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H Salari

Publications and source records attributed to H Salari.

At least 37 records · Page 2Linked to original sources
PubMed1992

Inhibition of protein kinase C by ether-linked lipids is not correlated with their antineoplastic activity on WEHI-3B and R6X-B15 cells.

To test the hypothesis that the action of antineoplastic ether-linked lipids in leukemic cells is associated with their ability to inhibit protein kinase C (PKC), we have compared the effects of two ether-linked lipids, 1-O-hexadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET16-OCH3-GPC) and 1-O-hexadecyl-2-O-methyl-sn-glycero-3-(S-beta-D-1'- thioglucopyranosyl)-sn-glycerol (ET16-OCH3-beta-thio-Glc), on two different leukemic cell lines (WEHI-3B and R6X-B15). ET16-OCH3-GPC killed WEHI-3B cells with an EC50 value of 2.5 microM, whereas it was far less effective against R6X-B15 cells (EC50 = 40 microM). In contrast, the beta anomer of ET16-OCH3-beta-thio-Glc did not kill either cell line at concentrations up to 40 microM. Both ET16-OCH3-GPC and ET16-OCH3-thio-Glc inhibited 12-O-tetradecanoylphorbol 12,13-dibutyrate (TPA)-induced PKC translocation in both WEHI-3B and R6X-B15 cells. When WEHI-3B cells were first exposed to TPA, and then to ET16-OCH3-GPC, no significant decrease in PKC activity in the particulate fraction was noticed. When, however, the cells were first exposed to ET16-OCH3-GPC and then to TPA, the enzyme activity in the particulate fraction was decreased by 20-30%. A phorbol dibutyrate binding assay showed that the decrease in membrane-associated PKC activity and the increase in cytosolic PKC activity did not result from impeded enzyme translocation. These results suggest that the similar PKC inhibitory potency of ET16-OCH3-GPC and ET16-OCH3-beta-thio-Glc: (a) is not correlated with the widely different cytotoxicities of these agents and (b) is probably due to interference with the binding of diacylglycerol/phosphatidylserine or TPA to PKC. Taken together, these results suggest that the ether-linked lipids compete with diacylglycerol/phosphatidylserine or TPA for binding sites on PKC required for enzyme activation.

Antineoplastic Agents↗
PubMed1992

Protein kinase C impairs the coupling of the GTP-binding protein to LTB4 receptor in neutrophil.

In the present study, the mechanism of LTB4 receptor down regulation by protein kinase C (PKC) has been investigated using porcine neutrophil membranes. Pretreatment of intact porcine neutrophils with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 2 min prior to the preparation of plasma membrane, demonstrated a reduced binding sites (Bmax) for LTB4 without altering the receptor affinity (Kd). This effect of TPA on LTB4 receptor binding was found to be due to the activation of PKC as membrane treated with purified PKC (type III) produced the same effect. When membranes from neutrophils pretreated with TPA were exposed to non-hydrolyzable GTP analog, GTP-gamma S, or GMP-PNP, no further decrease in receptor Kd was observed, while the Bmax was reduced to the level observed in TPA treated samples. Treatment of isolated neutrophil membranes with purified PKC reduced the Bmax and blocked the effect of GTP analogs on the receptor affinity. These results suggest that, PKC interrupts the receptor binding to G-protein.

Animals↗
PubMed1992

Increased contraction and inositol phosphate formation of tracheal smooth muscle from hyperresponsive guinea pigs.

