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)

Endothelin-1 (ET-1) contracted the rabbit tracheal smooth muscle (RTSM), yielding a bell-shaped tension-concentration curve. Moreover, ET-1 induced concentration- and time-dependent increases in cAMP concentrations in RTSM (EC(50), 58 nM; t(1/2), 2.4 min). Pretreatment with the AC inhibitors, SQ-22536, or 2'-5'-dideoxyadenosine, enhanced contraction to ET-1 and converted its bell-shaped tension curve into a sigmoidal one, but left contraction to carbachol and KCl unaltered. The potent ET(B)-receptor agonists, ET-3 or sarafotoxin-c, mimicked ET-1's effects on cAMP levels (EC(50) values 55 and 50 nM). Further, cAMP formation by ETs was inhibited by BQ-788 (selective ET(B) receptor blocker; IC(50), 8 nM), but not by BQ-610 (selective ET(A) receptor blocker). Removal of the epithelium did not prevent ET-induced increases in cAMP levels. Unlike isoproterenol, ETs failed to activate AC in membrane fractions from RTSM. In intact RTSM, the c-PLA(2) inhibitor, AACOCF3, and the cyclooxygenase inhibitor, indomethacin, blocked ET-induced increases in cAMP levels. These findings reveal a novel, nonepithelial, c-PLA(2)-mediated, regulatory mechanism downstream from ET(B) receptors.
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PMID:ET(B) receptor activates adenylyl cyclase via a c-PLA(2)-dependent mechanism: a novel counterregulatory mechanism of ET-induced contraction in airway smooth muscle. 1150 50

In order to delineate the mechanism involved in the anti-inflammatory activity of rutaecarpine, its effects on the production of prostaglandin (PG) and therein involved enzymes were examined. Rutaecarpine reduced the production of PGE(2) in RAW264.7 cells treated with lipopolysaccharide (LPS) in a dose dependent manner when added to the culture media at the time of stimulation. However, the inhibition of total cellular cyclooxygenase (COX) activity under the same experimental condition was observed only at high concentrations of rutaecarpine. Rutaecarpine did not affected the levels of COX-2 mRNA and protein in macrophages stimulated with LPS. Calcium ionophore A23187 induced-PG production and [(3)H]-arachidonic acid release were significantly decreased by the pretreatment of rutaecarpine for 30 minutes. With the same treatment schedule, however, rutaecarpine failed to alter the activities of cellular COX-1 and COX-2. Collectively, our data suggest that anti-inflammatory effect of rutaecarpine is, at least in part, ascribed to the diminution of PG production through inhibition of arachidonic acid release albeit the nature of its effects on PLA(2) activity remains to be elaborated.
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PMID:Rutaecarpine, a quinazolinocarboline alkaloid, inhibits prostaglandin production in RAW264.7 macrophages. 1150 68

Vitamin A and its active metabolite retinoic acid (RA) modulate host-pathogen interactions by interfering with the host immune and inflammatory response including prostaglandin (PG) biosynthesis. The effects of RA on phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) isoforms in vitro are controversial, and few in vivo studies exist. We investigated the in vivo effects of RA on PG biosynthesis in the presence or absence of lipopolysaccharide (LPS) in rats. RA alone [10 mg/(kg. d) for 5 d] increased plasma and liver PG concentrations by increasing COX-1 protein expression (twofold that of control rats). RA acted synergistically with LPS to increase plasma (400-fold) and liver (15-fold) concentrations of prostaglandin E(2) (PGE(2)) and significantly, but to a lesser extent, other PG compared with RA rats, in the absence of major differences in PLA(2) expression or activity or COX-1 and COX-2 mRNA or protein expression. The RA + LPS-mediated increase in PGE(2) was significantly attenuated (97%) by aminoguanidine (AG), a relatively specific inhibitor of the inducible nitric oxide synthase (NOS2), consistent with the previously reported synergistic effect of RA and LPS on NOS2 expression and activity. In addition, RA and LPS induced the expression of the microsomal isoform of PGE synthase (mPGES). In conclusion, in vivo, RA and LPS increased PG and especially PGE(2) concentrations. The PGE(2) increase was associated with NOS2-mediated activation of COX and induction of mPGES. These results contribute to the characterization of the effects of vitamin A on the host inflammatory response.
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PMID:Retinoic acid and lipopolysaccharide act synergistically to increase prostanoid concentrations in rats in vivo. 1158 82

