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)

In this study, we hypothesized that histaminergic increases in venular permeability result from a cascade triggered by activation of phospholipase C (PLC), inducing the synthesis of nitric oxide (NO) and activating guanylate cyclase. The apparent permeability coefficient to albumin (Pa) was measured in isolated porcine coronary venules subjected to constant flow and hydrostatic and oncotic pressures. Histamine (2.5, 5, and 10 microM) transiently and progressively increased Pa. The PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC; 100 microM) decreased baseline permeability and abolished the effect of histamine. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10 microM) and the guanylate cyclase inhibitor 6-anilinoquinoline-5,8-quinone (LY 83583; 10 microM) also blocked the histamine-induced hyperpermeability. L-Arginine (3 mM) reversed the inhibition by L-NMMA. NG-monomethyl-D-arginine did not influence the effect of histamine. Furthermore, sodium nitroprusside (10 microM) augmented Pa by two- to threefold; this effect was blocked in the presence of LY 83583 but not altered in the presence of NCDC. The results suggest that histamine increases coronary venular permeability by a direct action on the venular endothelial cells through a PLC-NO synthase-guanylate cyclase-signaling cascade.
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PMID:Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade. 768 77

Clinical trials in RA usually involve the use of several laboratory assessments of disease activity. Their use is not universal and the relative value of many novel assessments has not been determined in relation to existing clinical and laboratory methods. This study attempts to investigate the value of established and novel assessments of disease activity during treatment with accepted DMARDs. Over a 48-week study period, changes in cytidine deaminase (CD), beta 2-microglobulin, alpha 1-acid glycoprotein (alpha 1-AGP), serum antibodies to Clostridium perfringens alpha-toxin, pre-albumin and caeruloplasmin were compared to a group of established clinical and laboratory assessments including plasma viscosity, CRP haemoglobin and platelet count during treatment with the established second-line drugs, D-penicillamine (n = 20), sulphasalazine (n = 17), gold (n = 12) and hydroxychloroquine (n = 18). Overall, the assessments showing the greatest degree of change were plasma viscosity, articular index, summated change score, platelet count, CD, white cell count, alpha 1-AGP, CRP and pain score. The assessments showing the greatest degree of change were not homologous between the treatment groups and no single assessment was outstanding for a particular drug treatment.
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PMID:Optimizing the assessment of disease activity during treatment with anti-rheumatoid drugs. 809 19

Pulmonary surfactant stabilizes alveoli but, by maintaining patency of peripheral conducting airways, will also lower resistance to airflow. A small quantity of a surfactant suspension (3 mg/ml) formed a blocking liquid column in a narrow section of a glass capillary. Pressure was raised on one side of that column, whereby it was forced to move out of the narrow section, and it did not return but left the capillary open for a free airflow. The surfactant capability to maintain free airflow was lost with the addition of albumin (> 10 mg/ml) or fibrinogen (> 0.5 mg/ml). Surfactant function was seriously affected by hydrolysis with phospholipase C but not with phospholipase A2. With a small quantity of albumin added (5 mg/ml), the ability to maintain openness was seriously affected at temperatures below 25 degrees C. An inflammatory reaction due to atopy, infection, or inhalation of irritating gases characterizes a variety of airway diseases, including asthma. If the in vitro studies can be transferred to in vivo conditions, surfactant dysfunction might contribute to certain types of airway disease.
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PMID:Disruption of pulmonary surfactant's ability to maintain openness of a narrow tube. 836 93

ADP-stimulation of washed human platelets suspended in Tyrode/albumin solution containing Ca2+ (2 mM) and fibrinogen (0.4 mg/ml) causes extensive, reversible aggregation without appreciable secretion of granule contents. Under these conditions ADP (10 microM) stimulation decreased the amounts of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) and phosphatidylinositol 4-phosphate (PtdInsP) at 10 s. Omitting fibrinogen from the suspending medium or blocking fibrinogen binding to the platelets using Arg-Gly-Asp-Ser (RGDS, 0.23 mM) inhibited these decreases in PtdInsP2 and PtdInsP. In contrast, ADP-induced decreases in PtdInsP2 and increases in PtdInsP at 60 s compared to 10 s were not affected by RGDS or the absence of fibrinogen. In platelets prelabelled with [3H]glycerol and [32P]phosphate, changes in labelling of the inositol phospholipids paralleled the changes in amount. The ADP-induced changes in phosphatidic acid (PtdOH) at 10 s were unaffected by RGDS; this finding supported previous reports that phospholipase C was not the cause of the early decreases in PtdInsP2 and PtdInsP. These results indicate that the early decreases in PtdInsP2 and PtdInsP at 10 s are dependent on fibrinogen binding to the platelets and occur after fibrinogen binding which is activated by ADP stimulation. It is proposed that the fibrinogen-dependent changes in PtdInsP2 and PtdInsP may have a feedback role augmenting platelet aggregation or other responses of platelets that might occur after fibrinogen binding, possibly due to effects on actin polymerisation.
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PMID:ADP-stimulated fibrinogen binding is necessary for some of the inositol phospholipid changes found in ADP-stimulated platelets. 839 29

