Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disulfiram (an alcohol-aversive drug) and related compounds are known to provoke several side effects involving behavioral and neurological complications. N,N-diethyldithiocarbamate (DDC) is considered as one of the main toxic species of disulfiram and acts as an inhibitor of superoxide dismutase. Since arachidonic acid (AA) formation is regulated by reactive oxygen species (ROS) and related to toxicity in neuronal cells, we investigated the effects of DDC on AA release and expression of the alpha type of cytosolic phospholipase A(2) (cPLA(2)alpha) in PC12 cells. Treatment with 80-120 microM DDC that causes a moderate increase in ROS levels without cell toxicity stimulated cPLA(2)alpha mRNA and its protein expression. The expression was mediated by extracellular-signal-regulated kinase (ERK1/2), one of the mitogen-activated protein kinases. Treatment with N(G) nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase, 1 mM) and oxy-hemoglobin (a scavenger of nitric oxide, 2 mg/mL) abolished the DDC-induced responses (ERK1/2 phosphorylation and cPLA(2)alpha expression). We also showed DDC-induced up-regulation of the mRNA expression of lipocortin 1, an inhibitor of PLA(2). Furthermore, DDC treatment of the cells enhanced Ca(2+)-ionophore-induced AA release in 30 min, although the effect was limited. Changes in AA metabolism in DDC-treated cells may have a potential role in mediating neurotoxic actions of disulfiram. In this study, we show the first to demonstrate the up-regulation of cPLA(2)alpha expression by DDC treatment in neuronal cells.
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PMID:Up-regulation of cytosolic phospholipase A2alpha expression by N,N-diethyldithiocarbamate in PC12 cells; involvement of reactive oxygen species and nitric oxide. 1660 13

Nitric oxide produced in various human tissues by nitric oxide synthase is involved in the regulation of many physiological processes. Mechanism of its action is diverse. The most important physiological activity of nitric oxide is guanylate cyclase activation and an increase of cGMP synthesis. At low concentrations NO plays a pivotal role in vessel relaxation and possesses antithrombotic, antiproliferative and anti-inflammatory features as well. An excessive production of nitric oxide can disturb vascular hemostasis and contribute to development of cardiovascular diseases. Studies provide that NO also participate in fibrynolysis regulation by the influence on the PAI-1 and t-PA expression, what may have important clinical implications. The aim of this review is to present current knowledge about the role of nitric oxide in the regulation of these plasminogen activation system factors.
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PMID:[The influence of nitric oxide on the regulation of plasminogen activator inhibitor type 1 and tissue-type plasminogen activator expression]. 1667 75

Infusion of pentagastrin (20 microg kg(-1) h(-1), i.v.) for 10 min evokes protein output but no overt fluid secretion from the parotid gland of the rat, as revealed by increased protein concentration in a subsequent wash-out flow of saliva in response to a bolus injection of methacholine (5 microg kg(-1), i.v.) 10 min later. Using this experimental set-up, the contribution of nitric oxide (NO) generation to the protein and amylase response evoked by pentagastrin was investigated. Neither the neuronal type NO synthase inhibitor N(omega)-propyl-L-arginine (N-PLA; 30 mg kg(-1), i.v.) nor the non-selective NO synthase inhibitor L-NAME (30 mg kg(-1), i.v.) as such affected the methacholine-evoked volume response or the outputs of protein and amylase. However, when preceeded by the pentagastrin infusion, the expected increases in concentrations of protein (145%) and amylase activity (127%) of the methacholine-evoked response (compared to a pre-infusion methacholine response) were reduced to 68 and 74%, respectively, in the presence of N-PLA, and to 70 and 63%, respectively, in the presence of L-NAME. Thus, NO generation resulting from the activity of the neuronal type NO synthase, most probably of parenchymal origin, plays an important role in the pentagastrin-induced protein and amylase secretion of the rat parotid gland.
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PMID:Pentagastrin-induced nitric oxide-dependent protein secretion from the parotid gland of the anaesthetized rat. 1687 55

