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)

Cyclic AMP affects microvascular smooth muscle contraction and growth. Therefore, it is important to elucidate mechanisms regulating cyclic AMP production in microvascular smooth muscle. In this study, we determined whether several signal transduction pathways regulate receptor-induced cyclic AMP in isolated preglomerular microvessels and microvascular smooth muscle cells. Preglomerular microvessels were incubated with isoproterenol (beta-adrenoceptor agonist) and with and without U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), 1-butanol (phospholipase D inhibitor), CGP77675 (c-src inhibitor), HA1077 (Rho kinase inhibitor), Y27632 (Rho kinase inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), dipenyleneiodonium (NADPH oxidase inhibitor), or Tempol (superoxide dismutase mimetic). Cultured preglomerular microvascular smooth muscle cells were incubated with isoproterenol or forskolin (direct activator of adenylyl cyclase) and with or without U73122, C(2)-ceramide (phospholipase D inhibitor), or PP1 [src family inhibitor, 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine]. All studies were conducted with 3-isobutyl-1-methylxanthine (broad-spectrum phosphodiesterase inhibitor) to eliminate changes in cyclic AMP degradation. In microvessels isoproterenol-induced cyclic AMP was not affected by Y27632, HA1007, LY294002, dipenylene-iodonium, or Tempol; was increased by U73122 and GF109203X; and was decreased by 1-butanol and CGP77675. In cells, U73122 increased and C(2)-ceramide and PP1 decreased isoproterenol-induced cyclic AMP. Forskolin-induced cyclic AMP was not altered. These results indicate that receptor-mediated activation of adenylyl cyclase is 1) not modulated by Rho kinase, phosphatidylinositol-3-kinase, NADPH oxidase, or superoxide; 2) is attenuated by phospholipase C and protein kinase C; and 3) is augmented by phospholipase D and src. Phospholipase C, phospholipase D, and src modulate receptor-induced cyclic AMP by affecting beta-adrenoreceptor/G protein/adenylyl cyclase coupling rather than by directly affecting adenylyl cyclase activity.
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PMID:Modulation of cyclic AMP production by signal transduction pathways in preglomerular microvessels and microvascular smooth muscle cells. 1508 74

The involvement of phospholipase C/diacylglycerol kinase (PLC/DGK)-mediated signalling in oxidative burst and hypersensitive cell death was studied in rice suspension-cultured cells treated with benzothiadiazole (BTH) and infected by Xanthomonas oryza pv. oryza (Xoo), the causal agent of rice leaf blight disease. Treatment of rice suspension cells with BTH resulted in a significant oxidative burst, as indicated by accumulation of superoxide anion and H(2)O(2), and hypersensitive cell death, as determined by Evans blue staining. A peak in oxidative burst was detected 3-4 h after BTH treatment and hypersensitive cell death was observed 8 h after treatment. In addition, significant oxidative burst and hypersensitive cell death were detected in BTH-treated suspension cells, but not in untreated control cells, after Xoo infection. Scavengers and antioxidants of active oxygen species, e.g., superoxide dismutase, catalase, N-acetylcysteine, and flavone, reduced significantly the BTH-induced oxidative burst and hypersensitive cell death, indicating that oxidative burst is required for BTH-induced hypersensitive cell death. Expression of the PLC/DGK pathway genes, a diacylglycerol kinase gene, OsDAGK1, and a phosphoinositide-specific phospholipase C gene, OsPI-PLC1, and a defence-related EREBP transcriptional factor gene, OsBIERF3, was activated in rice cells after BTH treatment and in the BTH-treated cells after Xoo infection. Treatment of rice cells with phosphatidic acid, a phospholipid signalling molecule, resulted in the production of oxidative burst and hypersensitive cell death. However, neomycin, a PLC inhibitor, inhibited partially but not completely the production of oxidative burst, hypersensitive cell death, and expression of OsBIERF3 and OsDAGK1 induced by BTH in rice cells. These results suggest that PLC/DGK-mediated signalling plays an important role in BTH-induced oxidative burst, hypersensitive response, and activation of defence response in rice.
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PMID:Phospholipase C/diacylglycerol kinase-mediated signalling is required for benzothiadiazole-induced oxidative burst and hypersensitive cell death in rice suspension-cultured cells. 1711 Oct 96

