Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Hydroxynonenal is a major product formed by lipid peroxidation from omega 6-polyunsaturated fatty acids as linoleic acid and arachidonic acid. This aldehyde is cytotoxic at high concentrations (in the range of 100 microM), disturbs cell proliferation at low concentrations and exhibits genotoxic effects. Furthermore, in the submicromolar range 4-hydroxynonenal is chemotactic and stimulates phospholipase C. 4-Hydroxynonenal is rapidly metabolized in eucaryotic cells. Here the metabolism of 4-hydroxynonenal was studied in suspensions of Ehrlich mouse ascites cells at different periods of the tumor age. The Ehrlich ascites tumor is a convenient biological model for the investigation of tumor cells in different age and proliferation phases of the tumor. The main products of 4-hydroxynonenal which were identified in the Ehrlich ascites cells were glutathione-HNE-conjugate, hydroxynonenoic acid and 1,4-dihydroxynonene. The formation of glutathione conjugates following the addition of 4-hydroxynonenal was higher in cells of the early phase in comparison with cells of the late phase of tumor growth. That was in accordance with the increased consumption of the reduced form of glutathione during 4-hydroxynonenal utilization. The degradation of 4-hydroxynonenal and other aldehydic products of lipid peroxidation is postulated to be an important part of the intracellular antioxidative defense system.
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PMID:The metabolism of 4-hydroxynonenal, a lipid peroxidation product, is dependent on tumor age in Ehrlich mouse ascites cells. 145 May 80

Polymorphonuclear leukocytes (PMNs) exert most of their physiological functions while adherent to surfaces rather than in suspension. PMN adhesion is largely dependent on the function of the beta 2 integrins, CD11a,b,c/CD18. We mimicked engagement of beta 2 integrins by antibody cross-linking of CD18 on isolated human PMNs using both intact monoclonal antibody and F(ab')2 fragments. Within seconds of CD18 cross-linking, we observed a significant, transient rise of intracellular free Ca2+ concentration by 200-300 nM, which was largely due to Ca2+ mobilization from intracellular stores. The Ca2+ signal was blocked after pretreatment with phorbol myristate acetate, an activator of protein kinase C, but not with herbimycin A, a potent inhibitor of tyrosine kinases. In addition to the rise of intracellular free Ca2+ concentration, CD18 cross-linking induced exocytosis of azurophilic granules (release of 26% of total PMN elastase), which was significantly inhibited by herbimycin A. Moreover, 2.2-fold up-regulation of CD18 antigen and significant down-regulation of surface expression of the granulocyte adhesion molecule L-selectin were induced. Granulocyte F-actin content as measured by nitrobenzoxadiazole-phallacidin increased significantly 1 min after CD18 cross-linking. By contrast, CD18 cross-linking by soluble antibodies did not induce superoxide production, but PMNs bound to immobilized monoclonal antibodies against CD18 released significant amounts of superoxide. Initial signaling through beta 2 integrins does not appear to be mediated by a phospholipase C isoform activated through tyrosine phosphorylation, because the Ca2+ signal was not altered by herbimycin A. However, more complex cellular responses including exocytosis were found to require tyrosine phosphorylation. We show that engagement of beta 2 integrins provides an important stimulatory signal to PMNs inducing degranulation, modulation of L-selectin, and cytoskeletal changes.
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PMID:Cross-linking of CD18 in human neutrophils induces an increase of intracellular free Ca2+, exocytosis of azurophilic granules, quantitative up-regulation of CD18, shedding of L-selectin, and actin polymerization. 752 20

Addition of micromolar concentrations of 4-hydroxynonenal (4-HNE), a reactive end-product of lipid peroxidation, to isolated rat hepatocytes was found to cause an early and transient increase in cytosolic Ca2+ concentration followed by a more pronounced and progressive elevation. Such a late effect of 4-HNE was prevented by chelation of extracellular Ca2+ with EGTA or by the addition of GdCl3, which is known to block the activity of store operated Ca2+ channels in the hepatocyte plasma membrane. Moreover, the preincubation of isolated hepatocytes with the phospholipase C inhibitor U73122 resulted in a complete inhibition of both the early increase of cytosolic Ca2+ and the subsequent Ca2+ inflow. When 4-HNE was added to the hepatocytes 5 min after the emptying of intracellular Ca2+ pools by thapsigargin, the aldehyde caused a further increase in the accumulation of Ca2+ which was prevented in the presence of GdCl3. Taken together these results indicate that in hepatocytes 4-HNE causes Ca2+ inflow across GdCl3-sensitive Ca2+ channels. The mechanism responsible for such an effect is triggered by the emptying of intracellular Ca2+ pools likely resulting from 4-HNE mediated stimulation of phospholypase C, but 4-HNE also appears to interfere with the channel protein(s) or with the mechanism(s) regulating capacitative Ca2+ inflow.
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PMID:4-Hydroxynonenal triggers Ca2+ influx in isolated rat hepatocytes. 857 89