In vitro studies suggested that tissue plasminogen activator (t-PA) may aggravate ischemic injury by enhancing N-methyl-D-aspartate (NMDA) receptor signalling. It remained unclear whether NMDA signalling is also relevant for t-PA toxicity in vivo. We herein examined effects of intravenous t-PA (10 mg/kg), administered alone or in combination with the NMDA antagonist MK-801 (0.2 mg/kg), following 90 min of middle cerebral artery occlusion in mice. In our study, MK-801 alone, administered intraperitoneally, neither affected infarct volume nor brain swelling at 24 h after reperfusion. t-PA significantly increased infarct size, in accordance with previous findings. t-PA-induced ischemic injury was completely abolished and brain swelling markedly reduced when t-PA-treated animals received additional MK-801 injections. To elucidate how t-PA influences brain damage, we examined actions of t-PA on the expression of NO synthases by immunohistochemistry, showing that t-PA does not influence neuronal NO synthase, but increases inducible NO synthase in ischemic areas. The effect of t-PA on inducible NO synthase levels was completely reversed after cotreatment with MK-801. Our study provides in vivo evidence in a model of focal cerebral ischemia that t-PA-induced brain injury involves an NMDA receptor-dependent mechanism.
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PMID:Tissue plasminogen activator-induced ischemic injury is reversed by NMDA antagonist MK-801 in vivo. 1690 47

Coagulation abnormalities have been implicated in the pathogenesis of sepsis and organ dysfunction. Nitric oxide (NO) is regarded as a critical mediator of many vascular pathologies, including sepsis. However, limited evidence is available to document a relationship between NO generated by inducible NO synthase (iNOS) and hemostatic abnormalities in sepsis. Therefore, we evaluated the effects of selective iNOS inhibition on markers of endothelial and coagulation homeostasis in a clinically relevant model of porcine bacteremia induced and maintained for 24 hours (h) with a continuous infusion of live P. aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n=7) or continuous infusion of selective iNOS inhibitor L-NIL (n=7). Before as well as 12, 18 and 24 h after starting P. aeruginosa following variables related to i) endothelial dysfunction (von Willebrand factor [vWf]; tissue plasminogen activator activity [t-PA]; ii) coagulation (thrombin-antithrombin complexes [TAT]; platelet count); iii) fibrinolysis (t-PA activity, activity of plasminogen activator inhibitor type 1 (PAI-1 act); and iv) oxidative/nitrosative stress (isoprostanes, nitrate/nitrite levels) were measured. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite and isoprostanes concentrations, prevented hypotension and acidosis. L-NIL significantly attenuated sepsis-induced rise in plasma vWF and TAT. P. aeruginosa-induced drop in t-PA activity was blunted by iNOS inhibition, while increased PAI-1 and reduced platelet count were not reversed by the treatment. In conclusion, selective iNOS inhibition was associated with attenuation of sepsis-induced coagulation and endothelial dysfunction suggesting the interplay between mediators of vascular system and hemostatic balance. Reduction of oxidative stress probably contributes to the beneficial effects afforded by iNOS blockade.
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PMID:Coagulation and endothelial dysfunction during longterm hyperdynamic porcine bacteremia--effects of selective inducible nitric oxide synthase inhibition. 1726 61

Picolinic acid (PA) potentiates macrophage (MPhi) antimicrobial activity against intracellular Mycobacterium avium complex (MAC). Here, we studied the mechanisms of this phenomenon using human THP-1 MPhis. First, when PA-treated MAC-infected MPhis were cultured in the presence or absence of reactive oxygen intermediate (ROI) scavengers, nitric oxide synthase (NOS) inhibitors or phospholipase A(2) (PLA(2)) inhibitors, none of these agents blocked the activity of PA in potentiating MPhi anti-MAC activity. Second, when PA was added to the in vitro anti-MAC bactericidal system consisting of either ROIs, reactive nitrogen intermediates (RNIs) or free fatty acid (FFA) molecules, which are the major MPhi antimicrobial effectors, PA inhibited the activity of ROIs and conversely potentiated the activity of RNIs; PA did not affect the activity of FFAs. Third, PA reduced mRNA expression of NADPH oxidase and beta-defensin-1 by MAC-infected MPhis, whilst neither cytosolic PLA(2) nor CAP37 mRNA expression was affected. Notably, inducible NOS and secretory PLA(2) mRNA expression was not detected for MAC-infected MPhis even when given PA treatment. These findings suggest that ROIs, RNIs, FFAs and beta-defensin-1 do not play important roles in the PA-induced potentiation of MPhi anti-MAC activity.
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PMID:Effects of picolinic acid on the antimicrobial functions of host macrophages against Mycobacterium avium complex. 1729 87

