Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: CAS:22276-27-3 (hexadecyl)
 2,701 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel, facile and sensitive scintillation proximity radioimmunoassay (SPRIA) for quantitation of PAF has been developed. No separation of antibody bound [3H]PAF from free [3H]PAF is required as the assay employs protein A - coated fluomicrospheres (beads containing scintillant). The assay system was suitable for the quantitation of 0.03 to 2 pmol of 1-hexadecyl-2-acetyl-sn-glycero-3- phosphocholine. The cross-reactivity was high with 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine but was very low with PAF analogs such as 1-alkyl- and 1-acyl-2-lyso-sn-glycero-3-phosphocholine, 1-acyl-2-acetyl-sn-glycero-3-phosphocholine, and 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine. The specificity of SPRIA was higher than that of bioassay (platelet degranulation assay). PAF receptor antagonists (L-652,731, WEB2086, and FR900452) at up to 10 nmol per tube had no affect on the SPRIA. These observations indicate that the specificity of the PAF antibody is quite different from that of the platelet receptor. The values obtained using SPRIA for the measurement of PAF produced in polymorphonuclear leukocytes with stimuli are comparable to those obtained by SIM/GC/MS analysis.
 ...
PMID:Development of a novel scintillation proximity radioimmunoassay for platelet-activating factor measurement: comparison with bioassay and GC/MS techniques. 211 68

PAF, a potent phospholipid mediator of inflammation, is present in normal human, mixed saliva. However, the anatomic origin of PAF is not known. In this study, PAF levels in mixed saliva of edentulous subjects were estimated in comparison to that of dentate individuals. PAF activity was assessed in bioassay and expressed relative to the activity of known amounts of authentic PAF, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC). PAF was not detected in the saliva of 60% of the edentulous subjects; moreover, when present, the PAF levels were significantly less (635 +/- 82 AGEPC fmole equivalents/ml saliva, mean +/- SEM, n = 6) than in dentate subjects (5568 +/- 1135 AGEPC fmole equivalents/ml saliva, n = 27). Of relevance, the numbers of polymorphonuclear leukocytes in the mixed saliva samples of edentulous subjects were markedly reduced when compared to those of normal subjects. These findings suggest that salivary PAF most likely originates from the crevicular space, and derives from inflammatory cells within the gingival and/or periodontal tissues.
 ...
PMID:Deficiency of salivary PAF in edentulous individuals. 214 47

A new series of 4-alkyl-1,4-dihydropyridines (1,4-DHP) were synthesized and evaluated for their ability to inhibit washed rabbit platelet aggregation induced by PAF-acether (1-O-hexadecyl/octadecyl-2-O-acetyl-sn-glycero-3-phosphorylcholine) and to reverse PAF-induced hypotension in anesthetized rats. Additionally, compounds were evaluated for their ability to inhibit the binding of radiolabeled PAF to its receptor on rabbit platelets. Among these compounds, 6I and 6L were the most potent and specific antagonists. At concentrations up to 100 microM, neither compound 6I nor compound 6L caused platelet aggregation nor did they inhibit platelet aggregation induced by collagen or adenosine diphosphate. Compound 6L did not show in vitro calcium channel blocker activity measured on vascular smooth muscle preparations of rabbit aorta and on [3H]nitrendipine binding assays. The compound did not show any cardiovascular effects in anesthetized rat at iv doses up to 1000 micrograms/kg, and the Ki value was 568.62 nmol. These results indicate that compound 6L is a potent and specific PAF antagonist with 1,4-dihydropyridine structure but devoid of a significant cardiovascular activity related to calcium-antagonist properties.
 ...
PMID:4-Alkyl-1,4-dihydropyridines derivatives as specific PAF-acether antagonists. 217 57