The effect of sodium azide (NaN(3)) upon platelet Ca(2+) signalling has been investigated. A 60 s preincubation with 1 mM NaN(3) reduced the Ca(2+) response to 1 microM serotonin without a corresponding reduction in the responses to 52 mU/ml thrombin or 70 microM beta-amyloid(25-35) (A beta(25-35)). The effect of NaN(3) upon the response to serotonin, which was not blocked by either glutathione ethyl ester (GTEE) or dithiothreitol (DTT), was similar in platelets obtained from patients with Alzheimer's disease and from age- and gender-matched controls. After a preincubation time of 5 min was used, the Ca(2+) response to thrombin was greatly reduced by 1 mM NaN(3), but not by 50 microM 4-hydroxynonenal (HNE, 50 microM). Platelet levels of HNE and malondialdehyde were not significantly affected by up to 30 min of incubation with NaN(3) at room temperature. It is concluded that the rapid effect of NaN(3) upon the Ca(2+) response to serotonin in human platelets is not mediated by an inhibition of cytochrome c oxidase, and is due to an action proximal to phosphoinositide-specific phospholipase C.
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PMID:Rapid inhibition by sodium azide of the phosphoinositide-mediated calcium response to serotonin stimulation in human platelets: preservation in Alzheimer's disease. 1091 62

We have established that treatment of cultured human skin fibroblasts with tropoelastin or with heterogenic peptides, obtained after organo-alkaline or leukocyte elastase hydrolysis of insoluble elastin, induces a high expression of pro-collagenase-1 (pro-matrix metalloproteinase-1 (pro-MMP-1)). The identical effect was achieved after stimulation with a VGVAPG synthetic peptide, reflecting the elastin-derived domain known to bind to the 67-kDa elastin-binding protein. This clearly indicated involvement of this receptor in the described phenomenon. This notion was further reinforced by the fact that elastin peptides-dependent MMP-1 up-regulation has not been demonstrated in cultures preincubated with 1 mm lactose, which causes shedding of the elastin-binding protein and with pertussis toxin, which blocks the elastin-binding protein-dependent signaling pathway involving G protein, phospholipase C, and protein kinase C. Moreover, we demonstrated that diverse peptides maintaining GXXPG sequences can also induce similar cellular effects as a "principal" VGVAPG ligand of the elastin receptor. Results of our biophysical studies suggest that this peculiar consensus sequence stabilizes a type VIII beta-turn in several similar, but not identical, peptides that maintain a sufficient conformation to be recognized by the elastin receptor. We have also established that GXXPG elastin-derived peptides, in addition to pro-MMP-1, cause up-regulation of pro-matrix metalloproteinase-3 (pro-stromelysin 1). Furthermore, we found that the presence of plasmin in the culture medium activated these MMP proenzymes, leading to a consequent degradation of collagen substrate. Our results may be, therefore, relevant to pathobiology of inflammation, in which elastin-derived peptides bearing the GXXPG conformation (created after leukocyte-dependent proteolysis) bind to the elastin receptor of local fibroblasts and trigger signals leading to expression and activation of MMP-1 and MMP-3, which in turn exacerbate local connective tissue damage.
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PMID:Conformational dependence of collagenase (matrix metalloproteinase-1) up-regulation by elastin peptides in cultured fibroblasts. 1108 20