In the previous research, we found that D609 (tricyclodecan-9-yl-xanthogenate) could induce human marrow stromal cell (hMSC) differentiation to neuron-like cells. In this study, to understand the possible mechanism, we sequentially investigated the changes of phosphatidylcholine-specific phospholipase C (PC-PLC) activity, the expression of Rb, the intracellular reactive oxygen species (ROS) levels, NADPH oxidase and superoxide dismutase (SOD) activities when D609 induced neuronal differentiation in rat mesenchymal stem cells (MSCs). The results showed that D609 obviously inhibited the activity of PC-PLC when it induced neuronal differentiation in rat MSCs. Simultaneously, ROS level and the activity of NADPH oxidase increased significantly, but the MnSOD and Cu/ZnSOD activities were not altered. Furthermore, the level of Rb protein was evidently elevated. Our data suggested that PC-PLC mediated neuronal differentiation of rat MSCs by elevating NADPH oxidase activity, ROS level, and up-regulating the expression of Rb protein.
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PMID:Suppressing phosphatidylcholine-specific phospholipase C and elevating ROS level, NADPH oxidase activity and Rb level induced neuronal differentiation in mesenchymal stem cells. 1721 51

Alkyl-lysophospholipids (ALPs), developed initially to be antitumor agents, have proved highly effective in the treatment of visceral leishmaniasis, a disease caused by the species making up the protozoan complex Leishmania donovani. Although their effectiveness is known, the mode of action against this parasite is not completely understood. In the present work, we have studied the effect of 3 derivatives, edelfosine, miltefosine, and ilmofosine. Using nuclear magnetic resonance spectroscopy ('H-NMR), we have examined the excreted catabolites from glucose metabolism in the promastigote forms treated with these compounds. The ALPs at concentrations of 19 and 38 microM inhibit the excretion of acetate, succinate, and pyruvate. The effect of edelfosine, miltefosine, and ilmofosine on the activity of the enzymes hexokinase, glycerolkinase 3-PD, phosphoglucose isomerase, superoxide dismutase, and phospholipase C were also examined. Glycerolkinase 3-PD and phosphoglucose isomerase are generally insensitive to the compounds, whereas hexokinase and superoxide dismutase are inhibited by miltefosine and ilmofosine. The ALPs exhibited an activated effect against the phospholipase C activity. Alkyl-lysophospholipids were shown to have a significant effect on several enzymes in important biochemical pathways indispensable for the survival of L. donovani promasigotes.
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PMID:Effect of alkyl-lysophospholipids on some aspects of the metabolism of Leishmania donovani. 1816 58

Alpha(2)-adrenoceptors potentiate renal vascular responses to angiotensin II via coincident signaling at phospholipase C. This leads to increased activation of the phospholipase C/protein kinase C/c-src pathway. Studies suggest that c-src activates the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase/superoxide system, and reactive oxygen species stimulate the RhoA/Rho kinase pathway. Therefore, we hypothesized that NADPH oxidase/superoxide and RhoA/Rho kinase are downstream components of the signal transduction pathway that mediate the interaction between alpha(2)-adrenoceptors and angiotensin II on renal vascular resistance. In rat kidneys, both in vivo and in vitro, intrarenal infusions of angiotensin II increased renal vascular resistance, and UK14,304 (alpha(2)-adrenoceptor agonist) enhanced this response. Intrarenal Tempol (superoxide dismutase mimetic) or Y27632 (Rho kinase inhibitor) abolished the interaction between UK14,304 and angiotensin II both in vivo and in vitro. The interaction was also blocked by inhibitors of NADPH oxidase (in vivo using chronic gp91ds-tat administration and in vitro with diphenyleneiodonium). In cultured preglomerular vascular smooth muscle cells, UK14,304 enhanced angiotensin II-induced intracellular superoxide (2-hydroxyethidium production) and potentiated activation of RhoA (Western blot of activated RhoA bound to the binding domain of rhotekin). The interaction between angiotensin II and UK14,304 on superoxide generation and RhoA activation was blocked by inhibitors of phospholipase C (U73312), protein kinase C (GF109203X), c-src (PP1), NADPH oxidase (diphenyleneiodonium), or superoxide (Tempol). We conclude that NADPH oxidase/superoxide and RhoA/Rho kinase are involved in the interaction between alpha(2)-adrenoceptors and angiotensin II on renal vascular resistance by mediating signaling events downstream of the phospholipase C/protein kinase C/c-src pathway.
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PMID:Alpha2-adrenoceptors enhance angiotensin II-induced renal vasoconstriction: role for NADPH oxidase and RhoA. 1825 Mar 67