Tracheal smooth muscle from guinea pigs with documented airway hyperresponsiveness in vivo after multiple antigen challenges produced 30% to 50% greater force than tracheas from control guinea pigs, when stimulated with carbachol, histamine, or leukotriene D4. When cultured smooth muscle cells were incubated with myo[2-3H]inositol, basal uptake of [3H]inositol was similar in cells from normal and hyperresponsive guinea pigs, but when these cells were stimulated with contractile agonists, there was increased uptake of inositol in hyperresponsive cells. Analysis of inositol phosphates by column chromatography and high-performance liquid chromatography revealed the presence of inositol-1,4,5-triphosphate, inositol-1,3,4-trisphosphate, inositol-1,4-bisphosphate, and inositol-1-monophosphate. The release of inositol-1,4,5-triphosphate, inositol-1,4-biphosphate, and inositol-1-monophosphate by smooth muscle cells stimulated with carbachol, leukotriene D4, or histamine was 20% to 40% greater in cells derived from hyperresponsive animals than cells from normal animals. These data demonstrate that the increased muscle contraction of hyperresponsive guinea pig tracheas is associated with increased inositol phosphate metabolism in these cells. Delineating the mechanisms of airway smooth muscle contraction should provide new pharmacologic targets for the inhibition of bronchoconstriction in asthma.

Animals↗
PubMed1992

Inhibition of human neutrophil responses by alpha-cyano-3,4-dihydroxythiocinnamamide; a protein-tyrosine kinase inhibitor.

1. Activation of neutrophils results in increased tyrosine phosphorylation of several proteins that may have important roles in receptor/effector coupling. In this study, the effect of a protein tyrosine kinase inhibitor on receptor-mediated neutrophil activation by platelet-activating factor (PAF), leukotriene, B4 (LTB4) and N-formylmethionylleucylphenylalanine (FMLP) is investigated. 2. alpha-Cyano-3,4-dihydroxythiocinnamamide dose-dependently inhibited intracellular calcium release and superoxide generation from human neutrophils activated by 1 microM LTB4, PAF, and FMLP. 3. In the presence of cytochalasin B, FMLP stimulated elastase release from neutrophils was also inhibited to unstimulated levels by 5 min pretreatment with alpha-cyano-3,4-dihydroxythiocinnamamide. 4. The inhibitory action of alpha-cyano-3,4-dihydroxythiocinnamamide was found to be at or upstream of phospholipase C activation, blocking both phosphatidylinositol hydrolysis and protein kinase C activation. alpha-Cyano-3,4-dihydroxythiocinnamamide did not affect agonist receptor binding sites or receptor affinity in neutrophils. 5. Immunoblot analysis demonstrated the tyrosine phosphorylation of proteins of 41, 56, 66, and 104 kDa in neutrophils treated with agonists. Treatment of neutrophils with alpha-cyano-3,4-dihydroxythiocinnamamide prior to stimulation with chemoattractants reduced tyrosine phosphorylation of the above phosphoproteins. 6. These results indicate that alpha-cyano-3,4-dihydroxythiocinnamamide might be a useful agent in characterizing the essential proteins and biochemical pathways that regulate neutrophil activation.

Calcium↗
PubMed1992

Two different sites of action for platelet activating factor and 1-O-alkyl-2-O-methyl-sn-glycero-3-phosphocholine on platelets and leukemic cells.

