Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultrastructural studies of blood cells during the acute stage of the hemolytic-uremic syndrome (HUS) revealed striking, but transient, changes in erythrocyte structure. These included membrane disruption, vacuolar degeneration, and Heinz body formation. There was also evidence of platelet injury, and there were peculiar tactile interactions between histiocytes and impaired red cells. These changes disappeared as the patients recovered. These changes were considered to be important in the pathogenesis of the hemolytic and thrombolytic features of HUS, and studies were directed at reproducing them in vitro and in vivo. Treatment of red cells with purified clostridial phospholipase C induced changes in red cells and platelets that were comparable to those encountered in HUS. Rats infused with phospholipase C developed hemolysis, thrombocytopenia, and hemoglobinuria. Their kidneys did not, however, reveal glomerular alterations similar to those seen in patients with HUS. It is proposed that HUS in some cases might be initiated by a nonspecific infectious injury to the intestinal mucosa thereby allowing increased absorption of toxins derived from indigenous gut flora and that these toxins could be responsible for the hemolysis, thrombolysis, and even the renal injury.
 ...
PMID:Experimental studies on the hemolytic-uremic syndrome. 397 83

Previous studies provide inconclusive data concerning the nephrotoxicity of myoglobin following muscle injury. We investigated the possibility that released muscle constituents other than myoglobin may be associated with renal damage, and studied accompanying hematological and coagulation changes. An extract of homologous or autologous muscle was infused intravenously in rabbits in a dose of 100 mg of muscle extract protein/kg; equine myoglobin was given to control animals. Experimental animals developed proteinuria, cylindruria, and a 50% reduction in glomerular filtration rate. Leukopenia, thrombocytopenia and evidence of intravascular coagulation also were seen. The muscle extract was shown to have thromboplastic activity; however inhibition of this by phospholipase C did not prevent the changes induced by muscle extract infusion possibly because the intrinsic changes coagulation pathway still was activated. Although moderate hypotension and ECG changes developed in some rabbits, these were not consistent and the renal functional changes appeared to be independent of these factors. Pulmonary and glomerular microthrombi were seen in experimental animals and there was vacuolation of the renal proximal tubular cells. The studies indicate that a number of biological systems are activated following muscle extract infusion and that these may be more important than the nephrotoxicity of myoglobin in the pathogenesis of the renal injury.
 ...
PMID:Muscle extract infusion in rabbits. A new experimental model of the crush syndrome. 723 89

The Gova/b alloantigens are expressed on a 175-kD protein (GP175) on human platelets. Anti-Gov alloantibodies have been implicated in posttransfusion purpura and alloimmune neonatal thrombocytopenia. In this report we characterize the immunochemistry of the alloantigens and identify the platelet protein that expresses the Gov epitopes. Approximately 50% of GP175 containing the Gov epitope was released from platelets treated with phosphatidylinositol-specific phospholipase C, indicating that at least some of this protein exists as a glycosylphosphatidylinositol (GPI)-linked isoform. Radioimmunoprecipitation and immunodepletion studies indicated that the Gova/b alloantigens are expressed on the GPI-anchored CDw109 protein. The Gova/b epitopes were expressed on an extracellular, 120-kD soluble fragment (p120) of CDw109 produced by calcium-dependent protease cleavage. Anti-Gov immunoprecipitates of chymotryptic digests of p120 contained 70- and 52-kD fragments of CDw109. Deglycosylation of native CDw109 had no effect on recognition by Gov alloantisera; however, the epitopes were destroyed after exposure to sodium dodecyl sulfate. Gova/b alloantigens were expressed on platelets and PHA-activated T-cells, cultured human umbilical vein endothelial cells, and by many different tumor cell lines, consistent with the tissue distribution of CDw109.
 ...
PMID:Characterization and localization of the Gova/b alloantigens to the glycosylphosphatidylinositol-anchored protein CDw109 on human platelets. 767 Jan 16

Clostridium perfringens type A strains which differed in alpha-toxin (phospholipase C [PLC]) productivity were inoculated intraperitoneally or intravenously into mice, and then their 50% mouse lethal doses (LD50) were determined. Strain NCTC 8237 produced ninefold higher PLC activity than strain 13. The mean LD50 for the former was 1 log unit lower than that for the latter. Two isogenic strains were constructed from strain 13: strain 13(pJIR418 alpha) (pJIR418 alpha contains the plc gene), which produced ninefold higher PLC activity than strain 13; and strain 13 PLC-, which showed no PLC productivity at all because of transformation-mediated gene disruption. The mean LD50 for strain 13(pJIR418 alpha) was 1 log unit lower than those for strain 13 PLC- and strain 13. These results indicate that PLC functions as a virulence-determining factor when it is produced in a sufficient amount. Such a difference in LD50 was also observed between Bacillus subtilis with and without the cloned plc gene. Inoculation of B. subtilis PLC+ intravenously into mice caused marked thrombocytopenia and leukocytosis. Mice inoculated with B. subtilis at 2 LD50 died because of circulatory collapse. Histological examination revealed that intravascular coagulation and vascular congestion occurred most prominently in the lungs. These results suggest that PLC plays a key role in the systemic intoxication of clostridial myonecrosis, probably by affecting the functions of platelets and phagocytes.
 ...
PMID:Role of alpha-toxin in Clostridium perfringens infection determined by using recombinants of C. perfringens and Bacillus subtilis. 792 85