Reactive oxygen species play a key role in vascular disease, pulmonary hypertension, and hypoxic pulmonary vasoconstriction. We investigated contractile responses, intracellular Ca(2+) ([Ca(2+)](i)), Rho-kinase translocation, and phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and of myosin light chain (MLC(20)) in response to LY83583, a generator of superoxide anion, in small intrapulmonary arteries (IPA) of rat. LY83583 caused concentration-dependent constrictions in IPA and greatly enhanced submaximal PGF(2alpha)-mediated preconstriction. In small femoral or mesenteric arteries of rat, LY83583 alone was without effect, but it relaxed a PGF(2)alpha-mediated preconstriction. Constrictions in IPA were inhibited by superoxide dismutase and tempol, but not catalase, and were endothelium and guanylate cyclase independent. Constrictions were also inhibited by the Rho-kinase inhibitor Y27632 and the Src-family kinase inhibitor SU6656. LY83583 did not raise [Ca(2+)](i), but caused a Y27632-sensitive constriction in alpha-toxin-permeabilized IPA. LY83583 triggered translocation of Rho-kinase from the nucleus to the cytosol in pulmonary artery smooth muscle cells and enhanced phosphorylation of MYPT-1 at Thr-855 and of MLC(20) at Ser-19 in IPA. This enhancement was inhibited by superoxide dismutase and abolished by Y27632. Hydrogen peroxide did not activate Rho-kinase. We conclude that in rat small pulmonary artery, superoxide triggers Rho-kinase-mediated Ca(2+) sensitization and vasoconstriction independent of hydrogen peroxide.
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PMID:Superoxide constricts rat pulmonary arteries via Rho-kinase-mediated Ca(2+) sensitization. 1910 85

Hypoxia in solid tumors is a major obstacle in conventional treatment because of inefficient delivery of therapeutic agents to the lesions, but offers the potential for anaerobic bacterial colonization that can lead to tumor destruction. We have previously reported a recombinant Clostridium perfringens (Cp) strain constructed by deletion of the superoxide dismutase (sod) gene and insertion of the Panton-Valentine leukocidin (PVL) gene, Cp/sod(-)/PVL, which showed elevated oxygen sensitivity, tumor selectivity, and oncopathic potency in an orthotopic model of pancreatic cancer in immune-competent and syngeneic mice, and that led to substantial prolongation of animal survival. A major limitation to Cp/sod(-)/PVL in clinical applications is that it expresses phospholipase C (plc), the alpha-toxin and the major virulence determinant in Cp that is causative in the development of gas gangrene. In this study, the plc gene in Cp/sod(-)/PVL was knocked out to create Cp/plc(-)/sod(-)/PVL, which was shown to be incapable of inducing gas gangrene in mice. Intravenous injection of Cp/plc(-)/sod(-)/PVL spores led to a significant survival advantage in tumor-bearing mice with the same efficacy as Cp/sod(-)/PVL, indicating that the oncopathic potency of Cp is independent of a functional plc gene. The treatment also did not lead to an attenuated immune response to a subsequent pathogen challenge, indicating that a systemic immune-suppressive effect in the host is absent. Consequently, Cp/plc(-)/sod(-)/PVL is a novel oncopathic bacterial agent for the effective treatment of pancreatic cancer and other poorly vascularized tumors, with a substantially enhanced safety profile, which is essential for the development of translational studies in the future.
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PMID:The oncopathic potency of Clostridium perfringens is independent of its alpha-toxin gene. 2773 74