We evaluated the possible role of NO in modulating tissue plasminogen activator (t-PA) release in the forearm microcirculation of normotensive subjects and hypertensive patients. Essential hypertensive patients are characterized by endothelial dysfunction because of a reduced NO availability and also show an impaired t-PA release. In healthy volunteers and essential hypertensive patients, we studied local t-PA release and forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.45 and 1.5 microg/100 mL/min) and of sodium nitroprusside (0.5 and 1.0 microg/100 mL/min), an endothelium-dependent and -independent agonist, respectively. Acetylcholine was also repeated in the presence of intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-l-arginine (100 microg/100 mL/min). In normotensive subjects, vasodilation to acetylcholine was blunted by N(G)-monomethyl-l-arginine. In these subjects, acetylcholine infusion induced a significant, dose-dependent increase in net forearm t-PA release. N(G)-monomethyl-l-arginine significantly reduced basal t-PA release, as well as acetylcholine-induced t-PA release. In essential hypertensive patients, vasodilation to acetylcholine was reduced as compared with controls and resistant to N(G)-monomethyl-l-arginine. In contrast to what was observed in healthy control subjects, in hypertensive patients, acetylcholine had no effect on t-PA release. Similarly, N(G)-monomethyl-l-arginine failed to modify either the tonic or the agonist-induced t-PA release. Both tonic and agonist-induced release of NO are directly involved in t-PA release by endothelial cells. Essential hypertension, characterized by a reduction in tonic and stimulated NO availability, is also associated with impaired capacity of t-PA release, suggesting a major role of impaired NO availability in worsening both vasodilation and t-PA release.
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PMID:Nitric oxide modulates tissue plasminogen activator release in normotensive subjects and hypertensive patients. 1733 40

Inducible nitric oxide synthase (iNOS) is expressed in a variety of cell types, in particular in inflammatory cells, in response to diverse pro-inflammatory stimuli. This process requires critical levels of arachidonic acid (AA), generated by constitutive phospholipase A(2) (PLA(2)), promoting tyrosine kinase-dependent phosphorylation, and inhibition, of constitutive NOS. Lowering basal NO levels is indeed critical for the activation of nuclear factor-kappaB (NF-kappaB), and thus for the expression of genes (e.g. iNOS) regulated by this transcription factor. It is interesting to note that NO and AA, two small lipid soluble molecules, rapidly cross the plasma membrane thereby allowing the triggering of the above responses in distal cells. That is, constitutive NO might inhibit NF-kappaB activity in the same cells (e.g. astrocytes) in which it is generated, as well as in other cells that do not express constitutive NOS (e.g. microglia). NO from cells unable to respond to pro-inflammatory stimuli (e.g. neurons) will also contribute to these effects. Along the same line, AA released by pro-inflammatory molecules in specific cell types (e.g. astrocytes) might suppress constitutive NOS activity in the same cells as well as in other cells (e.g. neurons). Thus, AA produced at the very early stages of the inflammatory response is a likely critical signal switching the regulation of the "NO tone" from physiological (i.e. mediated by constitutive NOS) to pathological (i.e. mediated by iNOS). This second phase of the inflammatory response is often accompanied by the onset of deleterious effects in the tissue in which a critical role is played by iNOS-derived NO (directly or indirectly, i.e. via formation of peroxynitrite) as well as by products of the AA cascade. In summary, we suggest that the relative amounts of NO and AA, released by their constitutive enzymes, produce autocrine and paracrine effects regulating the onset of an inflammatory response in which, in addition to other factors, NO and AA are extensively released by their inducible enzymes.
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PMID:Cross-talk between NO and arachidonic acid in inflammation. 1769 36