1. Hydrogen peroxide (H(2)O(2)) caused a transient contraction in endothelium-intact (E+) and -denuded (E-) mesenteric arteries (MA) from 8 - 10-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) in a concentration-dependent manner (10(-5) M to 10(-3) M). 2. The contraction to H(2)O(2) in MA (E+ or E-) was greater in SHR than in WKY. Removal of endothelium potentiated the contraction to H(2)O(2) in WKY but not in SHR. Tachyphylaxis to H(2)O(2) was less prominent in SHR than in WKY. 3. The contraction of aorta to H(2)O(2) (5 x 10(-4) M), expressed as a percentage of 80 mM KCl-induced contraction, was approximately half of that found in the MA. A greater contraction was found in E+ but not E- SHR aortic rings. 4. The contraction of MA to H(2)O(2) (5 x 10(-4) M) was greatly inhibited by SQ 29548 and ICI 192605 (thromboxane A(2) (TXA(2))/prostaglandin H(2) receptor antagonists), quinacrine (a phospholipase A(2) (PLA(2)) inhibitor), indomethacin and diclofenac (cyclooxygenase (COX) inhibitors), and furegrelate (a TXA(2) synthase inhibitor). 5. Production of thromboxane B(2) induced by H(2)O(2) (5 x 10(-4) M) was greater in SHR MA than in WKY, and was inhibited by quinacrine, indomethacin and diclofenac, and furegrelate, but not by SQ 29584 and ICI 192605. 6. These results suggested (1) that SHR MA exhibits a higher contraction involving an increased smooth muscle reactivity and less tachyphylaxis to H(2)O(2) than WKY; (2) that a greater production of TXA(2) through activation of PLA(2)-COX-TXA(2) synthase pathway appeared to be responsible for the enhanced contraction in SHR MA. The enhanced vascular response to H(2)O(2) may be related to hypertension in SHR.
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PMID:Hydrogen peroxide induces a greater contraction in mesenteric arteries of spontaneously hypertensive rats through thromboxane A(2) production. 1173 39

Geniposide is one of the constituents of Gardenia fruit (Gardenia jasminoides Ellis, Rubiaceae), which has been used in traditional medicine. Although its anti-inflammatory and antithrombotic effects have been reported, the way it acts is still unclear. We have investigated the effects of geniposide and its metabolite genipin on thrombogenesis and platelet aggregation. In an in vivo model, geniposide and genipin significantly (P < 0.05) prolonged the time required for thrombotic occlusion induced by photochemical reaction in the mouse femoral artery. In an in vitro study, both geniposide and genipin inhibited collagen-induced, but did not inhibit arachidonate-induced, mouse platelet aggregation. However aspirin, a cyclooxygenase inhibitor, inhibited arachidonate-induced platelet aggregation but only partially inhibited the collagen-induced one. We also showed, by measuring PLA(2)-catalyzed arachidonic acid release, that geniposide inhibited phospholipase A(2) (PLA(2)) activity. We conclude that geniposide showed an antithrombotic effect in vivo due to the suppression of platelet aggregation. PLA(2) inhibition by geniposide is one possible anti-platelet mechanism.
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PMID:Antithrombotic effect of geniposide and genipin in the mouse thrombosis model. 1174 15

