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Biomedical subjects

S Colli

Publications and source records attributed to S Colli.

At least 37 records · Page 2Linked to original sources
PubMed1993

Changes of n-3 and n-6 fatty acids in plasma and circulating cells of normal subjects, after prolonged administration of 20:5 (EPA) and 22:6 (DHA) ethyl esters and prolonged washout.

Eight normal volunteers (four men and four women) were treated with 3 x 1 g capsules of n-3 fatty acid ethyl esters for a period of 18 weeks, followed by a 24 week washout. Fatty acids of plasma, platelets, monocytes and red blood cells were analyzed at 0, 6, 12 and 18 weeks of treatment and at 4, 14 and 24 weeks of washout. During treatment, accumulation of EPA in plasma and cells was almost maximal at 6 weeks, whereas that of DHA reached a peak at 18 weeks. Arachidonic acid declined somewhat at 12 weeks in plasma and more markedly at 18 weeks in red blood cells and monocytes. During washout, EPA returned rapidly toward pretreatment values in all compartments, but it remained significantly higher in plasma and platelets at the end of washout. DHA declined more slowly, maintaining higher than basal values in plasma and platelets and lower than basal in red blood cells, at the end of washout. Rebound increments of AA occurred in plasma. Finally, the plasma levels of AA, but not those of the n-3 fatty acids, were more markedly modified in males than in females. The presented results suggest interactions between circulating fatty acids in the different compartment after n-3 FA administration, and indicate that very long washouts are necessary for a complete recovery from the induced fatty acid modifications.

Adult↗
PubMed1993

Influences of lipid-modifying agents on hemostasis.

Drugs affecting lipid metabolism may influence, to a variable extent, the hemostatic system, that is, platelet activation, fibrinogen, and fibrinolysis. These effects may or may not be linked to the activity of these compounds on the lipid/lipoprotein profile. For this reason it may be important to consider the effects of hypolipidemic drugs on the different aspects of hemostasis, because this may allow a better understanding of their clinical use, as well as, eventually, a more proper selection in individual patients. Among the major lipid-lowering agents, fibric acids belong to a multifaceted series of abnormal fatty acids known to interact with a liver nuclear receptor, in turn activating fatty acid catabolism. A similar activity may be exerted by n-3 fatty acids from fish, as well as by other chemically related or unrelated compounds. Among fibric acids all but gemfibrozil can reduce fibrinogen levels; this last drug can, however, apparently activate fibrinolysis. Among the selective cholesterol-lowering medications, both resins and HMG CoA reductase inhibitors may reduce, in some patients, over prolonged periods of treatment, platelet sensitivity to major aggregants. This effect may be seen best with non-liver-selective agents (e.g., simvastatin), although recent data cast doubt on its constancy. A direct comparative evaluation of different HMG CoA reductase inhibitors on platelet aggregability has never been carried out. These last drugs may also reduce the circulating levels of the tissue factor pathway inhibitor (TFPI), transported by LDL in plasma, which is a potentially negative effect. A lipid-lowering molecule with antioxidant activity, for example, probucol, may also possibly play a role in controlling platelet activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗
PubMed1993

Increased synthesis of plasminogen activator inhibitor-1 by cultured human endothelial cells exposed to native and modified LDLs. An LDL receptor-independent phenomenon.

The effects of native and acetylated low density lipoproteins (LDLs and acetyl-LDLs, respectively) on the release of plasminogen activator inhibitor type 1 (PAI-1) by cultured human umbilical vein endothelial cells (ECs) were evaluated. LDL and acetyl-LDL incubated with ECs for 16-18 hours increased the PAI-1 antigen levels in conditioned medium. At a concentration of 100 micrograms/mL, LDL and acetyl-LDL increased PAI-1 by 10.8 and 12.0 ng/mL, respectively (p < 0.05 and p < 0.01 versus control). The increases in PAI-1 antigen levels exerted by the lipoproteins paralleled the changes in PAI-1 activity. The effect of LDL and acetyl-LDL was concentration dependent and specific for PAI-1 because tissue-type plasminogen activator and expression of procoagulant activity were not affected by either lipoprotein. In addition, total protein synthesis evaluated in [35S] methionine-labeled ECs was not affected, and studies with cycloheximide showed that the effect of LDL and acetyl-LDL on PAI-1 release was due to de novo protein synthesis. Experiments using the C7 monoclonal antibody against the LDL receptor and binding-defective LDL indicated that the effect of LDL on the synthesis of PAI-1 was not dependent on the interaction of the LDLs with their specific receptors. Finally, extensive oxidation of LDL prevented and even reversed the effect of LDL on PAI-1 release by ECs. It is concluded that LDL specifically increases the synthesis of PAI-1 by ECs with mechanisms that are not receptor mediated.