To evaluate the potential role of extracellular proteins in the pathogenicity and virulence of Burkholderia pseudomallei, the activities of several enzymes in the culture filtrates of nine clinical and six environmental isolates were investigated in vitro and in vivo in ICR strain of mice. The production of protease, phosphatase, phospholipase C, superoxide dismutase, catalase and peroxidase were detected in the culture filtrates of all the 15 isolates at different time points of growth 4-24h. Over time, activity of each enzyme at each time point varied. Profile of secretion was similar among the 15 isolates irrespective of source, that is clinical or environmental. Catalase, phosphatase and phospholipase C were found to be increased in 60-100% of the isolates post-passage in mice. In vivo inoculation studies in ICR mice demonstrated a wide difference in their ability to cause bacteraemia, splenic or external abscesses and mortality rate ranged from few days to several weeks.
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PMID:Comparative analysis of extracellular enzymes and virulence exhibited by Burkholderia pseudomallei from different sources. 1952 61

Cellular signaling can inhibit the membrane Na(+)-K(+) pump via protein kinase C (PKC)-dependent activation of NADPH oxidase and a downstream oxidative modification, glutathionylation, of the beta(1) subunit of the pump alpha/beta heterodimer. It is firmly established that cAMP-dependent signaling also regulates the pump, and we have now examined the hypothesis that such regulation can be mediated by glutathionylation. Exposure of rabbit cardiac myocytes to the adenylyl cyclase activator forskolin increased the co-immunoprecipitation of NADPH oxidase subunits p47(phox) and p22(phox), required for its activation, and increased superoxide-sensitive fluorescence. Forskolin also increased glutathionylation of the Na(+)-K(+) pump beta(1) subunit and decreased its co-immunoprecipitation with the alpha(1) subunit, findings similar to those already established for PKC-dependent signaling. The decrease in co-immunoprecipitation indicates a decrease in the alpha(1)/beta(1) subunit interaction known to be critical for pump function. In agreement with this, forskolin decreased ouabain-sensitive electrogenic Na(+)-K(+) pump current (arising from the 3:2 Na(+):K(+) exchange ratio) of voltage-clamped, internally perfused myocytes. The decrease was abolished by the inclusion of superoxide dismutase, the inhibitory peptide for the epsilon-isoform of PKC or inhibitory peptide for NADPH oxidase in patch pipette solutions that perfuse the intracellular compartment. Pump inhibition was also abolished by inhibitors of protein kinase A and phospholipase C. We conclude that cAMP- and PKC-dependent inhibition of the cardiac Na(+)-K(+) pump occurs via a shared downstream oxidative signaling pathway involving NADPH oxidase activation and glutathionylation of the pump beta(1) subunit.
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PMID:Activation of cAMP-dependent signaling induces oxidative modification of the cardiac Na+-K+ pump and inhibits its activity. 2019 11

Induction of heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, heme-arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP(3)) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volume-overload model characterized by elevated endothelin (ET-1) and mineralocorticoid-induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX-Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+heme-arginate; (D) UnX-DOCA-salt+heme-arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+heme-arginate, (G) UnX-DOCA-salt+vehicle dissolving heme-arginate and CrMP and (H) normal-SD+heme-arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor kappaB (NF-kappaB) and ET-1 were markedly reduced. Furthermore, heme-arginate suppressed PLC activity, attenuated IP(3) and reduced resting intracellular calcium. The effects of heme-arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In heme-arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP(3) and NF-kappaB were less accentuated, suggesting greater selectivity of HO against the ET-1-PLC-IP(3)-NF-kappaB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP(3), which in turn activates NF-kappaB, the concomitant reduction of ET-1, PLC, IP(3) and NF-kappaB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by heme-arginate.
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PMID:Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats. 2020 87


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