After wounding, the corneal endothelium heals primarily by migration of adjacent cells into the denuded wound area. In this study, it has been attempted to identify elements of the intracellular signaling pathway activated through basic Fibroblast Growth Factor (FGF-2)- and Protein Kinase C (PKC)-modulated migration, using specific inhibitors and stimulators of second messengers in a cell culture model. Bovine corneal endothelial cells (BCEC) were grown to confluency and experiments performed with first passage cells under serum-free conditions. A central circular 'wound' was made with a specially designed trephine. In different experiments, cells were incubated with either FGF-2 (10 ng ml(-1)), pertussis toxin (PTX; 1-50 ng ml(-1)), phorbol 12-myristate 13-acetate (PMA; 50 ng ml(-1)), 2,4'-di-bromoacetophenone (DAP; 5 microM), 1-(5-iosquinolinesulphonyl)-2-methyl-piperazine dihydrochloride (H7; 10 microM), indomethacin (5 ng ml(-1)), nordihydroguaiaretic acid (NDGA; 10 ng ml(-1)), 2-(4-morpholinyl)-8-pheny-4H-1-benzopyran-4-one (LY294002; 10 microM) or different combinations of these agents. Unsupplemented cultures served as controls. Migration was quantitated by counting the cells inside the denuded area in one randomly chosen section from the wound edge 72 hr after wounding. Cell toxicity was determined with the trypan blue exclusion test. Results were statistically analysed by Student's t-test. FGF-2 and PMA (a protein kinase C activator) both stimulated migration of endothelial cells at 2.2- and 3.1-fold, respectively. The PLA(2) inhibitor DAP and the PKC inhibitor H7 both significantly reduced PMA-stimulated migration to control levels but had no effect (DAP) or even stimulated (H7) FGF-2-modulated migration. PTX did not affect FGF-2-stimulated migration. The phosphoinositol (3)-kinase inhibitor LY294002 significantly reduced FGF-2-mediated stimulation of endothelial migration similar to the rate of control cultures. LY294002 had no effect when applied together with PMA. The cyclooxygenase inhibitor indomethacin did not influence migration rates of the cells added either alone or in combination with PMA and FGF-2, respectively. The lipoxygenase inhibitor NDGA significantly reduced the number of migrating cells in cultures with no other supplements, or of those supplemented with either PMA or FGF-2. FGF-2-induced endothelial migration in vitro is not dependent on PKC/PLA(2) or pertussis-toxin sensitive G-protein pathways but rather requires activation of a phosphoinositol (3)-kinase-like enzyme and/or arachidonic acid release with subsequent liberation of lipoxygenase products. Independent of FGF-2, PKC is a major intracellular effector of corneal endothelial migration activity after wounding and stimulates migration via the PLA(2)-dependent generation of lipoxygenase metabolites.
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PMID:Intracellular signaling pathway of FGF-2-modulated corneal endothelial cell migration during wound healing in vitro. 1174 64

Phospholipase A2 (PLA(2)) activation generates the release of arachidonic acid (AA) and platelet-activating factor (PAF), two compounds which may be involved in neuroplasticity. In previous studies, we found that PLA(2) activation is involved in the development of stimulant sensitization. In the present study, we have examined the roles of AA and PAF in the development of stimulant sensitization using agonists and antagonists selective for PAF receptors or the induction of various AA cascade-mediated eicosanoids. Sprague-Dawley rats were treated for 5 days with cocaine (30 mg/kg) or D-amphetamine (1 mg/kg) preceded 15 min earlier by various antagonists, and then tested following a 10-day withdrawal period for cocaine (15 mg/kg) or D-amphetamine (0.5 mg/kg)-induced locomotion. Consistent with our earlier work, pretreatment with the PLA(2) inhibitor quinacrine (25 mg/kg) blocked the development of cocaine and amphetamine sensitization. The lipoxygenase (LOX) inhibitors nordihydroguaiaretic acid (NDGA) (5-10 mg/kg) and MK-886 (1 mg/kg) had no effect on cocaine sensitization. The PAF receptor antagonist WEB 2086 (5-10 mg/kg) reduced the development of cocaine sensitization. The cyclooxygenase (COX) inhibitors indomethacin (1-2 mg/kg), piroxicam (0.5-1 mg/kg), 6-methoxy-2-napthylacetic acid (6-MNA; 0.5-1 mg/kg), and NS-398 (0.5-1 mg/kg) blocked the development of cocaine sensitization. The COX inhibitors indomethacin (2 mg/kg) and 6-MNA (1 mg/kg) also reduced the development of amphetamine sensitization. Rats were administered bilateral intraventral tegmental area (VTA) injections of D-amphetamine (5 microg/side) or saline coadministered with indomethacin (0.5 microg/side) or vehicle three times over 5 days and were then tested after a 10-day withdrawal for D-amphetamine (0.5 mg/kg ip)-induced locomotion. Intra-VTA amphetamine induced a robust form of amphetamine sensitization, which was blocked by coadministration of indomethacin. Unilateral intra-VTA injections of PAF (1 microg) did not significantly alter cocaine (15 mg/kg ip)-induced locomotion when tested after a 3-day withdrawal. These findings suggest that COX, and possibly PAF, activity is involved in the development of stimulant sensitization. Neuroanatomical studies demonstrate that this may occur at the level of the VTA.
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PMID:Evidence for the involvement of cyclooxygenase activity in the development of cocaine sensitization. 1181 6

Phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) are two key enzymes in PG synthesis; the latter has two forms, COX-1 and COX-2. mRNA was extracted from single preimplantation embryos and examined for PLA(2), COX-1, and COX-2 gene expression by RT-PCR to investigate whether PLA(2) and COX genes are expressed in human preimplantation conceptuses from zygote to blastocyst stage and to compare COX-1 and COX-2 gene expression within the same stage of embryonic development. Expression of PLA(2), COX-1, and COX-2 was detected in 48, 37, and 45%, respectively, of total embryos examined. COX-1 was expressed in approximately 66% of early human preimplantation embryos from zygote to two-cell stage, whereas COX-2 was expressed in about 58% of later stage embryos from eight-cell to blastocyst stage (P < 0.05). Furthermore, COX-2 mRNA and protein were localized to trophectoderm in blastocyst stage embryos. In conclusion, PLA(2), COX-1, and COX-2 are expressed during early human embryonic development and may contribute to the production of PGs such as PGE(2) in human embryogenesis. COX-1 and COX-2 are differentially expressed, with COX-2 being primarily expressed by trophectoderm in late-stage human preimplantation embryos, which may promote embryonic differentiation and implantation.
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PMID:Phospholipase A(2) and cyclooxygenase gene expression in human preimplantation embryos. 1205 Feb 27

Guinea pig gallbladder muscle strips were used to investigate the contribution of different sources of diacylglicerol (DAG) in the cholecystokinin (CCK)-induced contraction. The involvement of arachidonic acid (AA) in this response was also investigated. Three distinct pathways for DAG production were investigated with specific phospholipase (PL) inhibitors. U-73122 (10 microM) was used for inhibition of phosphoinositide-specific-PLC (PI-PLC), D-609 (100 microM) for phosphatidylcholine specific-PLC (PC-PLC), and propranolol (100 microM) for phospholipase D (PLD). Separate or combined inhibition of each of these enzymes showed that the CCK-induced output of DAG involves the parallel activation of each of these phospholipases. Thus, after inhibition of a PL subtype, the remaining subtypes were able to functionally compensate in mediating CCK-induced contraction. Inhibition of AA production via DAG-lipase or phospholipase A(2) (PLA(2)) was accomplished using RHC-80267 (40 microM), mepacrine (100 microM) and 4-BPB (100 microM). These inhibitors diminished contractile response, indicating that AA is an important modulator of CCK-induced contraction. Indomethacin (10 microM) and nordihydroguaiaretic acid (NDGA, 100 microM), which inhibit subsequent steps in AA metabolism through the cyclooxygenase and 5-lipooxygenase pathways, also inhibited contractions. Taken together, these results show that CCK redundantly activates PC-PLC, PI-PLC and PLD, to produce DAG, which in turn stimulates PKC and provides a substrate for the generation of AA. sPLA(2) is also a source of AA, whose metabolites are, in part, responsible for determining the magnitude of the CCK-evoked contraction.
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PMID:Contribution of different phospholipases and arachidonic acid metabolites in the response of gallbladder smooth muscle to cholecystokinin. 1223 20

Very little is known regarding the mechanism of action for the endothelium-derived hyperpolarizing factor (EDHF) response in cerebral vessels. The authors tested two hypotheses: (1) activation of the cytoplasmic form of phospholipase A (cPLA ) is involved with EDHF-mediated dilations in rat middle cerebral arteries; and (2) activation of the cPLA involves an increase in endothelial Ca through activation of phospholipase C. Middle cerebral arteries were isolated from the rat, pressurized to 85 mm Hg, and luminally perfused. The EDHF response was elicited by luminal application of uridine triphosphate (UTP) after NO synthase and cyclooxygenase inhibition (10 mol/L -nitro-l-arginine methyl ester and 10 mol/L indomethacin, respectively). AACOCF and PACOCF, inhibitors of cPLA (Ca -sensitive) and Ca -insensitive PLA (iPLA ), dose dependently attenuated the EDHF response. A selective inhibitor for iPLA2, haloenol lactone suicide substrate, had no effect on the EDHF response. The EDHF response elicited by UTP was accompanied by an increase in endothelial Ca (144 to 468 nmol/L), and the EDHF dilation was attenuated with U73122, a phospholipase C inhibitor. The authors conclude that the EDHF response elicited by luminal UTP in rat middle cerebral arteries involved activation of phospholipase C, an increase in endothelial Ca, and activation of cPLA.
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PMID:Role of cytoplasmic phospholipase A2 in endothelium-derived hyperpolarizing factor dilations of rat middle cerebral arteries. 1236 63


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