Cells, Cultured↗
PubMed1993

Effect of atherogenic lipoproteins on PAI-1 synthesis by endothelial cells.

Cultured human umbilical vein endothelial cells (EC) exposed to native and acetylated low density lipoproteins (LDL and acetyl-LDL) show an increased synthesis of PAI-1. Confluent EC monolayers were incubated for 16-18 hours in medium 199 with or without different concentrations of LDL and acetyl-LDL and PAI-1 antigen levels were measured in conditioned medium. LDL and acetyl-LDL increased the release of PAI-1 by EC in a concentration-dependent manner. The effect was specific for PAI-1 because tissue type plasminogen activator (t-PA) and expression of procoagulant activity were not affected by either lipoprotein. The observation that native and acetyl-LDL, which are known to interact with different receptors on EC, exert the same stimulatory effect on PAI-1 release rules out the possibility of an involvement of the LDL receptor in mediating this effect. Experiments carried out incubating native LDL in the presence of a monoclonal antibody against LDL receptor and using binding-defective LDL with a reduced affinity for the LDL receptor (approximately 50% with respect to normal LDL) further excluded an involvement of the classical LDL receptor in mediating the effect of the lipoproteins on PAI-1 synthesis by EC.

Arteriosclerosis↗
PubMed1993

Quantitative changes of hydroxyacid formation during platelet-neutrophil interaction.

In recent years the interactions between lipoxygenase enzymes present in platelets and leukocytes, resulting in the transcellular biosynthesis of eicosanoids, have been discovered and their relevance in thrombotic and inflammatory disorders recognized. However, attention has focused on the synthesis of novel products, not normally formed by the single-cell population. Less information is available on the changes in hydroxyacid formation during platelet-neutrophil interactions. In this study, we evaluated the quantitative changes of the levels of 12- and 5-hydroxyeicosatetraenoic acids, leukotriene B4, and thromboxane B2 occurring during the incubation of platelet-neutrophil mixed suspensions stimulated with the calcium ionophore A23187. Cell-to-cell interaction resulted in quantitative changes of the level of hydroxyacids; in mixed platelet-neutrophil suspensions, the levels of 12-hydroxyeicosatetraenoic acid were significantly increased with respect to those measured in platelets incubated alone. The amount of 5-hydroxyeicosatetraenoic acid formed by neutrophils was significantly decreased by the presence of platelets in the incubation medium. In addition, a slight but significant reduction in leukotriene B4 synthesis was observed. Concomitantly with these changes, the formation of thromboxane B2 by platelets was modified, indicating that--besides the lipoxygenase pathway--the arachidonic acid metabolism by cyclooxygenase is affected. Our study demonstrates that in mixed platelet-neutrophil suspensions profound quantitative modifications in hydroxyacid and thromboxane synthesis occur, indicating that the overall balance of arachidonic acid products may be altered in pathologic conditions in which early events of multicellular origin have been recognized.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1992

Olive oil, corn oil, and n-3 fatty acids differently affect lipids, lipoproteins, platelets, and superoxide formation in type II hypercholesterolemia.