2-O-Methyl analogs of platelet activating factor (PAF) are potent anticancer agents. The sites of action and mechanisms of cell toxicity of these agents are as yet unknown. To better understand the mode of action of this class of anticancer agents, we examined the ability of 1-O-hexadecyl-2-acetylglycero-3-phosphocholine with the S or R configuration at C2 ((R)-PAF and (S)-PAF) and 1-O-hexadecyl-2-methoxyglycero-3-phosphocholine with the S or R configuration at C2 ((R)-ET-16-OCH3-GPC and (S)-ET-16-OCH3-GPC) to induce rabbit platelet aggregation and to inhibit [3H]thymidine uptake into WEHI-3B cells, HL-60 cells, and normal blood lymphocytes. The four chiral ether-linked lipids caused aggregation of rabbit platelets with the following order of potency: (R)-PAF greater than (S)-PAF greater than (R)-ET-16-OCH3-GPC greater than (S)-ET-16-OCH3-GPC; the EC50 values were 1 pM, 50 nM, 1 microM, and 50 microM, respectively. The cytotoxic effects of these ether lipids in leukemic cells was in reverse order to that observed for aggregation of platelets. The order of potency for inhibition of [3H]thymidine uptake by WEHI-3B and HL-60 cells was (R)-ET-16-OCH3-GPC = (S)-ET-16-OCH3-GPC greater than (S)-PAF greater than (R)-PAF; the EC50 values were 2, 2, 15, and greater than 40 microM, respectively. PAF antagonists (WEB 2086, CV 3988, triazolam, and SRI 63,441) blocked the action of the four ether lipids on platelets, while SRI 63,441 blocked the antineoplastic activity of the ether lipids on WEHI-3B and HL-60 cells. None of the four lipids was able to kill normal lymphocytes significantly. Scatchard analysis of PAF receptor binding revealed that HL-60 and WEHI-3B cells, which are sensitive to the cytotoxic action of ether-linked lipids, do not possess PAF receptors, whereas both normal lymphocytes and platelets do possess a PAF receptor. The present data indicate that the cytotoxic action of antineoplastic ether-linked lipids does not involve the PAF receptor. The protective role of SRI 63,441 in blocking the proaggregatory activity of the ether lipids in rabbit platelets involves PAF receptor, but cytotoxic activity against WEHI-3B and HL-60 cells does not result from its ability to act as a PAF antagonist.

Animals↗
PubMed1991

Solubilization of a functionally active platelet-activating factor receptor from rabbit platelets.

Binding of platelet-activating factor (PAF) to a specific high-affinity membrane receptor has been demonstrated in numerous cell types, but very little is known about the molecular nature of this receptor. The receptor from rabbit platelets was solubilized using CHAPS, digitonin, octyl glucoside, Nonidet P-40 or sodium cholate, either with pre-bound [3H]PAF or in the absence of ligand. We have been able to demonstrate for the first time that the receptor solubilized with CHAPS, in the absence of ligand, could retain its binding activity. It migrated as a high molecular mass complex (greater than 350 kDa) on a Bio-Gel A-0.5 m gel filtration column. Binding to solubilized receptor rapidly reached an equilibrium at room temperature, but was much slower at 0 degrees C. Scatchard plots were used to calculate the number (approx. 100 per cell) and the affinity (Kd 2.5 +/- 1.4 nM) of the solubilized receptors. These values were comparable with those obtained from whole-cell binding experiments. Competition by PAF antagonists also verified that the assay was measuring PAF receptor binding activity. The presence of a protein in the receptor complex was demonstrated by heat and trypsin inactivation of binding activity. Trypsin had no effect on binding of PAF to whole cells, but was able to decrease binding activity in solubilized receptor preparations. Attempts to demonstrate the involvement of a glycoprotein by use of various lectin columns proved unsuccessful. The latter results are consistent with findings suggesting that the binding site of the PAF receptor may not be exposed at the cell surface.

Animals↗
PubMed1991

Characterization of calcium-independent forms of protein kinase C-beta in phorbol ester-treated rabbit platelets.

