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)

The effect of several gold complexes on the activity of phospholipase C from human blood platelets was studied in vitro. Aurothiomalate and auranofin--2 agents used for the chrysotherapy of rheumatoid arthritis--, gold chloride, (triethylphosphine)gold chloride, and 5 newly synthesized (triethylphosphine)gold complexes dose-dependently inhibited the enzyme with IC50 values between 0.8 mumol/l ((triethylphosphine)gold chloride) and over 100 mumol/l (auranofin). None of the compounds affected phospholipase A2 from human polymorphonuclear leukocytes at concentrations up to 100 mumol/l. Inhibition of phospholipase C by (triethylphosphine)gold chloride, aurothiomalate, and compound 3 was not significantly different at substrate concentrations of 20 and 100 mumol/l phosphatidylinositol, suggesting that these gold complexes do not inhibit phospholipase C by competing with the substrate. After confirming the Ca2+ dependence of the human platelet phospholipase C by demonstrating inhibition by the Ca2+ chelators EDTA and EGTA--but no inhibition by the Zn2+ chelator 1,10-phenanthroline--the inhibition of the enzyme by (triethylphosphine)gold chloride, aurothiomalate, and compound 3 was studied at 3 different concentrations of Ca2+ in the range of 0.2 to 2 mmol/l. Inhibition by (triethylphosphine)gold chloride was not affected by changes of Ca2+, whereas inhibition by aurothiomalate and compound 3 was markedly suppressed by increasing the Ca2+ concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of human phospholipase C by aurothiomalate and (triethylphosphine) gold complexes. 135 62

Eicosanoids are important mediators of the inflammatory response to monosodium urate crystals (MSUC) that results in gout. Phospholipase enzymes cleave fatty acids from membrane phospholipids, and this is thought to be the rate-limiting step in eicosanoid production. To understand better the mechanism of eicosanoid production in this disease, we stimulated human peripheral blood neutrophils and monocytes with MSUC and measured phospholipase enzyme activities. MSUC stimulated both intracellular and secretory phospholipase A2 enzyme activities in a time and concentration-dependent manner. Specificity was observed, as phospholipase C activities were not affected. Pretreatment with colchicine, but not aspirin, indomethacin, allopurinol, or islet activating protein, abrogated the enhanced phospholipase A2 activities. We have recently isolated and characterized a phospholipase A2 activating protein termed PLAP from synovial fluid from patients with rheumatoid arthritis, and from murine and bovine cell lines. PLAP was detected in gouty synovial fluid by immunodot blotting and ELISA assays and expressed the same characteristics as PLAP identified from other sources. To examine the role of PLAP in MSUC-induced phospholipase A2 stimulation, we treated cells with MSUC and observed an increase in immunoreactive PLAP. This response also could be blunted by colchicine, but not other drugs. Both phospholipase A2 and PLAP induced production by human monocytes of PGE2 and leukotriene B4 by neutrophils. These findings suggest that phospholipase A2 activation in response to MSUC requires an intact microtubule structure, and that phospholipase A2 and PLAP may be important modulators of at least a portion of the gouty inflammatory response.
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PMID:Monosodium urate crystals stimulate phospholipase A2 enzyme activities and the synthesis of a phospholipase A2-activating protein. 223 Jan 25

Auranofin (AF) is an orally active chrysotherapeutic agent used for the treatment of rheumatoid arthritis, a self-perpetuating inflammatory disease. Because of reports suggesting that AF and other gold complexes can, under certain circumstances, exacerbate rheumatoid inflammatory lesions in humans and adjuvant arthritic rats and that phospholipase C (PLC) and phospholipase A2 activities are increased in rheumatoid patients, the effects of AF and a related gold complex on in situ mammalian and purified Bacillus cereus PLC were examined. Results of our studies show that 1) AF and triethylphosphine gold chloride (TEPG), an AF analog, stimulated PLC activity in the sonicate of RAW 264.7 macrophages; 2) AF and TEPG stimulated B. cereus PLC activity in a concentration-dependent manner, but the pattern of stimulation and concentrations of drugs required to stimulate the purified enzyme differ from those seen with the macrophage PLC; 3) metals (cobalt and zinc) and sulfhydryl reagents (N-ethylmaleimide, iodoacetic acid, and glutathione), tested at the same concentrations of AF that enhanced PLC activity, had no effect on the enzyme. These data suggest that stimulation of PLC may be a generic phenomenon since two divergent PLCs are affected by gold complexes. Additionally, these studies may provide one potential explanation for rheumatoid lesion flares seen in patients and animals on chrysotherapy.
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PMID:Effect of auranofin and other gold complexes on the activity of phospholipase C. 311 79