This report describes the partial characterization of the enzymatic activity responsible for the hydrolysis of acetate from 1-alkyl-2-acetyl-sn-glycerol, the immediate precursor in the de novo synthesis of PAF (platelet-activating factor or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) by Ehrlich ascites cells. The highest acetylhydrolase activity for this neutral lipid was associated with the membrane fractions from Ehrlich ascites cells (greater than 90% of total activity); only a minimal level of activity (less than 10%) was observed in the cytosol which contrasts with the cytosolic site of PAF acetylhydrolase in normal cells. Hydrolysis of 1-[3H]hexadecyl-2-acetyl-sn-glycerol by the membrane fraction at pH 7.5 and 37 degrees C gave apparent values for Km and Vmax of 45 microM and 179 nmol/min per mg protein, respectively. Hydrolysis of acetate from 1-[3H]hexadecyl-2-acetyl-sn-glycerol by the membrane fraction was not affected by 5 mM concentrations of Ca+2, Mg+2 or EDTA, but was significantly inhibited (80% reduction) by 10 mM NaF. Based on differences in both the subcellular distribution and response to inhibition by NaF, the neutral lipid acetylhydrolase does not appear to be the same enzyme that hydrolyzes acetate from platelet-activating factor. In contrast to inhibition of diacylglycerol lipase by p-chloromercuribenzoate and N-ethylmaleimide, we found no significant inhibition of acetate hydrolysis from 1-[3H]hexadecyl-2-acetyl-sn-glycerol by either of these compounds. Also, p-nitrophenyl acetate (a nonspecific esterase substrate) failed to inhibit acetate hydrolysis of 1-[3H]hexadecyl-2-acetyl-sn-glycerol. Our studies of this enzyme would indicate that it may play an important role in regulating the levels of platelet-activating factor synthesized by the de novo pathway via hydrolysis of the immediate precursor of PAF.
 ...
PMID:Characterization of the enzymatic hydrolysis of acetate from alkylacetylglycerols in the de novo pathway of PAF biosynthesis. 230 14

SM-10661 [(+/-)-(cis)-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl] displayed marked in vitro inhibition of rabbit platelet aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (alkyl-PAF), 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16-PAF), and 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine, with IC50, values of 5.50, 5.94, and 3.68 microM, respectively. It also inhibited alkyl-PAF-induced aggregation of human platelets with an IC50 of 3.00 microM, but it did not inhibit platelet aggregation induced by ADP, collagen, arachidonic acid, the thromboxane A2 agonist U46619, or the Ca ionophore A23187, at concentrations up to 400 microM. Furthermore, SM-10661 antagonized [3H]-C16-PAF binding to rabbit platelets competitively, with an IC50 of 1.0 microM. SM-10661 protected against alkyl-PAF-induced lethality in mice with an ID50 of 6.0 mg/kg intravenously or 24 mg/kg orally. In guinea pig, SM-10661 inhibited the alkyl-PAF (0.1 micrograms/kg)-induced increase in bronchial pressure, with an ID50 of 0.7 mg/kg intravenously or 15 mg/kg orally. Bronchial hyperreactivity to bombesin after the infusion of alkyl-PAF was also inhibited dose-dependently by the infusion of SM-10661, with an ID50 of 25 mg/kg. In addition, SM-10661 inhibited alkyl-PAF (0.01 micrograms/kg)-induced hypotension in rats, with an ID50 of 0.36 mg/kg intravenously or 33 mg/kg orally. SM-10661, when given orally, showed rapid absorption and good duration of pharmacological activity in rats and rabbits.
 ...
PMID:Biological effect of orally active platelet-activating factor receptor antagonist SM-10661. 240 27

The effects of dietary salt on circulating levels of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16 PAF) in patients with essential hypertension were studied by gas chromatography/mass spectrometry with negative ion chemical ionization. Circulating levels of C16 PAF in patients with essential hypertension (18.1 +/- 5.3 pg/ml, n = 16) were not changed compared with those in normotensive subjects (17.2 +/- 7.2 pg/ml, n = 14). Although changes in circulating levels of C16 PAF were small with changes in dietary salt, net changes in circulating C16 PAF levels significantly and positively correlated with net changes in mean arterial blood pressure (r = 0.47, P less than 0.05). Changes in C16 PAF levels also correlated with changes in creatinine clearance (r = 0.55, P less than 0.05). However, changes in C16 PAF levels did not correlate with changes in plasma sodium concentration, plasma chloride concentration and plasma volume. These results indicate that C16 PAF plays an antihypertensive role and this may be reflected as small changes in circulating levels of C16 PAF.
 ...
PMID:Dietary salt, blood pressure and circulating levels of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine in patients with essential hypertension. 251 2