To evaluate which dietary fat may provide the best response in terms of plasma lipids and lipoproteins and also of platelet aggregability and superoxide formation by white blood cells, 12 type II patients were randomly allocated to three different diets, which provided polyunsaturated fatty acids (corn oil), monounsaturated fatty acids (olive oil), and a supplementation of ethyl esters of n-3 fatty acids to a prudent diet. Olive oil and, more significantly, n-3 ethyl esters lowered total cholesterol best (-2.2% and -5.8%, respectively); the latter diet, as expected, also significantly lowered triglyceridemia (-21.4%). The corn-oil diet exerted a small, statistically significant reduction of high-density-lipoprotein cholesterol (HDL) (-4.3%), and it also lowered plasma total apo B concentrations (-3.8%). n-3 ethyl esters significantly raised both total (+3.1%) and particularly HDL2 cholesterol (+24%). Platelet reactivity was insignificantly reduced by the three regimens, but all three significantly reduced thrombin-stimulated formation of thromboxane B2. Finally, only the n-3 fatty acid supplementation significantly reduced O2- generation by adherent monocytes. Dietary unsaturated fatty acids are generally effective on the plasma lipid and lipoproteins in type II patients, but significant differences may be found between the three tested regimens.

Apolipoproteins↗
PubMed1991

Effects of tenoxicam on superoxide anion formation, beta-glucuronidase release and fMLP binding in human neutrophils: comparison with other NSAIDs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are considered to exert their activity by interfering with the generation of arachidonate metabolites in various cells, mainly in neutrophils and monocytes. The inhibition of cellular cyclooxygenase enzyme, however, does not always correlate with the in vivo activity of these drugs. Recent evidence indicates that several NSAIDs may interfere with the stimulus-response coupling of inflammatory cells. In this study, the effects of tenoxicam, an oxicam derivative with a thienothiazine structure, on neutrophil activation were evaluated by the assessment of the following parameters: (1) superoxide anion generation by neutrophils and whole blood stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP), the calcium ionophore A23187 and serum treated zymosan (STZ); (2) beta-glucuronidase release from neutrophils stimulated with fMLP, A23187 and STZ; (3) binding of [3H]fMLP to intact neutrophils. The results were compared to those obtained using piroxicam and diclofenac. Tenoxicam, added in vitro to whole blood, at concentrations ranging between 10(-5) and 3 x 10(-4) M, significantly inhibited the generation of superoxide anion induced by fMLP, A23187 and STZ. The activity of tenoxicam on whole blood was similar to that of piroxicam, whereas diclofenac had only minimal effects on this experimental system. In isolated cells tenoxicam inhibited the generation of superoxide anion induced by A23187 and STZ. In addition, at the 3 x 10(-4) M concentration, tenoxicam and diclofenac similarly inhibited O2- generation by neutrophils stimulated with fMLP, whereas piroxicam only minimally affected this parameter. Tenoxicam also slightly, but not significantly, inhibited beta-glucuronidase release by isolated neutrophils induced by all the agonists used. Specific binding of [3H]fMLP to neutrophils was inhibited by the three NSAIDs tested in a dose-dependent fashion and tenoxicam was the most potent. The affinities (Kd) of tenoxicam, piroxicam and diclofenac were 1.11, 1.80 and 2.70 x 10(-5) M, respectively. The mechanism of inhibition of [3H]fMLP binding by tenoxicam was non-competitive. It is concluded that tenoxicam, at concentrations achievable in plasma at steady state, effectively inhibits some of the processes involved in neutrophil activation, which bear some relevance in the inflammatory disease.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Multiple effects of dipyridamole on neutrophils and mononuclear leukocytes: adenosine-dependent and adenosine-independent mechanisms.

