Design and synthesis of conformationally restricted phospholipids as phospholipase A2 inhibitors

Magolda, Ronald L.; Galbraith, W.

doi:10.1002/jcb.240400313

Cited by 16 publications

(11 citation statements)

References 29 publications

(13 reference statements)

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“…For PB x , inhibitition of release of arachidonic acid has been demonstrated (Rosenthal et al 1992). Oleyloxyethyl phosphocholine inhibits pancreatic (group I) secreted PLA 2 (Magolda and Galbraith 1989) but may also inhibit other PLA 2 activities since all PLA 2 inhibitors seem to have a broad speci®city towards dierent animal phospholipases of the A 2 -type. In summary, the chemical structures of the inhibitors used in this study are so diverse yet their speci®city is suciently narrow that application of these compounds at low concentrations in plants should inhibit only those metabolic pathways concerning the liberation of fatty acids and, perhaps, their subsequent metabolism by lipoxygenase and cyclooxygenase.…”

Section: Discussionmentioning

confidence: 99%

“…Some of these inhibitors have also been shown to inhibit agonist-induced responses involving the animal cytosolic PLA 2 (Gerrard 1985;Vishnawath This paper is dedicated to Professor A. Sievers on the occasion of his retirement Abbreviations: 2,4-D = 2,4-dichlorophenoxyacetic acid; ETYA = 5,8,11, Inhibitors of animal phospholipase A 2 enzymes are selective inhibitors of auxin-dependent growth. Implications for auxin-induced signal transduction et al 1988;Magolda and Galbraith 1989;Ondrey et al 1989;Hannigan and Williamson 1991;Ponzoni et al 1992;Rosenthal et al 1992;Sa and Fox 1994). In order to test our working hypothesis that PLA activation could have a similar role in both plant and animal signal transduction it seemed appropriate to test the inhibitory capacity of these PLA 2 inhibitors in a well-known classical auxin biotest, the growth test, using cut segments of etiolated tissue which also grow in response to the fungal toxin fusicoccin (MarreÁ et al 1973;Yamagata and Masuda 1975).…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of animal phospholipase A 2 enzymes are selective inhibitors of auxin-dependent growth. Implications for auxin-induced signal transduction

Scherer

Arnold

1997

Planta

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Auxin and elicitors reportedly activate phospolipase A. A number of inhibitors known to inhibit animal phospholipase A 2 were tested for their ability to inhibit hormone and fusicoccin-induced growth. To this end, growth induced by indolyl-3-acetic acid and 2,4-dichlorophenoxyacetic acid in hypocotyl segments of etiolated zucchini (Cucurbita pepo L.) seedlings was determined in the presence of the inhibitors nordihydroguajaretic acid (NDGA), aristolochic acid, 5,8,11,14-eicosatetraynoic acid (ETYA), PB x (a prostaglandin derivative), and oleylethyl phosphocholine. Each chemical proved inhibitory to auxin-induced growth, oleylethyl phosphocholine being the least eective. The eects of the ®rst three inhibitors were investigated in more detail. Growth induced by 10 lM 2,4-dichlorophenoxyacetic acid or 1 lM indolyl-3-acetic acid was inhibited 50% by about 30±50 lM NDGA, by about 25 lM aristolochic acid, and by about 10±20 lM EYTA. Growth inhibition was reversible and became apparent 0.5±1 h after inhibitor addition. Growth induced by 0.5 or 1 lM fusicoccin was much less inhibited by NDGA and by ETYA, whereas aristolochic acid was only slightly less eective on fusicoccin-induced than on auxin-induced growth. These three inhibitors were also tested for their eects on gibberellin-induced growth in light-grown peas (Pisum sativum L.) and on cytokinin-induced expansion growth in excised cotyledons from radish (Raphanus sativum L.) seedlings. In both tests, aristolochic acid had toxic side-eects although gibberellin-induced growth was still apparent. In the gibberellin test, neither NDGA at up to 100 lM nor ETYA at 80 lM was inhibitory to hormone-induced growth. Moreover, 40 lM ETYA was not inhibitory to kinetin-induced growth. We hypothesize that the selectivity of phospholipase A 2 inhibitors for auxin-induced growth implies a dierent signal transduction pathway for each of the dierent signal substances tested, and that auxins might use fatty acid(s) and/or lysophospholipid(s) or their derivatives as the preferred second messengers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibitors of animal phospholipase A 2 enzymes are selective inhibitors of auxin-dependent growth. Implications for auxin-induced signal transduction

Scherer

Arnold

1997

Planta

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“…BEL, an inhibitor of the calcium-independent PLA 2 (Ackermann et al 1995), attenuated the 2244-TCB-mediated increase in 3 H-AA release. Incubation with either OP, an inhibitor of the cytosolic and secretory isoforms of PLA 2 (Magolda and Galbraith, 1989), or SB-202190, an inhibitor of p38 MAP kinase (Lee et al 1994), had no effect on 2244-TCBinduced 3 H-AA release.…”

Section: Effects Of Signal Transduction Inhibitors On 2244-tcb-mediatmentioning

confidence: 93%

2,2′,4,4′-Tetrachlorobiphenyl upregulates cyclooxygenase-2 in HL-60 cells via p38 mitogen-activated protein kinase and NF-κB