The subcellular distribution, size, and activation state of protein kinase C (PKC) were studied after short term exposure of rabbit platelets to a saturating dose of 12-O-tetradecanoylphorbol 13-acetate (TPA). Cytosolic and Nonidet P-40-solubilized particulate extracts prepared from TPA-treated platelets were subjected to analytical column chromatography on Mono Q, hydroxylapatite, and Superose 6/12. PKC activity was assayed according to the ability of the enzyme to phosphorylate (i) histone H1 in the presence of the activators calcium, diacylglycerol, and phosphatidylserine; (ii) histone H1 after proteolytic activation of PKC with trypsin; and (iii) protamine in the absence of calcium and lipid. Within 1 min of TPA treatment of platelets, greater than 95% of the PKC activity was particulate associated, as assessed by all three methods. The particulate PKC activity from 1-min TPA-treated cells eluted from Mono Q with approximately 0.35 M NaCl (peak I), and it was highly dependent upon Ca2+ and lipid for optimal histone H1 phosphorylation. With longer exposure times of platelets to TPA, the disappearance of the Mono Q peak I form of PKC was correlated with the production of new PKC species that were released from Mono Q with approximately 0.4 M NaCl (peak II), approximately 0.5 M NaCl (peak III), and approximately 0.6 M NaCl (peak IV). These last forms of PKC were still lipid activated but exhibited little Ca2+ dependence. The Mono Q peak III form displayed a particularly high level of histone H1 phosphorylating activity in the absence of lipid and Ca2+. All of these forms behaved as approximately 65-kDa proteins on Superose 6/12, but on sodium dodecyl sulfate-polyacrylamide gels, Western blotting with anti-PKC-beta antibodies revealed immunoreactive polypeptides of approximately 79 kDa (Mono Q peaks I, II, and IV) and approximately 100-kDa (Mono Q peak III). Hydroxylapatite column chromatography permitted partial resolution of the Mono Q peaks I and II forms, which were eluted within a concentration range of potassium phosphate (100-150 mM) which was typical of the beta isozyme of PKC. Treatment of the Mono Q peak III and IV PKC forms with alkaline phosphatase resulted in the production of the peak I form, which implicated protein phosphorylation in the interconversion of the various PKC forms.

Alkaline Phosphatase↗
PubMed1991

The release of platelet-activating factor into plasma during allergen-induced bronchoconstriction.

Plasma histamine and platelet-activating factor (PAF) were measured in six subjects with mild seasonal asthma before and after allergen-induced bronchoconstriction, and in six other patients with asthma before and after methacholine-induced bronchoconstriction. A significant increase in plasma histamine and PAF levels was found in patients with mild seasonal asthma after allergen-induced bronchoconstriction but not in patients with asthma after bronchoconstriction induced by methacholine. There was a significant correlation between the baseline plasma PAF levels and the degree of bronchial hyperresponsiveness to methacholine. These findings suggests that PAF may be an important mediator in the pathogenesis of asthma and bronchial hyperresponsiveness.

Biological Assay↗
PubMed1991

Stimulation of human airway epithelial cells by platelet activating factor (PAF) and arachidonic acid produces 15-hydroxyeicosatetraenoic acid (15-HETE) capable of contracting bronchial smooth muscle.

Human airway epithelial cells grown to confluence were incubated with varying concentrations (10-100 microM) of arachidonic acid or platelet activating factor (PAF) for periods of 30 min to 24 h. Both stimuli caused the production of 15-hydroxyeicosatetraenoic acid (15-HETE) by epithelial cells as determined by HPLC. Neither stimulus caused the production of leukotrienes, thromboxane or prostaglandins aside from minimal amounts of PGE2. Maximal production of 15-HETE after arachidonic acid (10 microM; N = 9) occurred at 1 h (235 +/- 59 ng/mg protein), whereas maximum generation after PAF treatment (10 microM; N = 9) occurred at 6 h (153 +/- 48 ng/mg protein). Neither arachidonic acid nor PAF at concentrations up to 100 microM caused cell toxicity as determined by 51Cr release. 15-HETE at concentrations of greater than or equal to 0.1 microM contracted isolated human bronchus. An initial small amplitude, short-lasting (less than 15 min) contraction was followed by a much larger contraction beginning 30-60 min following 15-HETE challenge, reaching a maximum at approximately 2 hr. These results demonstrate that PAF may induce delayed airway smooth muscle contraction by the generation of 15-HETE from epithelial cells. The kinetics of 15-HETE generation and its contractile activity are compatible with it being a mediator of the late asthmatic reaction.

Arachidonic Acid↗
PubMed1991

Capsaicin inhibits airway hyperresponsiveness but not lipoxygenase activity or eosinophilia after repeated aerosolized antigen in guinea pigs.