Protease-activated receptors (PARs) compose a family of G protein-coupled receptors activated by proteolysis with exposure of their tethered ligand. Recently, we reported that a neutrophil-derived serine proteinase, proteinase 3 (PR3), activated human oral epithelial cells through PAR-2. The present study examined whether other neutrophil serine proteinases, human leukocyte elastase (HLE), and cathepsin G (Cat G) activate nonepithelial cells, human gingival fibroblasts (HGF). HLE and Cat G as well as PR3 activated HGF to produce IL-8 and monocyte chemoattractant protein 1. Human oral epithelial cells but not HGF express mRNA and protein of secretory leukocyte protease inhibitor, an inhibitor of HLE and Cat G, and recombinant secretory leukocyte protease inhibitor clearly inhibited the activation of HGF induced by HLE and Cat G but not by PR3. HGF express PAR-1 and PAR-2 mRNA in the cells and the proteins on the cell surface. HLE and Cat G cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand. Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca(2+) mobilization and rendered cells refractory to subsequent stimulation with HLE and Cat G. The production of cytokine induced by HLE and Cat G and the PAR-2 agonist peptide was completely abolished by inhibition of phospholipase C. These findings suggest that neutrophil serine proteinases have equal ability to activate human nonepithelial cells through PAR-2 to produce inflammatory cytokines and may control a number of inflammatory processes such as periodontitis.
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PMID:Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2. 2030 34

We have recently identified hyperforin, a lipophilic constituent of the herb Hypericum perforatum (St. John's wort), as a dual inhibitor of the proinflammatory enzymes cyclooxygenase-1 and 5-lipoxygenase. The aim of the present study was to further elucidate antiinflammatory properties and respective targets of hyperforin. We found that hyperforin inhibited the generation of reactive oxygen species (ROS) as well as the release of leukocyte elastase (degranulation) in human isolated polymorphonuclear leukocytes (PMNL), challenged by the G protein-coupled receptor (GPCR) ligand N-formyl-methionyl-leucyl-phenylalanine (fMLP) with an IC 50 approximately equal 0.3 microM. When PMNL were stimulated with phorbol-12-myristate-13-acetate (PMA) or ionomycin, hyperforin (up to 10 microM) failed to inhibit ROS production and elastase release, respectively. Moreover, hyperforin blocked receptor-mediated Ca(2+) mobilization ( IC 50 approximately equal 0.4 and 4 microM, respectively) in PMNL and monocytic cells, and caused a rapid decline of the intracellular Ca(2+) concentration in resting cells. In contrast, the Ca(2+) influx induced by ionomycin or thapsigargin was not suppressed. Comparative studies with the specific phospholipase C inhibitor U-73122 and hyperforin revealed similarities between both compounds. Thus, U-73122 and hyperforin blocked fMLP- and PAF-induced Ca(2+) mobilization, ROS formation, and elastase release, but failed to suppress these responses when cells were stimulated by PMA or ionomycin. Also, both compounds rapidly decreased basal Ca(2+) levels in resting cells and led to a rapid decline of the Ca(2+) elevations evoked by fMLP or PAF. Our data suggest that hyperforin targets component(s) within G protein signaling cascades that regulate Ca(2+) homeostasis, coupled to proinflammatory leukocyte functions.
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PMID:Suppression of receptor-mediated Ca2+ mobilization and functional leukocyte responses by hyperforin. 1504 70

The effect of reduced glutathione (GSH) was studied on exocytosis triggered by 4-hydroxynonenal in HL-60 cells induced to differentiate towards the granulocytic cell line by dimethylsulfoxide; we measured beta-glucuronidase secretion from cells incubated at 37 degrees C in the presence of 5 mM GSH. GSH addition to the cell suspensions failed to induce any significant change of the exocytosis stimulated by HNE concentrations between 10(-8) and 10(-6) M. In contrast however, 5 mM GSH was able to fully prevent the release of lactate dehydrogenase observed in the presence of 50 microM HNE, a concentration much higher than that able to stimulate the exocytotic secretion. As the activation of phosphoinositide-specific phospholipase C (PLC) has been shown to play a major role in HNE-induced exocytosis, we studied the GSH effect on the breakdown of phosphatidylinositol-4,5-bisphosphate added to plasma membranes isolated from rat neutrophils and incubated in the presence of increasing concentrations of the aldehyde. In neutrophil membranes HNE induced a significant increase of PLC activity when used in the same concentrations as those able to stimulate beta-glucuronidase secretion in DMSO-differentiated HL-60 cells; the presence of 5 mM GSH failed to prevent its action. Our results suggest that these low aldehyde concentrations, which have actually been found in exudates, may increase tissue damage in inflammation through the release of lytic enzymes by neutrophils; it seems unlikely that their effects could be influenced by the levels of -SH groups present in the exudate and by its protein concentration.
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PMID:The exocytosis induced in HL-60 cells by 4-hydroxynonenal, a lipid peroxidation product, is not prevented by reduced glutathione. 1618 24

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