Anti-cardiolipin Abs (ACLA) are present in the sera of patients with antiphospholipid syndrome (APLS) and are associated with high incidence of thromboembolic phenomena, fetal loss, thrombocytopenia, and prolongation of the phospholipid-dependent coagulation assays (lupus anticoagulant). Recently, it has been shown that APLS can be induced experimentally by using ACLA. However, the pathophysiology of thrombus formation in this syndrome is unknown. Monocytes generate a potent procoagulant activity (PCA) after stimulation with various substances. Increased PCA has been found in monocytes from patients with diseases that are associated with high incidence of thromboembolic phenomena. In the present study, we report that the monoclonal ACLA that were shown previously by us to induce APLS stimulate mononuclear cells to generate a potent PCA. The PCA resembled tissue factor (TF) in that it accelerated clotting through the extrinsic coagulation pathway, was abolished by phospholipase C, and was inhibited by anti-TF mAbs. The induction of TF-like activity by ACLA in monocytes was dose- and time-dependent. It was induced in monocytes and monocytic cell lines, but not in lymphoid or myeloid cells, and did not require T lymphocytes for expression. The generation of PCA was dependent on protein synthesis inasmuch as it was prevented by adding puromycin to the system and was not affected by cytarabine. The TF-like activity that is induced by ACLA in monocytes may activate coagulation and thereby play a major role in the pathogenesis of thrombus formation in APLS.
 ...
PMID:Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. 802 60

In a patient with immune thrombocytopenic purpura (ITP), we found a novel platelet-activating IgG (act-IgG) and an inhibitory IgG (inhi-IgG) that prevented activation induced by both CD9 monoclonal antibody (mAb) and the act-IgG. Purified IgG from the patient plasma caused a rise in [Ca2+]i and the aggregation of normal platelets, and bound to a 24 kD membrane protein. This aggregation was inhibited by aspirin, staurosporine, an inhibitor of protein kinase C, and F(ab')2 fragments of MALL13, a CD9 mAb. When the platelet count of this patient rose to normal range, the act-IgG disappeared. About 2 weeks later, the relapse of thrombocytopenia was observed. The purified IgG obtained in this period did not activate platelets but inhibited both the rise in [Ca2+]i and platelet aggregation stimulated by NNKY 1-19, a CD9 mAb, as well as the act-IgG, and bound to a 40 kD membrane protein. The inhi-IgG prevented the binding of IV-3, a mAb against Fc gamma receptor II (Fc gamma RII), but did not prevent the binding of NNKY 1-19 to its antigen. We suggest that the activating autoantibody recognized CD9 antigen and activated both the thromboxane- and phospholipase C-dependent pathways, while the inhibitory autoantibody recognized the Fc gamma RII and inhibited CD9 antibody-induced platelet activation mediated via this receptor.
 ...
PMID:Platelet activation induced by an antiplatelet autoantibody against CD9 antigen and its inhibition by another autoantibody in immune thrombocytopenic purpura. 821 30

Thrombopoietin (TPO), also known as the c-mpl ligand, stimulates rapid tyrosine phosphorylation of multiple proteins in human platelets including the Janus family kinases JAK2 and TYK2. On its own, TPO has no effect on platelet aggregation and dense-granule secretion but induces a general potentiation of these responses by other stimuli. The most dramatic effect is observed against threshold concentrations of agonists for aggregation. Shape change or weak reversible aggregation induced by low concentrations of thrombin, collagen and the thromboxane mimetic, U46619, are converted into irreversible aggregation in the presence of TPO. A similar result is obtained in the presence of the ADP scavenger apyrase and cyclo-oxygenase inhibitor indomethacin. TPO also induces potentiation of dense-granule secretion measured through release of 5-hydroxy[3H]-tryptamine. This effect is most striking against low concentrations of stimuli and is independent of aggregation as it is observed in the presence of chelation of extracellular Ca2+ with EGTA. TPO potentiates activation of phospholipase C and elevation of intracellular Ca2+, providing a molecular explanation for potentiation of functional responses. TPO may have an important physiological role in priming platelet activation in thrombocytopenia, an action that may help to compensate for the reduced platelet density.
 ...
PMID:Thrombopoietin potentiates activation of human platelets in association with JAK2 and TYK2 phosphorylation. 864 38