To evaluate the role of tachykinins in airway hyperresponsiveness following repeated aerosolized antigen challenge in guinea pigs, we treated 12 guinea pigs with capsaicin (105.6 mg cumulative dose given subcutaneously over 5 days) after sensitization to ovalbumin (OA) and before three repeated OA aerosol challenges per wk for 4 to 5 wk. Ten guinea pigs received identical OA sensitization and challenges without capsaicin treatment, and four of eight nonsensitized controls received capsaicin followed by saline challenges. Capsaicin treatment did not alter antibody responses to OA as assessed by passive cutaneous anaphylaxis, nor did it alter lipoxygenase products from OA-stimulated bronchial tissue in vitro. Capsaicin completely inhibited the increased pulmonary resistance (RL) to acetylcholine produced by repeated aerosolized OA, whereas it did not alter baseline RL or acetylcholine responses of controls. Capsaicin did not alter airway eosinophilia induced by repeated aerosolized OA. We conclude that neuropeptides play an important role in antigen-induced airway hyperresponsiveness without altering antibody levels, lipoxygenase mediator production, or airway eosinophilia.

Acetylcholine↗
PubMed1991

Actions of platelet-activating factor on isolated rat hearts.

The actions of Platelet-Activating Factor (PAF) on isolated rat hearts were investigated. In a dose-dependent manner PAF decreased peak systolic pressure and maximum rate of rise of intraventricular pressure (+dP/dt(max]. PAF dose-dependently decreased coronary flow, prolonged the P-R interval of the EKG, and decreased heart rate. These actions of PAF were only partially blocked by drugs blocking receptors for PAF (CV 3988, WEB 2086), thromboxanes (ONO 3708), or leukotrienes (FPL 55712, L-655,240) or by a blocker of eicosanoid production (ibuprofen). Since depressed contractions will of themselves reduce coronary flow, PAF's action on flow was also investigated in hearts whose contractions were blocked by elevated potassium concentrations plus tetrodotoxin. Such treatment did not prevent PAF reducing coronary flow, indicating that a direct vasoconstriction occurred. The reductions in coronary flow in non-contracting hearts induced by PAF were equal to those induced by the coronary vasoconstrictors vasopressin and ergonovine under the same conditions. In order to isolate direct effects of PAF on myocardial contractile cells from effects mediated via changes in coronary flow, PAF was given to hearts maximally dilated by a concentration of nifedipine (0.03 microM) which had no effect on contractility. This concentration of nifedipine increased flow from 15.5 +/- 1.4 mL/min to 18.1 +/- 2.4 mL/min. In the presence of this nifedipine-induced vasodilation, PAF still exhibited negative inotropic actions, but without reducing coronary flow. Thus the effects of PAF on isolated rat hearts involve direct actions on both myocardial contracting cells and on coronary vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Detection of lyso-platelet-activating factor by high-performance liquid chromatography after derivatisation with fluorescent fatty acids.

Lyso-platelet-activating factor (lyso-PAF) was derivatised with 9-anthracenepropionic acid in the presence of dicyclohexylcarbodiimide, p-toluenesulfonic acid and 4-dimethylaminopyridine. The reaction yield exceeded 90% when the fatty acid was present in double molar amounts versus lyso-PAF. The procedure was equally effective in the derivatisation of other lysophospholipids. The derivatized phospholipids are detected by ultraviolet absorption (lambda = 253 nm) or fluorescence detection (using excitation at 254 nm and emission at 450 nm). The technique was applied successfully to the detection of lyso-PAF in complement activated rabbit plasma.

4-Aminopyridine↗
PubMed1990

Translocation-independent activation of protein kinase C by platelet-activating factor, thrombin and prostacyclin. Lack of correlation with polyphosphoinositide hydrolysis in rabbit platelets.

