Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This investigation demonstrates the use of substitution-inert metal ions as site-specific amino acid modifying reagents. The approach involves the production of a chelating agent at the site of interest with the subsequent in situ oxidation of substitution-labile cobalt(II) to exchange-inert cobalt(III) with H2O2. We have produced the chelate complex ethylenediamine-N,N'-diacetato(arsanilazotyrosinato-248 carboxypeptidase A)cobalt(III) [CoIII(EDDA)(AA-CPA-Zn)]. Model CoIII(EDDA)(azophenolate) complexes have helped to define the reaction conditions necessary to produce the enzyme derivative and have proved invaluable in the spectral analysis of the cobalt(III)-enzyme complex. The modified enzyme contains one active-site zinc and one externally bound cobalt per enzyme monometer. Circular dichroism and visible spectra of the derivative and apoenzyme substantiate the site-specific nature of the incorporation. Concimitant with CoIIIEDDA incorporation, the enzyme loses its peptidase activity yet maintains with FeIIEDTA returns the original properties of the arsanilazotyrosine-248 enzyme.
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PMID:Development of a method for the incorporation of substitution-inert metal ions into proteins. Site-specific modification of arsanilazotyrosine-248 carboxypeptidase A with cobalt(III). 4 71

Cyclosporin A (CsA) is a potent inhibitor of cytokine (IL-2-IL-6, IFN gamma) production by CD4+ T lymphocytes stimulated via the T cell antigen receptor pathway. This action results in indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). Using experimental models, it has also been shown that the functional activities of mononuclear phagocytes (IFN-gamma) and other antigen-presenting cells, production of mast cells (IL-3) and eosinophils (IL-5) and the activity of natural killer (NK) cells may be inhibited indirectly by CsA. In addition, however, CsA blocks B cell responses to Ca(2+)-dependent signals (e.g., anti-IgM) downstream of phosphatidyl inositol diphosphate hydrolysis; Ca(2+)-independent responses (e.g., to LPS or IL-4) are largely unaffected. In general terms, the functions of macrophages are unchanged or reduced in the presence of CsA. These include phagocytic activity in vitro and in vivo, chemotactic migration, superoxide and H2O2 production, protein (including monokine) secretion and MHC gene product expression. Antigen presentation (e.g., by epidermal Langerhans cells) may be affected, especially at high drug concentrations. There is recent evidence that CsA inhibits mediator (histamine and prostaglandin) release from human mast cells and that mucosal mast cell numbers may be diminished in CsA-treated animals exhibiting graft-versus-host disease or helminth infections.
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PMID:The effects of cyclosporin A on non-T cell components of the immune system. 150 9

Alveolar macrophages (AMs) and mast cells reside in the airway, and both have been demonstrated to contribute independently to allergic inflammatory responses through the generation of respiratory-burst metabolites and the release of biologically active mediators, respectively. Since mast cell granules (MCGs) contain mediators that could potentially interact with the AM respiratory burst, we investigated the effects of isolated MCGs on this important inflammatory pathway of the AM. MCGs and AMs were obtained by peritoneal and tracheoalveolar lavage, respectively, of Sprague-Dawley rats. First, the overall respiratory-burst activity was measured by luminal-enhanced chemiluminescence (CL), and second, the individual oxygen species contributing to CL (superoxide anion [O2-], hydrogen peroxide [H2O2], and hypochlorous acid) were measured. MCGs alone enhanced AM CL responses to an equivalent degree compared to zymosan-stimulated AMs. However, AMs preincubated with MCGs followed by zymosan stimulation significantly and synergistically enhanced the CL responses. This enhanced CL was not due to an increased production of O2-, H2O2, or hypochlorous acid; in fact, there were decreased measured amounts of O2- and H2O2 from zymosan-stimulated AMs in the presence of MCGs, most likely caused by the content of granules of superoxide dismutase and peroxidase, respectively. The lipoxygenase inhibitor, nordihydroguaiaretic acid, completely abolished the enhanced CL of AM preincubated with MCGs and subsequently stimulated by zymosan, but O2- production was not affected by nordihydroguaiaretic acid. Taken together, these results suggest that derivatives of arachidonic acid metabolism, most likely those of the lipoxygenase pathway, are responsible for the enhanced AM CL response observed in the presence of MCGs. Thus, mast cell-macrophage interactions may be important within the airway in enhancing the generation of mediators that contribute to tissue inflammation and bronchospasm.
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PMID:Mast cell granules modulate alveolar macrophage respiratory-burst activity and eicosanoid metabolism. 217 47