Platelets express alloantigens that are platelet specific (eg, the HPA antigens) and alloantigens that are shared with other blood cells (eg, the ABH antigens). The blood group A and B determinants are expressed on glycolipids and on some intrinsic platelet membrane glycoproteins. This report characterizes multiple platelet proteins reacting with blood group antibodies in serum samples from mothers of children born with neonatal alloimmune thrombocytopenia. ABH antigens on additional platelet proteins are identified, including the glycosyl phosphatidylinositol-anchored protein CD109. The proteins that carry ABH antigens were identified by using monoclonal antibodies to glycoproteins Ib, IIb/IIIa, Ia/IIa, CD31, and CD109 and immunoprecipitation/immunoblotting techniques with monoclonal antibodies to A and B antigens. The maternal serum samples and anti-A and anti-B monoclonal antibodies immunoprecipitated identical radiolabeled platelet proteins including proteins at 220 and 175 kd and proteins with mobilities corresponding to glycoproteins Ib, IIb/IIIa, IV, and V. Treatment of platelets with phosphatidylinositol-specific phospholipase C released into the supernatant a 175-kd protein that expressed the blood group determinants. This protein comigrated with the glycosyl phosphatidylinositol-anchored protein CD109. When platelet proteins were purified by immunoprecipitation with monoclonal antibodies and then tested by immunoblotting, anti-A reacted with the glycosyl phosphatidylinositol-anchored protein CD109 and to glycoproteins Ib, IIb, IIa, IIIa, and CD31 (PECAM). These results indicate that structures for modification by glycosyltransferases exist on platelet CD109, which also expresses the Gov alloantigen system. This study indicates that certain platelet proteins express both platelet-specific and blood group antigens that may contribute to platelet transfusion refractoriness and to neonatal alloimmune thrombocytopenia.
 ...
PMID:ABH antigens on human platelets: expression on the glycosyl phosphatidylinositol-anchored protein CD109. 970 75

Platelets express a single class of Fcgamma receptor (FcgammaRIIA), which is involved in heparin-associated thrombocytopenia and possibly in inflammation. FcgammaRIIA cross-linking induces platelet secretion and aggregation, together with a number of cellular events such as tyrosine phosphorylation, activation of phospholipase C-gamma2 (PLC-gamma2), and calcium signaling. Here, we show that in response to FcgammaRIIA cross-linking, phosphatidylinositol (3,4, 5)-trisphosphate (PtdIns(3,4,5)P3) is rapidly produced, whereas phosphatidylinositol (3,4)-bisphosphate accumulates more slowly, demonstrating a marked activation of phosphoinositide 3-kinase (PI 3-kinase). Inhibition of PI 3-kinase by wortmannin or LY294002 abolished platelet secretion and aggregation, as well as phospholipase C (PLC) activation, indicating a role of this lipid kinase in the early phase of platelet activation. Inhibition of PLCgamma2 was not related to its tyrosine phosphorylation state, since wortmannin actually suppressed its dephosphorylation, which requires platelet aggregation and integrin alphaIIb/beta3 engagement. In contrast, the stable association of PLCgamma2 to the membrane/cytoskeleton interface observed at early stage of platelet activation was fully abolished upon inhibition of PI 3-kinase. In addition, PLCgamma2 was able to preferentially interact in vitro with PtdIns(3,4,5)P3. Finally, exogenous PtdIns(3,4,5)P3 restored PLC activation in permeabilized platelets treated with wortmannin. We propose that PI 3-kinase and its product PtdIns(3,4,5)P3 play a key role in the activation and adequate location of PLCgamma2 induced by FcgammaRIIA cross-linking.
 ...
PMID:Phosphatidylinositol 3,4,5-trisphosphate-dependent stimulation of phospholipase C-gamma2 is an early key event in FcgammaRIIA-mediated activation of human platelets. 973 17

FcgammaRIIA, the only Fcgamma receptor present in platelets, is involved in heparin-associated thrombocytopenia (HIT). Recently, adenosine diphosphate (ADP) has been shown to play a major role in platelet activation and aggregation induced by FcgammaRIIA cross-linking or by sera from HIT patients. Herein, we investigated the mechanism of action of ADP as a cofactor in FcgammaRIIA-dependent platelet activation, which is classically known to involve tyrosine kinases. We first got pharmacologic evidence that the ADP receptor coupled to Gi was required for HIT sera or FcgammaRIIA clustering-induced platelet secretion and aggregation. Interestingly, the signaling from this ADP receptor could be replaced by triggering another Gi-coupled receptor, the alpha(2A)-adrenergic receptor. ADP scavengers did not significantly affect the tyrosine phosphorylation cascade initiated by FcgammaRIIA cross-linking. Conversely, the Gi-dependent signaling pathway, initiated either by ADP or epinephrine, was required for FcgammaRIIA-mediated phospholipase C activation and calcium mobilization. Indeed, concomitant signaling from Gi and FcgammaRIIA itself was necessary for an efficient synthesis of phosphatidylinositol 3,4,5-trisphosphate, a second messenger playing a critical role in the process of phospholipase Cgamma2 activation. Altogether, our data demonstrate that converging signaling pathways from Gi and tyrosine kinases are required for platelet secretion and aggregation induced by FcgammaRIIA.
 ...
PMID:FcgammaRIIA requires a Gi-dependent pathway for an efficient stimulation of phosphoinositide 3-kinase, calcium mobilization, and platelet aggregation. 1107 39


1 2 Next >>