The relationship between polyphosphoinositide hydrolysis and protein kinase C (PKC) activation was explored in rabbit platelets treated with the agonists platelet-activating factor (PAF), thrombin and 12-O-tetradecanoylphorbol 13-acetate (TPA), and with the anti-aggregant prostacyclin (PGI2). Measurement of the hydrolysis of radiolabelled inositol-containing phospholipids relied upon the separation of the products [3H]inositol mono-, bis- and tris-phosphates by Dowex-1 chromatography. PKC activity, measured in platelet cytosolic and Nonidet-P40-solubilized particulate extracts that were fractionated by MonoQ chromatography, was based upon the ability of the enzyme to phosphorylate either histone H1 in the presence of the activators Ca2+, diacylglycerol and phosphatidylserine, or protamine in the absence of Ca2+ and lipid. Treatment of platelets for 1 min with PAF (2 nM) or thrombin (2 units/ml) led to the rapid hydrolysis of inositol-containing phospholipids, a 2-3-fold stimulation of both cytosolic and particulate-derived PKC activity, and platelet aggregation. Exposure to TPA (200 nM) for 5 min did not stimulate formation of phosphoinositides, but translocated more than 95% of cytosolic PKC into the particulate fraction, and induced a slower rate of aggregation. PGI2 (1 microgram/ml) did not enhance phosphoinositide production, and at higher concentrations (50 micrograms/ml) it antagonized the ability of PAF, but not that of thrombin, to induce inositol phospholipid turnover, even though platelet aggregation in response to both agonists was blocked by PGI2. On the other hand, PGI2 alone also appeared to activate (by 3-5-fold) cytosolic and particulate PKC by a translocation-independent mechanism. The activation of PKC by PGI2 was probably mediated via cyclic AMP (cAMP), as this effect was mimicked by the cAMP analogue 8-chlorophenylthio-cAMP. It is concluded that this novel mechanism of PKC regulation by platelet agonists may operate independently of polyphosphoinositide turnover, and that activation of cAMP-dependent protein kinase represents another route leading to PKC activation.

Animals↗
PubMed1990

Erbstatin blocks platelet activating factor-induced protein-tyrosine phosphorylation, polyphosphoinositide hydrolysis, protein kinase C activation, serotonin secretion and aggregation of rabbit platelets.

The role of protein-tyrosine phosphorylation in the signal transduction of platelet activating factor (PAF) was investigated in rabbit platelets with a range of synthetic compounds that inhibit protein-tyrosine kinases. In particular, erbstatin (IC50 approximately 20 micrograms/ml) abrogated a wide range of platelet responses to PAF, including tyrosine phosphorylation of cellular proteins, polyphosphoinositide turnover, activation of membranous protein kinase C, platelet aggregation, and serotonin secretion. With about a third of the potency of erbstatin, compound RG50864 also inhibited many of these responses, whereas at 100 micrograms/ml, genistein, 670C88 and ST271 were without effect. Finally, the ability of thrombin to cause platelet aggregation and serotonin secretion was also compromised by erbstatin.

Animals↗
PubMed1990

Protein kinase C activation by platelet-activating factor is independent of enzyme translocation.

The subcellular distribution and activation state of protein kinase C (PKC) was studied after short-term exposure of rabbit platelets to platelet-activating factor (PAF). Cytosolic and nonidet P-40-solubilized particulate extracts prepared from treated platelets were subjected to analytical column chromatography on MonoQ, hydroxylapatite and Superose 6/12. PKC activity was assayed by the ability of the enzyme to phosphorylate the following substrates: (i) histone H1 in the presence of the activators calcium, diacylglycerol and phosphatidylserine; (ii) histone H1 following proteolytic activation of PKC with 0.5 micrograms trypsin/ml; and (iii) protamine in the absence of calcium and lipid. PAF treatment for 1-20 min elicited a rapid 2-4-fold activation of both cytosolic and particulate-derived PKC as assessed by all three methods. On the other hand, there were no significant PAF-induced changes in the level of [3H]phorbol-12,13-dibutyrate binding by soluble and particulate-associated PKC. Hydroxyapatite column chromatography revealed that in non-treated rabbit platelets the type II (beta) form of PKC predominated, but PAF appeared to induce a shift in the elution profile from this resin. The stability of the PAF activation of PKC to column chromatography and the altered binding affinity to hydroxylapatite indicated that the stimulation might be a consequence of covalent modification, albeit minor, since PKC still eluted as an 80 kDa protein from Superose 6/12. As the PAF-induced increases in the kinase activity of PKC were preserved even after proteolytic activation with trypsin, but were without effect on the phorbol ester binding activity, such a putative modification may have occurred within or near the catalytic domain of PKC. These findings imply that PAF may directly modulate the activity of preexisting membrane-associated PKC by a novel mechanism, rather than by eliciting its recruitment from the cytoplasm.

