that in other organisms by being neither directly inhibited nor inactivated by O2.

Aerobiosis↗

PubMed2000

The effect of alpha-phenyl-tert-butyl nitrone (PBN) on free radical formation in transient focal ischaemia measured by microdialysis and 3,4-dihydroxybenzoate formation.

alpha-phenyl-tert-butyl nitrone (PBN) reduces infarct size, improves recovery of brain energy metabolism and delays the secondary increase in extracellular potassium after focal ischaemia, presumably by trapping OH radicals. We investigated the effect of PBN on the formation of 3,4-dihydroxybenzoic acid (3,4-DHBA) as a measure of OH radical formation, during and following middle cerebral artery occlusion (MCAO). Rats, subjected to 2 h of ischaemia followed by 3 h of recirculation, were injected with either vehicle or PBN (100 mg kg-1 i.p.) prior to MCAO or immediately after recirculation, respectively. The in vivo microdialysis technique was used to collect samples for analysis of 3,4-DHBA by HPLC. The basal levels of 3,4-DHBA were 56-77 nmol L-1 in the four groups. During ischaemia, the formation of 3,4-DHBA decreased by about 50% in all groups. Upon recirculation, a 3-fold rise in 3,4-DHBA formation was seen. At 2 h of recirculation the mean value of 3,4-DHBA in the pretreated, vehicle-injected animals was 125 +/- 18 nmol L-1 and in the PBN-injected 145 +/- 48 nmol L-1, respectively. When the animals were treated after MCAO either with vehicle or PBN the values at 2 h recirculation were 155 +/- 148 and 189 +/- 145 nmol L-1, respectively. No statistically significant difference between vehicle- and PBN-injected groups was seen. We conclude that during reperfusion following MCAO, hydroxyl radical formation increases. The increase is not ameliorated by PBN which suggests that PBN does not protect the brain by a general scavenging of OH radicals, although tissue specific actions cannot be excluded.

Animals↗

PubMed2000

Developmental arrest of the human malaria parasite Plasmodium falciparum within the mosquito midgut via CTRP gene disruption.

Apicomplexan protozoa possess a family of micronemal and cell surface-associated proteins, each comprised a combination of cell-adhesive vertebrate von Willebrand factor (vWF)-like A domains and thrombospondin (TSP) type 1-like domains. The human malaria parasite Plasmodium falciparum has in the extracellular portion of the CS protein TRAP-related protein (CTRP) six tandemly arrayed A domains followed by seven TSP type 1-like domains, whereas a second member of this family, thrombospondin-related anonymous protein (TRAP), contains a single vWF-like A domain and a single TSP type 1-like domain. Here we show that CTRP transcripts are present within the infected mosquito midgut and that CTRP protein is expressed with a punctate distribution and a predominance at the apical end of mosquito midgut-stage ookinetes. This expression pattern is analogous to micronemal expression of TRAP in Plasmodium sporozoites. Disruption of the CTRP gene by homologous recombination in cultures of the human malaria parasite P. falciparum demonstrates that CTRP is essential for mosquito midgut development. Oocyst formation was never observed following membrane feeds of CTRP disruptant lines to Anopheline mosquitoes, despite the development of mature ookinetes. We propose that CTRP is involved in essential recognition or motility processes at the ookinete cell surface within the mosquito midgut.

Animals↗

PubMed2006

Characterization of the Interleukin (IL)-6 Inhibitor IL-6-RFP: fused receptor domains act as high affinity cytokine-binding proteins.

Although fusion proteins of the extracellular parts of receptor subunits termed cytokine traps turned out to be promising cytokine inhibitors for anti-cytokine therapies, their mode of action has not been analyzed. We developed a fusion protein consisting of the ligand binding domains of the IL-6 receptor subunits IL-6Ralpha and gp130 that acts as a highly potent IL-6 inhibitor. Gp130 is a shared cytokine receptor also used by the IL-6-related cytokines oncostatin M and leukemia inhibitory factor. In this study, we have shown that the IL-6 receptor fusion protein (IL-6-RFP) is a specific IL-6 inhibitor that does not block oncostatin M or leukemia inhibitory factor. We characterized the complex of IL-6-RFP and fluorescently labeled IL-6 (YFPIL-6) by blue native PAGE and gel filtration. A 2-fold molar excess of IL-6-RFP over IL-6 was sufficient to entirely bind IL-6 in a complex with IL-6-RFP. As shown by treatment with urea and binding competition experiments, the complex of IL-6 and IL-6-RFP is more stable than the complex of IL-6, soluble IL-6Ralpha, and soluble gp130. By live cell imaging, we have demonstrated that YFP-IL-6 bound to the surface of cells expressing gp130-CFP is removed from the plasma membrane upon the addition of IL-6-RFP. The apparent molecular mass of the IL-6.IL-6-RFP complex determined by blue native PAGE and gel filtration suggests that IL-6 is trapped in a structure analogous to the native hexameric IL-6 receptor complex. Thus, fusion of the ligand binding domains of heteromeric receptors leads to highly specific cytokine inhibitors with superior activity compared with the separate soluble receptors.

Acute-Phase Reaction↗