Protein kinase C (PKC) (Ca2+/phospholipid-dependent enzyme) activators stimulated human neutrophils to reduce the availability of high affinity receptors for platelet-activating factor. These effects were concentration dependent, irreversible, temperature sensitive, and antagonized by a PKC blocker. The activators also inhibited 1-O-alkyl-65% hexadecyl, 25% octadecyl-2-acetyl-sn-glycero-3-phosphocholine (PAF)-induced Ca2+ transients; this inhibition correlated precisely with receptor depletion. Contrastingly, PKC activators could enhance as well as inhibit PAF-induced degranulation. Inhibition of degranulation occurred only at concentrations of the activators which depressed high affinity PAF binding by greater than 75%. Cells treated with lesser activator concentrations responded to PAF with reduced but still substantial rises in cytosolic Ca2+, markedly increased degranulation, and markedly increased PKC mobilization. The last two responses, however, failed to occur in cells that were (a) calcium depleted, (b) treated with high activator concentrations (which inhibited virtually all PAF binding and PAF-induced Ca2+ transients), or (c) treated with PAF 5 min before a PKC activator (PAF-induced rises in cytosolic Ca2+ reversed in less than 5 min). Thus, activated PKC down-regulates high affinity PAF receptors. This tends to reduce neutrophil responses to PAF. On the other hand, PAF, perhaps by raising cytosolic Ca2+, acts synergistically with PKC activators in mobilizing PKC. This may tend to enhance function but seems capable of influencing only those responses that are elicited by PKC activators (e.g. degranulation but not Ca2+ transients). The complex and bidirectional effects of PKC activators on other receptor-mediated, calcium mobilizing agonists in various cell types may reflect these opposing mechanisms.
 ...
PMID:Bidirectional effects of protein kinase C activators. Studies with human neutrophils and platelet-activating factor. 254 Jan 63

Stimulated human neutrophils are known to synthesize large quantities of 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) and 5,12-dihydroxy-6,14-cis-8,10-trans-transeicosatetraenoic acid (LTB4). However, in an isolated cell suspension the majority of synthesized PAF appears to remain cell associated. In addition, LTB4 is rapidly metabolized to an omega-oxidation product (20-OH-LTB4). Experiments were designed to test the hypothesis that the degree of association of PAF with the neutrophils and the metabolism of LTB4 by the neutrophils is a result of the in vitro condition used during cell activation. Here we have compared in paired experiments ionophore A23187-induced production of PAF and LTB4 by human neutrophils in a concentrated cell suspension, a diluted cell suspension and in a system in which the cells are placed on a matrix and superfused with buffer at a constant flow rate (dynamic system). There was little difference in the amount of PAF synthesized in the concentrated cell suspension and the dynamic system. However, less PAF was produced by neutrophils in the dilution system. The percent of PAF released was consistently greater in the dynamic and dilution systems than in the concentrated cell suspension. For example, more than 40% of PAF measured by incorporation of [3H]acetate or gas chromatography/mass spectrometry was released in the dynamic system and dilution systems. In contrast, less than 15% of the PAF synthesized was released from the cells in the concentrated cell suspension. 1-0-Hexadecyl-2-acetyl-3-GPC was primarily released from the neutrophils. By contrast both 1-0-hexadecyl and 1-0-octadecyl linked species of PAF were found within the cells. Exogenous PAF added to neutrophils in the dynamic or dilution systems was taken up and metabolized at a significantly lower rate than that added to cells in the concentrated cell suspension. Most of the leukotrienes synthesized by the neutrophil during A23187 stimulation were released from the cells. However, studies of LTB4 metabolism revealed differences between the dynamic and concentrated cell suspension designs. By 20 min, most of the LTB4 was recovered as 20-OH-LTB4 in the concentrated cell suspension, whereas in the dynamic system little 20-OH-LTB4 was found in the superfusate over 20 min. These experiments suggest that a large proportion of PAF synthesized by neutrophils may be released. They also suggest that the omega-hydroxylation of LTB4 by neutrophils occurs after synthesized LTB4 is released and taken back up by the cell.
 ...
PMID:Release of platelet-activating factor and the metabolism of leukotriene B4 by the human neutrophil when studied in a cell superfusion model. 255 14

