The effects of platelet activating factor (PAF) and its cell analogs 1-O-alk-1;-enyl-2-acetyl-sn-glycero-3-phosphocholine (1-alkenyl-PAF) and 1-acyl-2-acetyl-sn-glycero-3-phosphocholine (1-acyl-PAF) on chemotaxis of human leukocytes in vitro and their inflammatory and antiinflammatory activities in vivo were studied. Both analogs stimulated chemotaxis of human leukocytes in agarose gel. PAF and 1-alkenyl-PAF induced rat paw edema in the range of doses 0.1-10 and 10-100 micro g per paw, respectively. Paw edema induced by 1-acyl-PAF (10-100 micro g per paw) was more pronounced than that induced by PAF or 1-alkenyl-PAF. The latter also exhibited significant antiinflammatory effect by inhibiting PAF- or carrageenan-induced rat paw edema, and this effect exceeded that of dexamethasone. In these models of inflammation 1-acyl-PAF did not exhibit any antiinflammatory activity. The data suggest that PAF is not the only cell phospholipid mediating inflammation--its cell analogs, 1-acyl-PAF and 1-alkenyl-PAF, may also be involved into the inflammatory response. Possible interrelationships between cellular synthesis of 1-acyl-PAF, its formation in oxidized LDL, biological effects of lysolecithin, and penetration of LDL into the arterial wall are discussed.
The influence of acetyl salicylic acid (ASA) derivatives with platelet-activating factor (PAF) lipid analogs on PAF-induced human platelet aggregation has been studied. It was found that the ASA amide with an ethanolamine plasmalogen PAF analog (1-0-alk-1'-enyl-2-acetyl-sn-glycero-3-phospho-(N-2'-acetoxybenzoyl)ethanolamine) and the ASA ester with a choline plasmalogen PAF analog (1-0-alk-1'-enyl-2-(2'-acetoxybenzoyl)-sn-glycero-3-phosphocholine) at concentrations of 10-7-10-6 M effectively inhibit PAF-induced aggregation of human platelets. In contrast to these compounds, the ASA amide with an alkyl PAF analog (1-0-alkyl-2-acetyl-sn-glycero-3-phospho-(N-2'-acetoxybenzoyl)ethanolamine) did not inhibit PAF-induced platelet aggregation. As possible mechanisms of action of the studied compounds, the blockade of PAF-receptor and cyclooxygenase inhibition are proposed.
Prostaglandin (PG) El was demonstrated to stimulate the transfer of phosphatidylcholine and cholesterol esters from human high density lipoproteins (HDL3) to low density lipoproteins (LDL). The enhancement effect of PGE~ on the interlipoprotein lipid transfer was seen at low PG concentrations under conditions of spontaneous exchange as well as in the presence of lipoprotein-depleted plasma, or partly purified plasma lipid exchange protein. PGE2 and PGF2~ showed no significant influence on the interlipoprotein lipid transfer. Evidence is presented suggesting that the PGEl-induced stimulation of interlipoprotein lipid exchange results in enhancement of LCAT-catalyzed cholesterol esterification in plasma. It is proposed that the effect of PGEj is due to the previously described PGEi-induced reorganization of the HDL surface [(1984) FEBS Lett. 173,291-293] and that PG-lipoprotein interaction may be a factor regulating cholesterol homeostasis.