Serum stimulation of quiescent fibroblasts leads to a dramatic depolarization of the plasma membrane; however, the identity of the active serum factor(s) and the underlying mechanism are unknown. We find that this serum activity is attributable to albumin-bound lysophosphatidic acid (LPA) acting on its own G protein-coupled receptor, and that membrane depolarization is due to activation of an anion conductance mediating Cl- efflux. This depolarizing Cl- current can also be activated by thrombin and neuropeptide receptors; it is distinct from volume-regulated Cl- currents. Activation of the Cl- current consistently follows stimulation of phospholipase C and coincides with remodelling of the actin cytoskeleton, which is regulated by the Ras-related GTPase Rho. However, the response is not due to Ca2+/protein kinase C signalling and requires neither Rho nor Ras activation. The results indicate that in quiescent fibroblasts, LPA and other G protein-coupled receptor agonists evoke membrane depolarization by activating a new type of Cl- channel through a signalling pathway that is closely associated with phosphoinositide hydrolysis, yet independent of known second messengers.
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PMID:Serum-induced membrane depolarization in quiescent fibroblasts: activation of a chloride conductance through the G protein-coupled LPA receptor. 859 7

To determine biochemical changes associated with early parasite development, Haemonchus contortus larvae were cultured in vitro to the fourth stage (L4). Infective larvae developed from third to fourth stage in 48-96 h. Metabolic activity increased following stimulus of infective stages by CO2 secretion/excretion of significant amounts of protein into cultures and larval feeding did not occur until larvae had molted to the fourth stage. Larval feeding, as monitored by the ability of larvae to ingest fluorescein-labeled albumin, correlated with molting to the fourth stage and only fourth stage larvae were observed to feed. Fourth stage larvae secreted/excreted several enzymes into culture media including a metalloprotease, an acid phosphohydrolase, a cathepsin C-like enzyme, a phospholipase C-like enzyme and an N-acetyl-beta-D-glucosaminidase. Excretory-secretory (ES) products produced by L4 had antigenic homologies with parasite products produced during the second molt and with proteins and glycoproteins extracted from third and fourth stage larvae. ES products were recognized by sera from sheep infected with H. contortus. The enzymes identified here serve as markers for maturation to the fourth larval stage as well as the initiation of feeding and are likely to be involved in extracorporeal digestion. Further, they might serve as potential targets for immune or chemical control of trichostrongyle infections.
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PMID:Characterization of excretory-secretory products from larval stages of Haemonchus contortus cultured in vitro. 868 75

Dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) have potent biological effects on the blood(cells), the vasculature and they myocardium. In the epidemiological studies in which the benefit from the regular ingestion of n-3 PUFAs was reported, the responsible mechanisms remain obscure. A great deal of the PUFA-effect can be explained by the known interference with the eicosanoid metabolism. Many processes, believed to be involved in atherogenesis such as adhesion and infiltration of bloodcells (in)to the vasculature, platelet aggregation, secretion of endothelium-derived factors and mitogenic responses of vascular smooth muscle cells are partially mediated by receptor-activated phospholipases C-beta and A2. As PUFAs take part at many steps of the signalling pathways, the latter could represent important action sites to beneficially interfere with atherogenesis. In this brief review, we have discussed the results of studies on the influence of alteration of PUFA composition of the membrane phospholipids or of exogenously administered non-esterified PURAs on phospholipid signalling. For convenience, we have mainly focused our discussion on those studies available on the myocardium. By changing the PUFA composition of the phospholipids, the endogenous substrates for the membrane-associated phospholipase C-beta and A2 are changed. This is accompanied by changes in their hydrolytic action on these substrates resulting in altered products (the molecular species of 1,2-diacylglycerols and the non-esterified PUFAs) which on their turn evoke changes in events downstream of the signalling cascades: activation of distinct protein kinase C isoenzymes, formation of distinct eicosanoids and non-esterified PUFA effects on Ca2+ channels. It has also become more clear that the membrane physicochemical properties, in terms of fluidity and cholesterol content of the bilayer, might undergo changes due to altered PUFA incorporation into the membrane phospholipids. The latter effects could have consequences for the receptor functioning, receptor-GTP-binding protein coupling, GTP-binding protein-phospholipase C-beta or A2 coupling as well. It should be noted that most of these studies have been carried out with cardiomyocytes isolated from hearts of animals on PUFA diet or incubation of cultured cardiomyocytes with non-esterified PUFAs in the presence of albumin. Studies need to be performed to prove that the PUFA-diet induced modulations of the phospholipid signalling reactions do occur in vivo and that these effects are involved in the mechanism of beneficial effects of dietary PUFAs on the process of atherosclerosis.
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PMID:Polyunsaturated fatty acids and signalling via phospholipase C-beta and A2 in myocardium. 873 47

