Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the role of naturally occurring eosinophil chemotactic factors on leukotriene (LT)C4 production from highly purified (87.1 +/- 2.4%) normodense eosinophils. Platelet activating factor (PAF) directly induced LTC4 production from eosinophils in a dose (10(-9) to 10(-5) M) and a time-dependent manner. PAF (10(-5) M) induced 0.74 +/- 0.08 ng of LTC4 production/10(6) eosinophils. However, lyso-PAF, eosinophil chemotactic factor of anaphylaxis, and LTB4 failed to induce LTC4 production within the tested range. Furthermore, the pre-incubation of eosinophils with 5 micrograms/ml of cytochalasin B did not alter the chemotactic factor-induced LTC4 production. When eosinophils were stimulated by the submaximal concentration (1 microgram/ml) of calcium ionophore A23187, the pre-incubation of eosinophils with 10(-6) M or 10(-5) M of PAF, or 10(-5) M of eosinophil chemotactic factor of anaphylaxis significantly enhanced LTC4 production up to 163.9 +/- 17.5% (p less than 0.05), 279.2 +/- 32.9% (p less than 0.01) and 165.2 +/- 21.2% (p less than 0.05) of the control, respectively. However, the pre-incubation with lyso-PAF or LTB4 failed to enhance A23187-induced LTC4 production. The pre-incubation of eosinophils with phosphatidyl serine also failed to enhance A23187-induced LTC4 production. However, the direct stimulation of protein kinase C by PMA enhanced the submaximal concentration of A23187-induced LTC4 production from eosinophils up to 179.5 +/- 20.9% (p less than 0.05) of the control. Our findings indicate that PAF and ECF-A work not only as chemotactic factors but also induce a functionally active state of eosinophils probably through their post-receptor mechanisms, and contribute to the inflammatory processes.
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PMID:Leukotriene C4 production from human eosinophils in vitro. Role of eosinophil chemotactic factors on eosinophil activation. 284 92

The antiallergic and antiinflammatory effects of the new protein kinase C and calmodulin inhibitor K-252a (8R, 9S, 11S)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11- epoxy-1H,8H,11H-2,7b,11a-triazadibenzo [a,g]cycl oocta [cde] trinden-1-one) were investigated in animal models, and the following results were obtained: 1. Oral administration of K-252a, ketotifen or oxatomide showed a dose-dependent inhibition on 48 h homologous passive cutaneous anaphylaxis in rats and anaphylactic bronchoconstriction in passively sensitized guinea pigs. 2. K-252a (1-100 mg/kg p.o.) exerted a dose-dependent protection against platelet-activating factor (PAF)-induced mortality in mice. This protective effect of K-252a was sustained for 7 h. 3. K-252a (1-100 mg/kg p.o.), as well as dexamethasone (1 mg/kg s.c.), showed remarkable inhibitory effects on rat paw edema induced by carrageenin, zymosan, PAF, and antigen-antibody reaction (passive Arthus reaction) and on the croton oil-induced rat ear edema. On the other hand, indomethacin (10 mg/kg p.o.) significantly inhibited carrageenin-induced edema, but did not inhibit edema induced by other phlogistic agents. Based on these results it is suggested that K-252a, by oral administration, has antiallergic and antiinflammatory effects.
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PMID:Antiinflammatory and antiallergic effects of a novel metabolite of Nocardiopsis sp. as a potent protein kinase C inhibitor from microbial origin. 297 91

Isolated hearts from ovalbumin sensitized guinea-pigs were perfused according to Langendorff. Ovalbumin injection decreased coronary flow. Left ventricular pressure amplitude and heart rate increased initially and decreased thereafter. Concomitantly, the liberation of histamine, prostaglandin F2 alpha, as well as the sum of leukotrienes C4/D4/E4/F4, measured in the perfusate by radioimmunoassay, was augmented. Staurosporine (1 microM), an inhibitor of protein kinases, did not influence the liberation of mediators in response to antigen challenge, but inhibited all mechanical responses. Infusion of phorbol myristate acetate, an activator of protein kinase C, into non-sensitized hearts decreased coronary flow and left ventricular pressure amplitude, but did not liberate mediators. Staurosporine (1 microM) abolished these mechanical responses. The results indicate that staurosporine suppresses cardiac anaphylaxis by blockage of mediator effects rather than by inhibition of liberation or formation of mediators.
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PMID:Staurosporine inhibits the anaphylactic reaction of the isolated guinea-pig heart. 752 77