Increased concentrations of eicosanoids are found in synovial fluids (SF) from patients with rheumatoid arthritis (RA). SF polymorphonuclear leukocytes (PMN), which derive from peripheral blood, usually account for approximately 90% of the cells in RA SF. Since eicosanoid precursor fatty acids (FA) are liberated by phospholipases from membrane phospholipids, we examined phospholipase A2 and C activities in peripheral blood PMN from patients with RA. Peripheral blood PMN from patients with RA (RA-PMN) exhibit greater phospholipase A2 activities against phosphatidylcholine (PC) and phosphatidylethanolamine (PE), and greater phospholipase C activities against PC, PE, and phosphatidylinositol (PI) than PMN obtained from normal volunteers (N-PMN).
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PMID:Enhanced phospholipase A2 and C activities of peripheral blood polymorphonuclear leukocytes from patients with rheumatoid arthritis. 386 30

Peripheral blood monocytes (PBM) from patients with rheumatoid arthritis (RA) produce greater amounts of prostaglandins (PG) than do control cells. To further explore the reasons for the increased PG production, we assessed the phospholipase activities in these cells. We found that PBM from patients with severe RA expressed greater phospholipase A2 (PLA2) and phospholipase C (PLC) activities than did the control cells. Enhanced PLA2 activities were observed in RA patient cells when phosphatidylcholine (PC) or phosphatidylethanolamine (PE) were used as substrates. Enhanced PLC activities also were seen when PC, PE, and phosphatidylinositol (PI) were used as labeled substrates. Increased PLC activity was observed whether linoleic acid or arachidonic acid was esterified to the 2 position of the phospholipid substrate used. Because all patients with RA were treated with nonsteroidal antiinflammatory drugs, we examined the effects of aspirin ingestion on phospholipase activities. Aspirin had no consistent effect on PLA2 activities but markedly inhibited PLC activities against PC, PI, and PE with arachidonic acid in the R2 position. That aspirin enhanced PLC activities against PC and PI with linoleic acid in the R2 position, suggests that PLC activity may be regulated in part by the R2 fatty acid. Our results indicate that increased phospholipase activities exhibited by PBM from RA patients may help explain the increased PG production by these cells. The increased phospholipase activities in PBM from RA patients do not appear to be due solely to nonsteroidal antiinflammatory drug therapy.
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PMID:Enhanced phospholipase activity in peripheral blood monocytes from patients with rheumatoid arthritis. 396 11

Peptidoglycan, the basic structure of the staphylococcal cell wall, is a matrix of glycan strands that are cross-linked through short peptide side chains. Many of the biological activities of staphylococcal cells can be ascribed to the peptidoglycan moiety of their cell walls. Staphylococcal peptidoglycan can be shown to be immunogenic in laboratory animals; both humoral and cellular immune responses have been noted. Sensitive techniques, such as radio- or enzyme-immunoassay, have recently shown that virtually all normal human donors have detectable peptidoglycan IgG antibodies in their serum. Peptidoglycan IgG can be transplacentally transferred. The titers of peptidoglycan antibody vary widely among healthy donors. Increased production of peptidoglycan antibodies is found in most patients with complicated S. aureus septicaemia and also in many with uncomplicated bacteremia. Nonbacteremic S. aureus infections usually do not stimulate peptidoglycan antibody production. Compared to other S. aureus products such as teichoic acid, nuclease, and alpha-toxin, peptidoglycan may be the most sensitive antigen for detecting antibody responses during staphylococcal infections. Peptidoglycan antibodies may neutralize some of the toxic effects of the staphylococcal cell wall and promote phagocytosis of the organisms. However, increased peptidoglycan antibody titers with immuno-complex disease have also been associated with longstanding infections due to S. epidermidis, Streptococci and with rheumatoid arthritis. Thus, peptidoglycan antibodies may cross-react among Gram-positive bacterial species and have detrimental effects as well.
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PMID:Biology and clinical significance of peptidoglycan antibody response in staphylococcal infections. 658 47