Prostaglandin El has been shown to interact with serum high density lipoproteins (HDL) in a manner resembling the interaction of a ligand with a high affinity binding site. The presence of 10-12-10-'o M prostaglandin El induces a rearrangement of the HDL surface lipids and probably influences the biological functions of the lipoproteins. Fluorescent phospholipid probe High density lipoprotein Prostaglandin EI
Affinity resins containing covalently bound phospholipids were used to compare the affinity of the phosphatidylcholine transfer protein from beef liver and a low-specificity lipid transfer protein from rat hepatoma 27 to phosphatidylcholine and sphingomyelin. Binding experiments demonstrated that the beef liver protein associates specifically with immobilized phosphatidylcholine whereas the hepatoma protein showed a preference for sphingomyelin.Purified antiserum raised against the hepatoma sphingomyelin transfer protein was used to determine the presence of that protein in the cytosol of various experimental tumors as well as in those of normal, regenerating and fetal rat liver. The protein was found to be well expressed in all the tumors examined and in fetal liver as determined by immunodiffusion whereas only minute amounts could be detected in normal liver and in 30-h regenerated liver. The presence of the sphingomyelin transfer protein in cytosol was in parallel with the presence of sphingomyelin in the corresponding mitochondria. It is suggested that the occurrence of sphingomyelin in tumor and fetal liver mitochondria may be due to protein-catalyzed sphingomyelin transfer from the endoplasmic reticulum.A number of phospholipid transfer proteins have been purified from a variety of biological tissues (for reviews see [I, 21 and also [3-91). A common feature of all these intracellular transport lipoproteins is that they either do not use sphingomyelin as substrate or catalyze the transfer of sphingomyelin to a much smaller extent than that of phosphatidylcholine. Recently a new lipid transfer protein has been isolated from rat hepatoma 27 which is capable of transferring sphingomyelin at least as efficiently as phosphatidylcholine [lo]. Such a lipid transfer protein could not be detected in rat liver, and the liver postmicrosomal supernatant was not capable of transferring sphingomyelin from rat liver microsomes to mitochondria [lo].Since mitochondria from various tumors frequently show elevated sphingomyelin levels [I 1 -151 it seemed possible that the occurrence of sphingomyelin in tumor mitochondria may be related to the action of sphingomyelin transfer proteins that are absent or less expressed, in normal cells. In this connection it was thought of interest to study further the phospholipid specificity of the rat hepatoma lipid transfer protein and to find out whether the mitochondrial sphingomyelin content in different rat tissues correlates with the presence of sphingomyelin transfer protein in the corresponding cytosol. In this paper we compare the phosphatidylcholine and sphingomyelin binding capacities of the hepatoma lipid transfer protein to those of the specific phosphatidylcholine transfer protein from beef liver using affinity resins containing covalently bound sphingomyelin and phosphatidylcholine. We report further on an immunological examination of the presence of the hepatoma lipid transfer protein in the cytosol of several rat tumors, fetal, regenerating and normal liver. In addition dat...
, and phospholipids with ether and thioester bonds [7,8], and antibiotic mitomycin C conjugated with cholesteryloxycarbonylglycine [9]. The other group includes synthesized and characterized lipid derivatives of antiviml preparations such as acyclovir [10], phosphonoformate [11], and azidothymidine, dideoxycytidine, and dideoxythymidine known to be highly active with respect to the human immunodeficiency virus (HIV) [12]. Transformation of 7-aminobutyric acid (GABA) into 1,2-dipalmitoylglyceric or 1-acylglyceric esters allowed the concentration of this neuromediator in the brain to be increased by more than two orders of magnitude [13 -15]. Other promising directions are the modification of immunoglobulins [ 16], bacterial antigens and vaccinal preparations [17,18] that in many cases makes it possible to increase their efficiency. This work is not an attempt to consider and summarize the results of all investigations devoted to the lipophilic modification of biologically active compounds (including drugs) because these objects are rather dissimilar and differ markedly in their spectra and mechanisms of action. The purpose of this review is to demonstrate the possibilities and prospects of the lipophilic modification of biologically active compounds in the case of prostaglandins and nonsteroidal antiinflammatory drugs. The choice of these groups of biologically active compounds is mostly due to the fact
Plasma level of lipid-standardized vitamin E is decreased, while the concentration of inflammatory transmitters C3a(desArg) and C5a(desArg) is elevated in heterozygous familial hypercholesterolemia caused by apoB,E-receptor deficiency. Leukocytes isolated from these patients exhibit enhanced spontaneous aggregation of superoxide anion generation and are resistant to activation with exogenous platelet activation factor (10 -6 M).
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