Eicosanoids are involved in the mediation of inflammatory and allergic processes in the gut. In order to evaluate a potential beneficial effect of the diet, the effect of mediators of inflammation and of a sensitization against egg albumin on anion secretion across the colon was tested using rats fed on a diet containing 15% fish oil as compared to 15% olive oil as donor animals. Feeding on a fish oil diet significantly reduced the response to bradykinin or phospholipase C, known agonist of prostaglandin-induced secretion, by about 50%. The increase in short-circuit current (Isc) induced by the phospholipase A2 stimulator, melittin, or by distension of the gut wall were only insignificantly inhibited by 15-30%. Administration of egg albumin to the mucosas from animals sensitized against egg albumin induced an indomethacin- and tetrodotoxin-sensitive increase in Isc. This response was, however, only insignificantly (30%) reduced by the fish oil diet. In conclusion, the effect of fish oil diet depends on the stimulus used for activation of prostaglandin release. This suggested that different pools of arachidonic acid are differentially affected by the diet or that certain stimuli for phospholipases are strong enough to overcome the effect of a reduced substrate availability. Consequently, a diet rich in polyunsaturated n-3 fatty acids may only play an adjuvant role for the therapy of inflammatory or allergic intestinal diseases.
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PMID:Modulation by fish oil diet of eicosanoid-induced anion secretion in the rat distal colon. 900 Mar 30

We have previously demonstrated that agonists increase microvascular permeability through a phospholipase C-nitric oxide synthase-guanylate cyclase cascade. The aim of this study was to further investigate the downstream end of the signaling pathway with a focus on myosin light chain (MLC) phosphorylation. The apparent permeability coefficient to albumin was measured in isolated coronary venules. Under control conditions, the nitric oxide donor sodium nitroprusside, as well as the guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) activator 8-bromoguanosine 3',5'-cyclic monophosphate, increased venular permeability two- to threefold. Similarly, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate significantly elevated permeability. Inhibition of MLC phosphorylation with ML-7 significantly attenuated the hyperpermeability responses to the agonists. Furthermore, ML-7 dose dependently reduced basal venular permeability. Consistently, inhibition of dephosphorylation with the protein phosphatase inhibitor calyculin dramatically increased basal permeability. These results suggest that 1) PKG and PKC play an important signaling role in the regulation of endothelial barrier function and 2) MLC phosphorylation contributes to basal and agonist-stimulated microvascular permeability.
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PMID:Myosin light chain phosphorylation: modulation of basal and agonist-stimulated venular permeability. 908 22

The formation of inositol phosphates was compared in aspirin-treated, washed human platelets suspended in Tyrode's-albumin solution containing 2 mM calcium and stimulated with SFLLRN (thrombin receptor-activating peptide) or thrombin. SFLLRN (20 microM) and thrombin (1 U/ml) resulted in maximal irreversible aggregation and 80-90% secretion of dense granule contents. SFLLRN (50-100 microM) caused larger increases at 10 sec than 20 microM SFLLRN in the formation of inositol trisphosphate (IP3, measured as [3H]inositol label). These increases were not significantly less than those caused by thrombin (1 unit/ml). However, whereas the labeling of IP3 increased from 10-60 sec with thrombin, with SFLLRN it was much less at 60 sec than that at 10 sec. The decrease was not due to degradation of SFLLRN by ectopeptidases, since it was not prevented by amastatin, an inhibitor of ectopeptidases. Degradation of glycoprotein Ib (GPIb) with an O-sialoglycoprotein endopeptidase did not affect the thrombin-stimulated labeling of inositol phosphates, indicating that binding to GPIb is not involved in the sustained thrombin-induced formation of inositol phosphates. The finding that the thrombin-stimulated formation of IP3 was not dependent on Ca2+ in the medium (EGTA added) indicates that the transient SFLLRN-induced formation of IP3 is not due to failure to cause Ca2+ influx. The finding that formation of IP3 was transient in SFLLRN-stimulated platelets, whereas platelet aggregation and secretion were maximal, indicates that the sustained activation of phospholipase C caused by thrombin may have roles related to later processes in which platelets participate.
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PMID:Differences between platelet phosphoinositide metabolism stimulated by thrombin or SFLLRN are not accounted for by interaction of thrombin with glycoprotein Ib. 909 83


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