Bezdecny

Karmaus

Roth

et al. 2007

Toxicology and Applied Pharmacology

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Polychlorinated biphenyls (PCBs) are ubiquitous, persistent environmental contaminants that affect a number of cellular systems, including neutrophils. Among the effects caused by the noncoplanar PCB 2,2′,4,4′,-tetrachlorobiphenyl (2244-TCB) in granulocytic HL-60 cells are increases in superoxide anion production, activation of phospholipase A 2 with subsequent release of arachidonic acid (AA), and upregulation of the inflammatory gene cyclooxygenase-2 (COX-2). The objective of this study was to determine the signal transduction pathways involved in the upregulation of COX-2 by 2244-TCB. Treatment of HL-60 cells with 2244-TCB led to increased expression of COX-2 mRNA. This increase was prevented by the transcriptional inhibitor actinomycin D in cells pretreated with 2244-TCB for 10 minutes. The increase in COX-2 mRNA was associated with release of 3 H-AA, phosphorylation of p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinases, increased levels of nuclear NF-κB and increased superoxide anion production. Bromoenol lactone, an inhibitor of the calcium-independent phospholipase A 2 , reduced 3 H-AA release but had no effect on COX-2 mRNA, protein or activity. Pretreatment with SB-202190 or SB-203580, inhibitors of the p38 MAP kinase pathway, prevented the 2244-TCBmediated induction of COX-2 and phosphorylation of p38 and ERK MAP kinases. These inhibitors did not alter 3 H-AA release. Treatment with PD 98059 or U 0126, inhibitors of the MAP/ERK (MEK) pathway, prevented the 2244-TCB-mediated activation of ERK but had no effect on COX-2 induction or p38 phosphorylation. 2244-TCB treatment did not affect c-Jun N-terminal kinase (JNK) phosphorylation. 2244-TCB exposure increased the amount of nuclear NF-κB. This increase was prevented by pretreatment with p38 MAP kinase inhibitors, but not by pretreatment with MEK inhibitors. Pretreatment with inhibitors of NF-κB prevented the 2244-TCB-mediated induction of COX-2 mRNA. 2244-TCB-mediated increases in superoxide anion were prevented by the NADPH oxidase inhibitor apocynin or the free radical scavenger 4-hydroxy TEMPO, but neither of these inhibitors affected the 2244-TCB-induced changes in COX-2 mRNA levels or 3 H-AA release. Taken together these data suggest that p38 MAP kinase-dependent activation of NF-κB is critical for the 2244-TCB-mediated upregulation of COX-2 mRNA.

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“…Since quinacrine is a general inhibitor of phospholipase A,, we also examined the effects of 0.1 to 10 pM OEPC, which selectively inhibits secretory phospholipase A2 (Magolda and Galbraith, 1989) and of 0.1 to 10 pM AACOCF3, which is specific for cytosolic forms…”

Section: Phospholipase A2mentioning

confidence: 99%

“…Protein kinase C assay reagents were obtained from GIBCO-BRL (Gaithersburg, MD). The protein content of each sample was determined using the bicinchoninic acid (BCA) protein assay reagent (Smith et al, 1985) (Magolda and Galbraith, 1989), and arachidonyltrifluoromethylketone (AACOCF3) (Street et al, 1993) were obtained from BIOMOL Research Laboratories (Plymouth Meeting, PA).…”

mentioning

confidence: 99%

24,25-(OH)2D3 regulates protein kinase C through two distinct phospholipid-dependent mechanisms

et al. 1996

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We have previously shown that 24,25-(OH)2D3 plays a major role in resting zone (RC) chondrocyte differentiation and that this vitamin D metabolite regulates protein kinase C (PKC). The aim of the present study was to identify the signal transduction pathway used by 24,25-(OH)2D3 to stimulate PKC activation. Confluent, fourth passage RC cells from rat costochondral cartilage were used to evaluate the mechanism of PKC activation. Treatment of RC cultures with 24,25-(OH)2D3 for 90 min produced a dose-dependent increase in diacylglycerol (DAG). Addition of R59022, a diacylglycerol kinase inhibitor, significantly increased PKC activity in cultures treated with 24,25-(OH)2D3. Addition of dioctanoylglycerol (DOG) to plasma membranes isolated from RC increased PKC activity 447-fold. Addition of pertussis toxin or cholera toxin to control cultures elevated basal PKC activity. When added together with 10(-9) M 24,25-(OH)2D3, there was an additive effect on PKC activity but in cultures treated with 10(-8) M 24,25-(OH)2D3, only the hormone-dependent stimulation of PKC was observed. The phospholipase C inhibitor, U73-122, had no effect on PKC activity, indicating that the DAG produced in response to 24,25-(OH)2D3 is not derived from phosphatidylinositol. Addition of the tyrosine kinase inhibitor, genistein, also had no effect on 24,25-(OH)2D3-stimulated PKC, further supporting the hypothesis that phospholipase C is not involved in the mechanism and that phospholipase D is responsible for the increase in DAG production. Phospholipase A2 inhibitors, quinacrine and AACOCF3, and the cyclooxygenase inhibitor indomethacin increased PKC activity in the RC cultures. Exogenous PGE2, one of the downstream products of phospholipase A2 action, inhibited PKC activity. These results suggest that 24,25-(OH)2D3 regulates PKC activity by two distinct phospholipid-dependent mechanisms: production of DAG via phospholipase D and inhibition of the production of PGE2 via inhibition of phospholipase A2 and cyclooxygenase.

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Design and synthesis of conformationally restricted phospholipids as phospholipase A2 inhibitors

Cited by 16 publications

References 29 publications

Inhibitors of animal phospholipase A 2 enzymes are selective inhibitors of auxin-dependent growth. Implications for auxin-induced signal transduction

Inhibitors of animal phospholipase A 2 enzymes are selective inhibitors of auxin-dependent growth. Implications for auxin-induced signal transduction

2,2′,4,4′-Tetrachlorobiphenyl upregulates cyclooxygenase-2 in HL-60 cells via p38 mitogen-activated protein kinase and NF-κB

24,25-(OH)2D3 regulates protein kinase C through two distinct phospholipid-dependent mechanisms

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