Dipyridamole is an antithrombotic drug that has been shown to influence not only platelet function but also some aspects of leukocyte activation. In this study we demonstrate that dipyridamole effectively inhibits superoxide anion generation by neutrophils, mononuclear leukocytes, and whole blood stimulated with N-formyl-methionyl-leucyl phenylalanine and calcium ionophore A23187. In addition, the drug, at concentrations as low as 1 mumol/L, inhibits the expression of procoagulant activity--basal and stimulated--by mononuclear leukocytes. It is shown that, similar to its effect on platelets, dipyridamole influences these leukocyte functions indirectly, that is, through an increase of extracellular adenosine that in turn inhibits both superoxide anion generation by leukocytes and the expression of procoagulant activity by mononuclear leukocytes. In fact, adenosine deaminase, which metabolizes adenosine to inactive product, prevents the effects of dipyridamole on superoxide anion generation and on the expression of procoagulant activity by leukocytes. Experiments carried out with 8-phenyl-theophylline indicate that the adenosine-dependent effects of dipyridamole may involve multiple pathways, only some of which are dependent on the interaction of adenosine with its receptors. Dipyridamole also dose-dependently inhibits the synthesis of leukotrienes B4 and C4 by stimulated neutrophils and mononuclear leukocytes through a mechanism that is not mediated by the presence of adenosine in the extracellular medium. The reported effects of dipyridamole on separate and distinct pathways involved in leukocyte activation are of relevance in the overall evaluation of the antithrombotic activity of this drug.

Adenosine↗
PubMed1990

Diets rich in n-9, n-6 and n-3 fatty acids differentially affect the generation of inositol phosphates and of thromboxane by stimulated platelets, in the rabbit.

We have studied the effects of semi-synthetic diets rich in either n-9 (olive oil, OO) or n-6 (corn oil, CO), or n-3 (fish oil, FO, as MaxEPA) fatty acids on the levels of major PUFA in platelet lipids, on the generation of inositol phosphates by [3H]inositol labelled platelets after stimulation with thrombin and of thromboxane B2 (TxB2) by platelet rich plasma (PRP) after stimulation with collagen. The predicted elevations of oleic (OA), linoleic (LA) and eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids were observed in platelet lipids of each animal group, but in the MaxEPA fed group accumulation of EPA was associated with depletion of linoleic acid (LA) rather than of arachidonic acid (AA). Basal levels of inositol-tris-phosphate (IP3) in platelets were lowest in the OO group and highest in the CO group, whereas the increment after thrombin stimulation (1 unit/ml NIH) was maximal in the OO group and minimal in the FO group. Instead, when generation of TxB2 by stimulated platelets was evaluated, no appreciable difference among the various groups could be detected, in accordance with the limited modifications of platelet AA content induced by the diets. The overall data indicate that dietary fatty acids modulate the pathway of inositol phosphate generation in rabbit platelets, independently of modifications of TxB2 production.

Animals↗
PubMed1989

Inhibition of human neutrophil aggregation by albumin. Relationship with cytoskeleton reorganization.

Albumin, at concentration normally present in plasma (approximately 600 microM), significantly inhibited leukotriene B4 formation induced by a receptor mediated (fMet-Leu-Phe) and a receptor independent (calcium ionophore A23187) stimuli in human neutrophils. The inhibition of leukotriene B4 synthesis was accompanied by a concomitant reduction of neutrophil aggregation. In addition, this plasma protein prevented the increase in F-actin content of neutrophils stimulated with fMet-Leu-Phe and A23187, thus suppressing actin polymerization. These data indicate that albumin profoundly affects biochemical and functional aspects of neutrophils suggesting, for this plasma protein, a regulatory role in the overall pattern of the inflammatory reaction.

Actins↗
PubMed1989

Albumin interferes with arachidonate metabolism in platelets and neutrophils.

The in vitro effects of albumin (150-600 microM) on arachidonate metabolism are compared in two types of circulating cells, platelets and neutrophils. The effect of this plasma protein on a functional aspect common to both these blood components, i.e. aggregation, was also investigated. Bovine serum albumin (BSA) significantly inhibited thromboxane B2 formation by washed platelets stimulated with threshold concentrations of collagen. In addition, this protein profoundly affected the formation of the major products via the lipoxygenase pathways, i.e., 12-hydroxyeicosatetraenoic acid and leukotriene B4 by platelets and neutrophils, respectively. This inhibitory effect was also confirmed for both types of cells considered on aggregation. Albumins of human origin and human plasma behaved similarly to BSA on the above parameters. Although the mechanism(s) responsible for the described effects require(s) additional studies, albumin, affecting platelet and neutrophil arachidonate metabolism, as well as the aggregatory response, might influence, in some conditions, cell activation.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1988

Vitamin E influences the effects of fish oil on fatty acids and eicosanoid production in plasma and circulating cells in the rat.