Dihydropyrimidinase-like 3 (DPYSL3) is believed to play a role in neuronal differentiation, axonal outgrowth and neuronal regeneration, as well as cytoskeleton organization. Recently we have shown that glutamate excitotoxicity and oxidative stress result in calpain-dependent cleavage of DPYSL3, and that NOS plays a role in this process [R. Kowara, Q. Chen, M. Milliken, B. Chakravarthy, Calpain-mediated truncation of dihydropyrimidinase-like 3 protein (DPYSL3) in response to NMDA and H2O2 toxicity, J. Neurochem. 95 (2005) 466-474; R. Kowara, K.L. Moraleja, B. Chakravarthy, Involvement of nitric oxide synthase and ROS-mediated activation of L-type voltage-gated Ca(2+) channels in NMDA-induced DPYSL3 degradation, Brain Res. 1119 (2006) 40-49]. The present study investigates the involvement of PLA(2) signaling in NMDA-induced DPYSL3 degradation. Exposure of rat primary cortical neurons (PCN) to PLA(2) and COX-2 inhibitors significantly prevented NMDA-induced DPYSL3 degradation. Since the metabolic product of PLA(2) signaling, PGE(2), which augments toxic effect of NMDA, is known to stimulate cAMP, the effect of adenyl cyclase activator (forskolin plus IBMX) and inhibitor (MDL12,300) on NMDA-induced DPYSL3 degradation was tested. Our data indicate that the activation of adenyl cyclase contributes to NMDA-induced DPYSL3 degradation. Furthermore, cAMP-dependent protein kinase (PKA) inhibitor PKI (14-22) provided additional evidence of PKA involvement in NMDA-induced DPYSL3 degradation. In summary, the obtained data show the contribution of PLA(2) signaling to NMDA-induced calpain activation and subsequent degradation of synaptic protein DPYSL3.
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PMID:PLA(2) signaling is involved in calpain-mediated degradation of synaptic dihydropyrimidinase-like 3 protein in response to NMDA excitotoxicity. 1805 48

This study investigated the influence of an eicosapentaenoic acid (EPA)- or a docosahexaenoic acid (DHA)-supplemented diet on the deleterious effects of lysophosphatidylcholine (LPC) on endothelium-dependent vasorelaxation of Golden Syrian hamster thoracic aorta. In a second step, LPC-modulated phospholipase A(2) (PLA(2))-derived ways of relaxation were investigated. Golden Syrian hamsters were fed for 6 weeks with a control diet or an EPA- or DHA-supplemented diet. Aortic fatty acid composition was analyzed by gas chromatography. Aortic rings were incubated for 20 minutes with LPC before constructing cumulative concentration-response curves for acetylcholine (ACh; 3 nmol/L-30 micromol/L) or sodium nitroprusside (3 nmol/L-30 micromol/L). The EPA- or DHA-supplemented diet increased n-3 polyunsaturated fatty acids in aortic fatty acids content because of the increase of EPA or DHA content, respectively, and decreased arachidonic acid aortic content. Lysophosphatidylcholine (1, 10, 15, and 20 micromol/L) induced a concentration-dependent inhibition of ACh-induced relaxation of preconstricted aortic rings in the control group, but did not influence sodium nitroprusside-induced aortic relaxation. The DHA- or EPA-supplemented diet worsened LPC (20 micromol/L) inhibitory effects on ACh-induced vasorelaxation. In the control diet group, ACh-induced relaxation was abolished by the nitric oxide synthase inhibitor (l-N(G)-nitro-arginine methyl ester; 100 micromol/L), whether LPC was added or not. The ACh-induced vasorelaxation was partially inhibited by PLA(2) inhibitors methyl arachidonyl fluorophosphonate (25 micromol/L) and arachidonyl trifluoromethyl ketone (20 micromol/L) as well as by the combination of 2 Ca(2+)-dependent potassium (K(Ca)) channel inhibitors charybdotoxin (0.1 micromol/L) plus apamin (0.3 micromol/L). In the presence of LPC (20 micromol/L), ACh-induced vasorelaxation was abolished by these inhibitors. These effects were not influenced by DHA or EPA diet. Our results suggested that EPA- or DHA-supplemented diet did not exhibit any beneficial effect against LPC-induced inhibition of endothelium-dependent aortic relaxation in Golden Syrian hamsters. These LPC effects were associated in our study not only with an inhibition of nitric oxide-dependent vasorelaxation, but also with a concomitant activation of a compensatory vasorelaxant pathway depending both on PLA(2) metabolites and on K(Ca) channel opening.
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PMID:Dietary n-3 polyunsaturated fatty acids and endothelium dysfunction induced by lysophosphatidylcholine in Syrian hamster aorta. 1819 Oct 54


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