Vascular permeability factor (VPF/VEGF) is a highly conserved multifunctional cytokine that acts directly on endothelial cells (ECs) to activate phospholipase C and induce [CA2+]i transients. Two high-affinity receptors, both tyrosine kinases, have been described. VPF/VEGF has at least two important roles in tumor biology: (1) it potently increases microvascular permeability to plasma proteins, thereby modifying the tumor extracellular matrix to promote the ingrowth of fibroblasts and new blood vessels, and (2) it is a selective EC mitogen. VPF/VEGF is also involved in several other nonmalignant processes with a pathogenesis analogous to that of tumor stroma generation, including wound healing and rheumatoid arthritis.
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PMID:Vascular permeability factor, tumor angiogenesis and stroma generation. 754 75

Tenidap is a novel antirheumatic drug which combines non-steroidal antiinflammatory drug-like cyclooxygenase inhibition with cytokine modulating qualities in rheumatoid arthritis. We show herein that tenidap (5-20 microM) inhibited protein kinase C-mediated signalling leading to release of arachidonate in mouse macrophages by interfering with the up-regulation of the 85 kDa arachidonate-mobilizing phospholipase A2, although it did not inhibit this enzyme directly. The Ca(2+)-mediated activation of arachidonate mobilization was inhibited only at higher concentrations (20-40 microM). Studies of protein phosphorylation indicated that tenidap in itself was capable of inducing the phosphorylation of several protein bands through interaction with intracellular protein kinases and/or phosphatases. Importantly, tenidap inhibited both arachidonate release and the increase in intracellular protein phosphorylation when the cells were stimulated with zymosan. We propose that the main inhibitory influence of tenidap on the macrophage signalling investigated here is exerted at some level between protein kinase C and the 85 kDa phospholipase A2 and quite possibly also at the receptor-linked activation of phospholipase C.
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PMID:Effects of tenidap on Ca(2+)- and protein kinase C-mediated protein phosphorylation, activation of the arachidonate-mobilizing phospholipase A2 and subsequent eicosanoid formation in macrophages. 794 11

Tenidap is a novel, once-daily antirheumatic drug which has shown promising results against rheumatoid arthritis in extensive clinical trials. It combines NSAID-like cyclooxygenase inhibition with suppression of the acute phase response. In macrophages, tenidap inhibits the lipopolysaccharide-induced synthesis of interleukins-1 and -6, but it tends to potentiate the lipopolysaccharide-induced synthesis of tumor necrosis factor alpha, due to its cyclooxygenase inhibition. In macrophages, tenidap is a potent inhibitor of zymosan-induced responses, not only the induction of proinflammatory cytokines, but also arachidonate mobilization, protein phosphorylation, and inositol phosphate formation, possibly through interference with the receptor-mediated upregulation of phospholipase C. Tenidap also acts as an intracellular acidifier in many cell types, which may explain at least some of its other effects. Recent studies have indicated that, in addition to modulation of prostanoid and cytokine formation, tenidap has many other effects beneficial in rheumatic disease. It has been shown to inhibit bone resorption, neutrophil adhesion and degranulation, the interleukin-1-induced suppression of glycosaminoglycan synthesis, as well as the production of active metalloproteinases from chondrocytes.
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PMID:Effects of tenidap on intracellular signal transduction and the induction of proinflammatory cytokines: a review. 890 74

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.
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PMID:Tachykinins: receptor to effector. 892 4


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