Mast cells, when incubated in vitro with hydrogen peroxide (H2O2) and iodide, are cytotoxic to schistosomula of Schistosoma mansoni, as determined morphologically by dye exclusion, motility, and refractility and by transmission and scanning electron microscopy. When intact mast cells were incubated with schistosomula, mast cell degranulation with extracellular release of mast cell granules (MCG) was only observed in the presence of added H2O2 (10(-4) M). The secreted MCG, which contain small amounts of endogenous peroxidase activity, adhered to the surface of schistosomula. By 15 to 30 min, the mast cell-H2O2 system in the presence of iodide (10(-4) M) produced marked disruption of the tegumental and internal structures of the schistosomula. No helminthic damage was noted if any component of the incubation mixture (mast cells, H2O2 or iodide) was omitted. MCG could substitute for intact mast cells in the H2O2 and iodide-dependent cytotoxic system; MCG-mediated killing of schistosomula was inhibited by the hemeprotein inhibitor azide, suggesting that the cytotoxic reaction required endogenous peroxidase. The cytotoxicity was increased by eosinophil peroxidase bound to the MCG surface. These findings suggest a mechanism by which mast cells may contribute to the host cytotoxic response to helminths. H2O2 formed by nearby inflammatory cells may induce mast cell secretion, and the released MCG, through their endogenous peroxidase content (or bound eosinophil or neutrophil peroxidase), may react with H2O2 and a halide to form a system toxic to the adjacent helminth.
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PMID:Mast cell-mediated toxicity to schistosomula of Schistosoma mansoni: potentiation by exogenous peroxidase. 242 71

Cutaneous mast cell degranulation in rats results in tissue inflammation, and this species has therefore provided a useful model to study the pathogenesis of late phase reactions (LPRs). The mast cell dependency of LPRs has been confirmed by the demonstration that isolated rat mast cell granules (MCGs), when injected intradermally into rat skin, induce patterns of tissue inflammation similar to those seen after skin testing with anti-IgE antibody. Rat LPRs are neutrophil dependent, and, further, MCG-derived inflammatory factors can chemically attract rat neutrophils in vitro. To further study the relationships among MCGs, tissue inflammation, and neutrophil function, luminol-dependent chemiluminescence (CL) responses of rat peritoneal-elicited neutrophils in response to opsonized zymosan and phorbol myristate acetate (PMA) in the presence and absence of MCGs were analyzed. When MCGs (1.0, 10, and 100 micrograms/ml) alone were added to neutrophil suspensions, a rapid concentration-dependent increase in baseline CL responses was observed; these increases (maximum of sixfold) were modest, varied with cell concentrations, and followed different time courses compared with those seen after addition of preopsonized zymosan (0.5 mg/ml) (50-fold increases that peaked in 4 to 8 minutes). However, if neutrophils were preincubated (15 minutes) in the presence of MCGs, the CL response to opsonized zymosan (1.25 mg/ml) was significantly and synergistically enhanced compared with the response seen with MCGs alone. Similar but less pronounced effects were also noted after cell activation with PMA (2.5 and 25 ng/ml). To determine which component of the MCG was responsible for this enhancing activity, additional experiments were performed. Enhancement was still observed, albeit less intense, if MCGs were prepared membrane free and washed free of readily dissociable mediators such as histamine. Histamine (10(-6) and 10(-5) mol/L) had no enhancing effect nor did preparations of MCG membranes. MCG solubilization (3 mol/L NH4HCO3) revealed that the enhancing activity resided completely in the high molecular weight (greater than 10,000 daltons) fraction. Heat treatment of the granules and sodium azide preincubation completely abolished the enhancing effect. Exogenous horseradish peroxidase, at peroxidase activity levels contained within the MCGs (1 x 10(-4) to 10(-2) U/ml), reproduced the enhancing effect. After opsonized zymosan activation, neutrophils generated less H2O2 and superoxide anion in the presence of MCGs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mast cell granule enhancement of neutrophil chemiluminescence responses. 334 48

Eosinophil peroxidase (EPO) at relatively low levels (4-30 mU), when supplemented with H2O2 and a halide, induced mast cell degranulation. Histamine release occurred without concomitant release of the cytoplasmic marker lactic dehydrogenase (LDH), and this, together with ultrastructural studies, indicated a noncytotoxic effect comparable with that induced by other mast cell secretagogues. At pH 7.4, iodide was effective at concentrations down to 10(-5) M, and although chloride alone was ineffective at 0.1 M, a combination of 0.1 M chloride and 10(-6) iodide could meet the halide requirement. Chloride alone was effective at pH 6.5 and 6.0. EPO could be replaced by myeloperoxidase. When the EPO level was increased to 100 mU, combination with H2O2- and iodide-induced cytotoxic histamine release as indicated by concomitant LDH release and ultrastructural evidence of cell disruption. This cytotoxic response reverted to a secretory one on the addition of albumin. Peroxidase was detected on the surface of extruded granules by diaminobenzidine cytochemistry. The mast cell granule (MCG)/EPO complex when supplemented with H2O2 and iodide was more effective than free EPO in the stimulation of mast cell secretion. The stimulation of mast cell mediator release by the EPO-H2O2-halide system and the formation of MCG/EPO complexes with augmented cytotoxic activity may influence the adjacent inflammatory response.
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PMID:Eosinophil peroxidase-induced mast cell secretion. 615 83

