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1
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Interference by leptin with Helicobacter pylori lipopolysaccharide-induced cytosolic phospholipase A2 activation in gastric mucosal cells

100%
Slomiany B. L., Slomiany A.
Journal of Physiology and Pharmacology
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2007
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tom 58
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nr 1
Activation of cytosolic phospholipase A2 (cPLA2) by bacterial LPS for the rapid release of arachidonic acid from membrane phospholipids is considered a key step in the generation of platelet-activating factor (PAF), recognized as the most proximal mediator of inflammatory events triggered by bacterial infection. In this study, we report on the role of leptin in modulation of the detrimental consequences of H. pylori LPS-induced cPLA2 activation that result in the disturbances in gastric mucin synthesis. Employing gastric mucosal cells labeled with [3H] arachidonic acid, we show that H. pylori LPS-induced cPLA2 activation, associated with up-regulation in apoptosis and PAF generation, and the impairment in gastric mucin synthesis, was subject to a dose-dependent suppression by leptin, as well as the inhibition by MAFP, a specific inhibitor of cPLA2. A potentiation in the countering capacity of leptin on the LPS-induced up-regulation in apoptosis, arachidonic acid release and PAF generation was attained in the presence of ERK inhibitor, PD98059, while PI3K inhibitor, wortmannin had no effect. On the other hand, the prevention by leptin of the LPS detrimental effect on mucin synthesis was subject to suppression by wortmannin, an inhibitor of PI3K as well as the inhibitor of ERK, PD98059. Moreover, potentiation in the effect of leptin on the LPS-induced decrease in mucin synthesis was attained with cPLA2 inhibitor, MAFP as well as PAF receptor antagonist, BN52020. The results of our findings point to H. pylori LPS-induced ERK-dependent cPLA2 activation as a critical factor influencing the level of PAF generation, and hence the extent of pathological consequences of H. pylori infection on the synthesis of gastric mucin. Furthermore, we show that leptin counters the pathological consequences of H. pylori-induced cPLA2 activation on gastric mucin synthesis through the involvement in signaling events controlled by MAPK/ERK and PI3K pathways.
2

Cytosolic phospholipase A2 regulation in the hibernating thirteen-lined ground squirrel

84%
Woods A. K., Storey K. B.
Cellular and Molecular Biology Letters
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2007
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tom 12
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nr 4
621-632
Cytosolic calcium-dependent phospholipase A2 (cPLA2) has multiple roles including production of arachidonic acid (a key player in cellular signaling pathways) and membrane remodeling. Additionally, since catabolism of arachidonic acid generates free radicals, the enzyme is also implicated in ischemic injury to mammalian organs. Regulation of cPLA2 could be important in the suppression and prioritization of cellular pathways in animals that undergo reversible transitions into hypometabolic states. The present study examines the responses and regulation of cPLA2 in skeletal muscle and liver of hibernating thirteen-lined ground squirrels, Spermophilus tridecemlineatus. cPLA2 activity decreased significantly by 43% in liver during hibernation, compared with euthermic controls, and Km values for arachidonoyl thio-PC substrate fell in both organs during hibernation to 61% in liver and 28% in muscle of the corresponding euthermic value. To determine whether these responses were due to a change in the phosphorylation state of the enzyme, Western blotting was employed using antibodies recognizing phospho-Ser505 on α-cPLA2. The amount of phosphorylated α-cPLA2 in hibernator liver was just 38% of the value in euthermic liver. Furthermore, incubation of liver extracts under conditions that enhanced protein phosphatase action caused a greater reduction in the detectable amount of phospho-Ser505 enzyme content in euthermic, versus hibernator, extracts. The data are consistent with a suppression of cPLA2 function during torpor via enzyme dephosphorylation, an action that may contribute to the well-developed ischemia tolerance and lack of oxidative damage found in hibernating species over cycles of torpor and arousal.
3
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Role of epidermal growth factor receptor transactivation in the activation of cytosolic phospholipase A2 in leptin protection of salivary gland acinar cells against ethanol cytotoxicity

84%
Slomiany B. L., Slomiany A.
Journal of Physiology and Pharmacology
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2009
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tom 60
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nr 2
49-55
A pleiotropic hormone, leptin, secreted into saliva by the acinar cells of salivary glands is an important mediator of the processes of oral mucosal defense. Here, we report on the role of epidermal growth factor receptor (EGFR) transactivation in the signaling events that mediate leptin protection of sublingual salivary gland acinar cells against ethanol cytotoxicity. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR protein tyrosine kinase and cytosolic phospholipase A2 (cPLA2) activity, and characterized by a marked increase in matrix metalloproteinase MMP-9 and arachidonic acid (AA) release, and PGE2 generation. The loss in countering capacity of leptin against ethanol cytotoxicity was attained with JAK inhibitor AG490, Src inhibitor PP2, and EGFR inhibitor AG1478, as well as ERK inhibitor PD98059. Moreover, the agents evoked also the inhibition in leptin-induced up-regulation in cPLA2 activity, AA release, and PGE2 generation. The changes caused by leptin in EGFR phosphorylation, MMP-9, and cPLA2 activation were susceptible to suppression by metalloprotease inhibitor GM6001, but the production of MMP-9 was not affected by EGFR inhibitor AG1478 or PKC inhibitor Ro318220. These findings point to the involvement of MMP-9 in the event of leptin-induced EGFR transactivation that results in the signaling cascade leading to cPLA2 activation and up-regulation in PGE2 generation, thus providing new insights into the mechanism of oral mucosal protection against ethanol toxicity.
4

Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells

84%
Chalimoniuk M., Stolecka A., Cakala M., Hauptmann S., Schulz K., Lipka U., Leuner K., Eckert A., Muller W. E., Strosznajder J. B.
Acta Biochimica Polonica
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2007
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tom 54
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nr 3
Cytosolic phospholipase A2 (cPLA2) preferentially liberates arachidonic acid (AA), which is known to be elevated in Alzheimer's disease (AD). The aim of this study was to investigate the possible relationship between enhanced nitric oxide (NO) generation observed in AD and cPLA2 protein level, phosphorylation, and AA release in rat pheochromocytoma cell lines (PC12) differing in amyloid beta secretion. PC12 control cells, PC12 cells bearing the Swedish double mutation in amyloid beta precursor protein (APPsw), and PC12 cells transfected with human APP (APPwt) were used. The transfected APPwt and APPsw PC12 cells showed an about 2.8- and 4.8-fold increase of amyloid β (Aβ) secretion comparing to control PC12 cells. An increase of NO synthase activity, cGMP and free radical levels in APPsw and APPwt PC12 cells was observed. cPLA2 protein level was higher in APPsw and APPwt PC12 cells comparing to PC12 cells. Moreover, phosphorylated cPLA2 protein level and [3H]AA release were also higher in APP-transfected PC12 cells than in the control PC12 cells. An NO donor, sodium nitroprusside, stimulated [3H]AA release from prelabeled cells. The highest NO-induced AA release was observed in control PC12 cells, the effect in the other cell lines being statistically insignificant. Inhibition of cPLA2 by AACOCF3 significantly decreased the AA release. Inhibitors of nNOS and γ-secretase reduced AA release in APPsw and APPwt PC12 cells. The basal cytosolic [Ca2+]i and mitochondrial Ca2+ concentration was not changed in all investigated cell lines. Stimulation with thapsigargin increased the cytosolic and mitochondrial Ca2+ level, activated NOS and stimulated AA release in APP-transfected PC12 cells. These results indicate that Aβ peptides enhance the protein level and phosphorylation of cPLA2 and AA release by the NO signaling pathway.
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