The present study has examined the catabolism of 1-O-[3H]hexadecyl-2-acetyl-GPC (C16-PAF) and of 1-O-octadecyl-2-acetyl-GPC (C18-PAF) in spleen-derived PT-18 murine mast cells (mast cells). Mast cells catabolized exogenous PAF into two inactive metabolites, 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine (lysoPAF) and 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (1-O-alkyl-2-acyl-GPC). The rate of conversion of C16-PAF to metabolites was more rapid than that of C18-PAF. Analysis of the acyl composition of 1-O-alkyl-2-acyl-GPC formed during the metabolism of PAF revealed that arachidonic acid (20:4) was the major fatty acyl chain incorporated at the sn-2 position. However, 25% of newly formed 1-O-alkyl-2-acyl-GPC was reacylated with docosahexaenoic acid (22:6). The influence of cellular fatty acid content on PAF catabolism was further explored in mast cells in which the ratio of fatty acids within cellular phosphoglycerides had been altered by supplementing the cells with various fatty acids in culture. Mast cells supplemented with 20:4 or 22:6 converted PAF to 1-O-alkyl-2-acyl-GPC at a significantly higher rate than non-supplemented cells. In contrast, cells supplemented with linoleic acid (18:2) metabolized PAF at rates similar to non-supplemented cells. Analysis of the acyl composition of 1-O-alkyl-2-acyl-GPC derived from the metabolism of PAF in 20:4-supplemented cells indicated that 20:4 was incorporated exclusively into the sn-2 position. Conversely, 22:6-supplemented cells incorporated predominantly 22:6 at the sn-2 position of 1-alkyl-2-lyso-GPC. Supplementation with 18:2 had no effect on the acylation pattern seen in newly formed 1-O-alkyl-2-acyl-GPC. Activation of passively sensitized mast cells with antigen or with ionophore A23187 significantly enhanced the rate of catabolism of exogenously-provided PAF but had no effect on the acylation pattern of 1-O-alkyl-2-acyl-GPC. Experiments performed with the soluble fraction of the cells showed that acetyl hydrolase activity was increased in mast cells stimulated with antigen. In addition, supernatant fluids from antigen or ionophore-treated mast cells converted PAF to lysoPAF, suggesting that acetyl hydrolase activity was released during cell activation. These data indicate that the ability of mast cells to catabolize PAF to inactive metabolites is influenced by cell activation and by the cellular levels of certain fatty acids.
 ...
PMID:Influence of immunologic activation and cellular fatty acid levels on the catabolism of platelet-activating factor within the murine mast cell (PT-18). 257 73

Racemic heavy isotope analogs of 1-O-alkyl-sn-glycero-3-phosphocholine (lysoPAF) and 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (PAF) were prepared for use as internal standards to facilitate quantitative studies based on mass spectrometry. Starting from pentadecane-1,15-diol and rac-glycerol-1,2-acetonide, a convergent synthesis of 1-O-[16'-2H3]hexadecyl and 1-O-[18'-2H3]octadecyl rac-glycero-3-phosphocholine and their acetyl derivatives is described. Three deuterium atoms were introduced at the terminal position of the 1-O-alkyl group by displacement of the p-toluensulfonyl group from 1-O-alkyl-15'-p-toluensulfonate and 1-O-alkyl-17'-p-toluensulfonate with [2H3]-methylmagnesium iodide. The 1-O-alkyl-17'-p-toluensulfonate was obtained by reaction of the 1-O-alkyl-15'-p-toluensulfonate with allylmagnesium bromide, followed by reductive ozonolysis and treatment with p-toluene-sulfonyl chloride. The hydroxyl group at C-2 was protected by a benzyl group and removed at a late stage in the synthesis. This provided the corresponding lyso-derivatives or allowed preparation of racemic PAF by subsequent acetylation of the free hydroxy group. The phosphocholine moiety was introduced at glycerol C-3 by reaction with bromoethyldichlorophosphate and trimethylamine. The synthetic compounds were analyzed by FAB/MS and GC/NICIMS. They were shown to contain less than 0.6% protium impurity.
 ...
PMID:Synthesis of trideuterated O-alkyl platelet activating factor and lyso derivatives. 258 35


<< Previous 1 2 3 4 5 6 7 8 Next >>