An intense and reproducible peroxidase staining in the cutaneous mast cells of two patients with systemic mast cell disease and urticaria pigmentosa is demonstrated at the ultrastructural level. This enzyme activity was demonstrated by use of a cytochemical technique employing 3,3'- diaminobenzicine (DAB) as an oxidizable substrate, after fixation by a tannic acid-aldehyde mixture. Enzyme activity was localized in the perinuclear cisterna and strands of endoplasmic reticulum. Granules appeared unreactive. This peroxidase activity appears sensitive to fixation by aldehydes; it is inhibited by 3-amino-1,2,4-triazole (AMT) and by lack of H2O2 or DAB in the incubation medium. These characteristics are fundamentally different from the peroxidase activity of basophils, and the demonstration of this enzyme is therefore not a further argument for a common ontogenetic origin of both cells. On the other hand, the cytochemical characteristics of this enzyme are very similar to those of platelet peroxidase (P-PO), which has been connected to the synthesis by platelets of prostaglandins. Since the mast cell is known to generate prostaglandins, the relationship between the enzyme described and prostaglandin synthesis by mast cells is discussed.
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PMID:Peroxidase activity in human cutaneous mast cells: an ultrastructural demonstration. 632 7

Eosinophil peroxidase (EPO) and to a lesser degree neutrophil peroxidase (myeloperoxidase, MPO) bound tightly to mast cell granules (MCG), particularly when the latter were depleted of histamine by suspension in physiologic salt solutions. The bound EPO was localized on the surface of the granule, and its dissociation required salt concentrations of high enough ionic strength (greater than 0.75 M) to solubilize the MCG matrix. Elution of MPO from the complex occurred at a lower salt concentration. The MCG/EPO complex retained the capacity of the isolated EPO to catalyze the iodination reaction when supplemented with iodide, H2O2, and a protein acceptor and to kill microorganisms when supplemented with H2O2 and a halide (iodide, chloride). Indeed, the MCG/EPO complex had significantly greater iodinating and bactericidal activity than the free enzyme when standardized to equal guaiacol units of peroxidase activity. Thus, in areas of inflammation where mast cells and phagocytic leukocytes coexist, there is the potential for the formation of active complexes extracellularly between mast cell granules and molecules such as EPO (or MPO) that can affect the inflammatory response.
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PMID:Binding of eosinophil peroxidase to mast cell granules with retention of peroxidatic activity. 698 10

Mast cells, when supplemented with H2O2 and iodide, are cytotoxic to mammalian tumor cells as determined by 51Cr release, and transmission and scanning electron microscopy. H2O2 at the concentration employed (10(-4) M) initiates mast cell degranulation, and mast cell granules (MCG), which contain a small amount of endogenous peroxidase activity, are toxic to tumor cells when combined with H2O2 and iodide. This toxicity is greatly increased by binding eosinophil peroxidase (EPO) to the MCG surface. Each component of the mast cell, MCG, or MCG-EPO system was required and toxicity was inhibited by the addition of the hemeprotein inhibitors azide or aminotriazole, which is compatible with a requirement for peroxidase in the cytotoxic reaction. A sequence of reactions is proposed in which mast cells, stimulated to release their granules by H2O2 generated by adjacent phagocytes, react with H2O2 and a halide to damage tumor cells. EPO release from eosinophils may contribute to this sequence of reactions, both by stimulation of H2O2-induced mast cell secretion and by combination with MCG to form a complex with augmented tumoricidal activity. These rections may play a role in the host defense against neoplasms.
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PMID:Mast cell-mediated tumor-cell cytotoxicity. Role of the peroxidase system. 725 7

Human LDLs oxidized with Cu2+ are known to promote leukocyte-endothelial cell adhesion (LECA) and albumin leakage in postcapillary venules. The objective of this study was to compare the ability of LDL oxidized with Cu2+ (Cu-LDL), phospholipase A2 plus lipoxygenase (PLA2-LDL), horseradish peroxidase plus H2O2 (HRP-LDL), or -OCl (-OCl-LDL) to promote (1)neutrophil-endothelial cell adhesion (NECA) in vitro and (2)LECA and albumin leakage in rat mesenteric venules. In vitro adhesion assays revealed that only Cu-LDL elicited a dose-dependent NECA response, whereas PLA2-LDL but not normal (N-LDL), HRP-LDL, or -OCl-LDL increased NECA at the highest concentration studied (670 micrograms/mL). The magnitude of the NECA responses elicited by the different forms of oxidized LDL was related to the degree of lipid peroxidation but unrelated to the level of protein oxidation. Local intra-arterial infusion of Cu-LDL, PLA2-LDL, or -OCl-LDL but not N-LDL elicited significant increases in leukocyte adherence and emigration, mast cell degranulation, and albumin leakage in rat mesenteric venules. The LECA induced by all forms of oxidized LDL was not accompanied by significant alterations of venular shear rate.
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PMID:Oxidized LDL-induced microvascular dysfunction. Dependence on oxidation procedure. 748 57


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