The inflammatory exudate at the post-anaphylaxis phase of allergic inflammation in rats has an ability to enhance histamine production by bone marrow cells. To analyze the mechanism of the inflammatory exudate-induced histamine production pharmacologically, the effects of several drugs were examined in cultures of bone marrow cells. Incubation of the bone marrow cells in the presence of the inflammatory exudate that had been centrifuged and dialyzed against Hanks' balanced salt solution increased histidine decarboxylase activity in the cells and histamine concentration in the conditioned medium. The induction of histamine production by the inflammatory exudate was inhibited by actinomycin D (0.01-1 microM), an inhibitor of RNA synthesis, and cycloheximide (0.1-10 microM), a protein synthesis inhibitor. The protein kinase C inhibitors staurosporine (2-20 nM), K-252a (6-200 nM), and H-7 (10.3-103 microM) also inhibited the inflammatory exudate-induced histamine production in a concentration-dependent manner. The tyrosine kinase inhibitor genistein (3.7-37 microM) also inhibited the inflammatory exudate-induced histamine production, but the protein kinase A inhibitor H-89 (0.2 microM), and the adenylate cyclase activator forskolin (0.1 microM) showed no effect. These findings suggest that histamine production induced by the inflammatory exudate is mediated by the de novo synthesis of histidine decarboxylase and by the activation of protein kinase C and tyrosine kinase.
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PMID:Pharmacological analysis of the inflammatory exudate-induced histamine production in bone marrow cells. 913

Leukotriene C4 is an arachidonic acid metabolite and an important mediator of inflammation and anaphylaxis that is known to induce production of prostacyclin in endothelial cells. The goal of this study was to examine the signal transduction mechanisms activated by leukotriene C4 stimulation. Formation of inositol phosphates was measured to determine the activation of phospholipase C and pertussis toxin was used to explore the role of G-proteins. Additionally, we evaluated the role of protein kinase C in these events, especially whether there was an interaction between pertussis toxin mediated effects and the activity of protein kinase C. Leukotriene C4 induced a dose- and time-dependent formation of inositol phosphates and prostacyclin. The response to leukotriene C4 was greater than the response to leukotriene D4 even after treatment with L-serine borate complex, suggesting the presence of a specific leukotriene C4 receptor. Exposure to pertussis toxin potentiated, time-dependently, the leukotriene C4 induced formation of inositol phosphates and prostacyclin through a mechanism which was altered by manipulation of protein kinase C activity. The exact mechanism is not clear but our results are consistent with a postulated dual mechanism of phospholipase C control, in which leukotriene C4 induced stimulation is attenuated by a pertussis toxin sensitive G-protein.
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PMID:Potentiating effects of pertussis toxin on leukotriene C4 induced formation of inositol phosphate and prostacyclin in human umbilical vein endothelial cells. 973 50

Leukotriene D4 (LTD4) is one of the slow-reacting substances of anaphylaxis and is reported to have a diverse response including the mediation of glomerular nephritis. However, little is known about the functions of LTD4 and its mechanisms of action in primary cultured rabbit renal proximal tubular cells (PTCs). The purpose of this study is to investigate the effect of LTD4 on Na+ uptake and its related signal transduction pathways in PTCs. LTD4 (>10(-9) M) significantly inhibited the Na+ uptake after 15 min (in nmol/mg protein: controls 431.7+/-11.4 vs. LTD4 (10(-9) M) 355.0+/-23.6; p<0. 05); and its effect was blocked by MK-571 (10(-6) M), a leukotriene receptor antagonist, in PTCs. Preincubation with cilastatin, a renal dipeptidase inhibitor, and polyclonal antibody against renal dipeptidase potentiated the inhibitory effect of LTD4 on Na+ uptake. SQ 22536 (10(-6) M), an adenylate cyclase inhibitor, and the myristoylated protein kinase A inhibitor amide 14-22 (PKI; 10(-5) M) blocked the effect of LTD4 on Na+ uptake (in nmol/mg protein: LTD4 349.9+/-18.5 vs. SQ 22536+LTD4 476.5+/-22.0 and PKI+LTD4 440.3+/-19. 3; p<0.05), and LTD4 induced an increase in cyclic adenosine monophosphate (cAMP), suggesting the involvement of cAMP in the inhibition of Na+ uptake. In addition, U 73122 (10(-6) M) and neomycin (10(-4) M), phospholipase C (PLC) inhibitors, W-7 (10(-4) M), a calmodulin antagonist, and bisindolylmaleimide I, a protein kinase C (PKC) inhibitor, blocked the LTD4-induced inhibition of Na+ uptake, strongly suggesting involvement of the PLC-PKC signal pathways in the effect of LTD4. LTD4 significantly increased [Ca2]i by 49+/-7% as compared with baseline. TMB-8 (10(-5) M) and BAPTA/AM (10(-5) M), intracellular calcium mobilization blockers, completely blocked the LTD4-induced inhibition of Na+ uptake (in nmol/mg protein: LTD4 347.6+/-19.0 vs. TMB-8+LTD4 436.4+/-22.3 and BAPTA/AM+LTD4 419.9+/-14.3; p<0.05); however, EGTA (1 mM), a calcium chelator, partially blocked the LTD4-induced inhibition of Na+ uptake. In conclusion, LTD4-induced inhibition of Na+ uptake may be involved in both cAMP and PLC-PKC signal pathways in PTCs. In addition, Ca2+, which comes from the intracellular Ca2+ mobilization, is primarily responsible for the LTD4-induced inhibition of Na+ uptake.
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PMID:Leukotriene D4 inhibits Na+ uptake through cAMP and PLC pathways in primary cultured renal proximal tubular cells. 1039 8