Amino Acid Sequence↗
PubMed1990

Generation of platelet activating factor (PAF) by a human lung epithelial cell line.

A human lung epithelial cell line (ATC-CCL-185) was cultured in nutrient Ham-F12 medium. Cells in monolayers were stimulated with either ionophore A23187 (1 microM) or phorbol myristate acetate (PMA, 0.2 microM) for various periods of time. Samples were analysed by HPLC and the presence of platelet activating factor (PAF) was detected by bioassay of the release of [3H]serotonin from rabbit platelets undergoing aggregation. The ATC-CCL 185 cells were found to synthesize PAF following activation with either PMA or ionophore. Ionophore at 1 microM was found to be more potent than PMA at 0.2 microM in the induction of PAF synthesis (congruent to 80 ng/mg protein). The synthesis of PAF through ionophore stimulation reached a maximum at 5 min, whereas PMA stimulation peaked at 15-20 min. PMA induced approximately one third the level of PAF synthesis by the ionophore. The PAF synthesized by these CCL185 cells was found to be mainly associated with the cell membrane with less than 10% released into the medium. Release of PAF into cell supernatant was dependent on the presence of bovine serum albumin (BSA). In the absence of BSA, a large portion (approximately 90%) of PAF was found to be cell associated, and only 60% when BSA concentration reached greater than or equal to 0.2%. These results demonstrate the ability of this lung epithelial cell line to synthesis PAF thus, suggesting that epithelial cells might participate in the process of inflammatory lung diseases, through the generation of this important mediator.

Animals↗
PubMed1990

Synthesis and antineoplastic properties of ether-linked thioglycolipids.

Ether-linked glycero-alpha- and beta-D-glucopyranosides and glycero-1-thio-alpha- and beta-D-glucopyranosides have been synthesized by modifications of the Königs-Knorr procedure, and their antitumor activities have been evaluated. The bioactivities of these compounds have been evaluated in five different cell lines (WEHI 3B, C653, X63/OMIL3, R6X-B15, and HL-60) and compared with the activities of 1-O-hexadecyl-2-O-methyl-sn-3-glycerophosphocholine (GPC) and its enantiomer, 3-O-hexadecyl-2-O-methyl-sn-1-GPC. The results indicate that a alpha-D-thioglucopyranoside [1-O-hexadecyl-2-O-methyl-3-S-(alpha-D-1'- thioglucopyranosyl-sn-glycerol)] is selective with respect to its action on target cells, with high activity for killing of WEHI 3B and C653 cells as determined by inhibition of [3H]thymidine incorporation into DNA and HL-60 cell cytotoxicity, but unable to induce aggregation of rabbit platelets at 10(-5) M. The corresponding beta-linked thioglycolipid was ineffective with respect to cytotoxicity against each cell line tested, indicating the importance of configuration at the anomeric position; the beta-thioglycoside was also ineffective with respect to inducing platelet aggregation. 1-O-Hexadecyl-2-O-methyl-sn-3-GPC and 3-O-hexadecyl-2-O-methyl-sn-1-GPC were potent inhibitors of growth of each cell line tested but also caused rabbit platelet aggregation at concentrations greater than or equal to 10(-7) M. Thus, 3-S-(alpha-thioglycopyranosyl)-sn- glycerols bearing a long-chain O-alkyl group at the sn-1 position and a methoxy group at the sn-2 position of glycerol appear to be a promising class of antineoplastic agents with lower risk of inducing thrombosis than the widely studied platelet activating factor analogue, 1-O-octadecyl-2-O-methyl-rac-3-GPC.

Animals↗