An EPA enriched oil (MaxEPA, Seven Seas, U.K. containing 18% EPA and 12% DHA) alone or supplemented with 10 mg/ml/alpha tocopherol, was administered by gastric intubation at the dose of 3.2 ml/kg/day for a period of eight weeks to male rats fed a standard diet. An additional group of animals was treated with the same amount of olive oil. The administration of MaxEPA alone resulted, as expected, in accumulation of EPA and reduction of AA levels in plasma, platelet, red blood cell and PMNL phospholipids, when compared to values in the olive oil group. In addition, levels of linoleic acid were elevated, suggesting inhibition of the conversion of linoleic to arachidonic acid. Formation of i.r. TxB2 by stimulated PRP, of i.r. 6-keto-PGF1 alpha by perfused aortas, and of IR LTB4 and C4 by stimulated PMNL were reduced, but production of superoxide anion by PMNL was enhanced by MaxEPA treatment vs the olive oil treatment. Supplementation of MaxEPA with vitamin E caused a smaller reduction of 20:4 levels and a smaller increase of 20:5 levels in plasma and cell phospholipids and modified the effects of MaxEPA on eicosanoid and superoxide anion production, suggesting that lipid peroxidation may mediate some of the biological effects of omega 3 fatty acids.

Animals↗
PubMed1988

Phosphatidylinositol (PI) and PI-associated arachidonate are elevated in platelet total membranes of type IIa hypercholesterolemic subjects.

The lipid composition (phospholipid distribution and fatty acid patterns of individual glycerophospholipids) and levels of lipid components (cholesterol, total and individual phospholipid classes, arachidonic acid) have been determined in total membranes of platelets from type IIa hypercholesterolemic (HC) and control (C) subjects. Levels of cholesterol and total phospholipid, relative to the protein content, were about 80% and 60% higher respectively in platelet total membranes from HC subjects. Small differences between the two groups of samples were observed for the phospholipid distribution and the fatty acid patterns. Concentrations of individual phospholipid classes, were on the average 60% higher in HC than in C platelet membranes, with an even greater difference for phosphatidylinositol (PI) and sphingomyelin. Levels of arachidonic acid, relative to the protein content, were also 60-80% higher in membranes from HC platelet with a more than 100% increase in PI. The higher levels of the eicosanoid precursor fatty acid in phospholipids and especially in PI, which is considered a donor pool for eicosanoid synthesis, may be a contributing factor for the greater thromboxane formation and enhanced aggregation, upon stimulation, of platelets from HC patients in comparison to platelets from control subjects.

Adult↗
PubMed1988

Reduced platelet aggregability and increased vascular prostacyclin formation in a variant rat strain (IVA-SIV) with endogenous hypertriglyceridemia.

The Ivanovas-Sieve (IVA-SIV) rat represents the only available animal model of endogenous hypertriglyceridemia, in the absence of obesity and/or overt diabetes. Since plasma lipids/lipoproteins can modulate platelet reactivity and eicosanoid metabolism, these were examined in two groups of Charles River (CR) and IVA-SIV rats of identical age. The IVA-SIV rats had 2-fold higher plasma triglycerides and a 55% higher number of circulating platelets; the number of platelets was significantly correlated with triglyceridemia. Platelet reactivity to ADP and to collagen was significantly reduced in these animals, whereas the formation of thromboxane B2 did not differ from that of the CR. After perfusion of platelet-rich plasma (PRP) through the aortas of animals of the two strains, platelet aggregability, already lower in the IVA-SIV, was reduced to a higher extent compared to the CR. Increased levels of the prostacyclin metabolite 6-keto-PGF1 alpha were identified in the perfusate from the aortas of IVA-SIV rats. Platelets from these animals also showed an increased sensitivity to Iloprost, a stable prostacyclin analogue, with an IC50 1.7-fold lower compared to CR rats. Spontaneous hypertriglyceridemia in the IVA-SIV model is not associated with platelet hyperresponsiveness, but rather with a reduced sensitivity to major aggregants.

6-Ketoprostaglandin F1 alpha↗