Phagocyte migration and activation at sites of inflammation is mediated through chemoattractant receptors that are coupled to G-proteins. Early studies from our laboratory demonstrated G-protein-mediated phospholipase C activation by chemoattractants. Recently, this laboratory developed cellular and animal models to allow biochemical, cell biological and molecular genetic approaches to be used in determining the mechanisms of chemoattractant receptor function, regulation, and cross regulation. These studies provided evidence that chemoattractant receptors activate distinct pathways for chemotaxis and exocytosis and cross-regulate each other's function at multiple levels. A major site of regulation is through phosphorylation of receptors by G-protein-coupled receptor kinases and by protein kinase C. In addition, the activation of phospholipase C by chemoattractants is also regulated at additional sites distal to receptor phosphorylation. These may include modulation of G-protein activation by regulators of G-protein signaling (RGS) and modification of phospholipase C. Phosphorylation of phospholipase Cbeta3 by both protein kinase A and protein kinase C has been demonstrated. The function and regulation of chemoattractant receptors are also being examined in mouse models. In these studies, mice deficient in leukotriene B4 receptors have been generated by targeted gene disruption. These mice displayed reduced neutrophil accumulation in certain inflammation models and sex-related differences in platelet-activating-factor induced anaphylaxis.
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PMID:Function and regulation of chemoattractant receptors. 1133 62

The mechanism of action of feG, an anti-inflammatory peptide, was explored using data mining, molecular modeling, and enzymatic techniques. The molecular coordinates of protein kinase A (PKA) were used to create six virtual isoforms of protein kinase C (PKCalpha, betaI, betaII, delta, iota, and zeta). With in silico techniques a binding site for feG was identified on PKCbetaI that correlated significantly with a biological activity, the inhibition of intestinal anaphylaxis. Since feG selectively increased the binding of a PKCbetaI antibody, it is proposed that this peptide inhibits the reassociation of the hydrophobic tail of PKCbetaI with its binding site and prevents the enzyme from assuming an inactive conformation.
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PMID:Identification of a binding site for the anti-inflammatory tripeptide feG. 1461 94

Spleen tyrosine kinase (Syk) is a non-receptor-type tyrosine kinase which mediates diverse responses in haematopoietic cells. Therefore, Syk is an attractive therapeutic target, and in a study of Syk inhibitors as potentially new therapeutic agents, we discovered the 4-anilinopyrimidine-5-carboxamides. Enzyme screening indicated that an aminoethylamino moiety at the 2-position of the pyrimidine ring was important for Syk inhibitory activity, and an investigation of the substituents at the 4-position revealed that an anilino moiety substituted at the meta position was preferred. These compounds showed high selectivity for Syk, compared to other kinases, such as ZAP-70, c-Src, and PKC, and exhibited good inhibitory activities against 5-HT release from RBL-cells. Among them, compound 9a inhibited the passive cutaneous anaphylaxis reaction in mice, with an ID50 of 13 mg/kg following subcutaneous administration. These results suggest that our compounds are worthy of further evaluation as new anti-allergic agents.
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PMID:Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives. 1599 Mar 16

Sphingosine-1-phosphate, a key mediator in immune cell trafficking, is elevated in the lungs of asthmatic patients and regulates pulmonary epithelium permeability. Stimulation of mast cells by allergens induces two mammalian sphingosine kinases (Sphk1 and Sphk2) to produce sphingosine-1-phosphate (S1P). Little is known about the individual role of these kinases in regulating immune cell function. Here we show that in mast cells, Sphk2 is required for production of S1P, for calcium influx, for activation of protein kinase C, and for cytokine production and degranulation. However, susceptibility to in vivo anaphylaxis is determined both by S1P within the mast cell compartment and by circulating S1P generated by Sphk1 predominantly from a non-mast cell source(s). Thus, sphingosine kinases are determinants of mast cell responsiveness, demonstrating a previously unrecognized relationship with anaphylaxis.
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PMID:The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. 1737 88


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