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Biomedical subjects

E Tremoli

Publications and source records attributed to E Tremoli.

At least 73 records · Page 4Linked to original sources
PubMed1993

Functionally abnormal monocytes in hypercholesterolemia.

We investigated some functions of monocytes from 20 type IIa hypercholesterolemic (HC) and five homozygous familial hypercholesterolemic (FH) patients. Monocytes from the HC patients contained as much cholesterol and formed as much thromboxane B2 in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) or calcium ionophore A23187 as those from normal individuals. In contrast, the generation of prostaglandin E2 and 6-ketoprostaglandin F1 alpha in response to these agonists was 1.5-3 times normal, and that of leukotriene B4 was 40-60% of the normal value (p < 0.05 for all). Studies in which the combination of fMLP or A23187 with sodium arachidonate were employed suggested that these abnormalities were independent of the availability of the endogenous substrate for the lipoxygenase or cyclooxygenase enzymes. Quantitatively and qualitatively comparable abnormalities were found in monocytes from the five FH patients, and these were little affected when the patients' plasma cholesterol levels were almost normalized by low density lipoprotein apheresis. In keeping with the abnormalities in the eicosanoid metabolism, monocytes from HC patients exhibited a defective ability (p < 0.05) to generate O2-, the extent of which was correlated with the impaired formation of leukotriene B4. On the other hand, adhesion studies indicated that patients' cells exhibited an abnormally high ability to adhere to glass (p < 0.01). These data indicate the presence of functionally abnormal monocytes in hypercholesterolemia and suggest a direction to be followed to understand the importance of such cells in the premature atherosclerosis that occurs in these patients.

Adolescent↗
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

In human monocytes interleukin-1 stimulates a phospholipase C active on phosphatidylcholine and inactive on phosphatidylinositol.

Interleukin-1 (IL-1) can initiate the synthesis of prostaglandins which in turn act as endogenous modulators of IL-1 production. The human monocyte/macrophage synthesizes various eicosanoids through the activation of the cellular phospholipase system. Cell stimulation results in the activation of phospholipase A2 (PLA2) whose major substrate is phosphatidylcholine (PC) and the release of the eicosanoid precursor arachidonic acid (AA) from PC. Another pathway is the stimulation of a phospholipase C (PLC) mainly active on phosphoinositides and the resulting formation of inositol phosphates (IPs) and diacylglycerol (DAG). Phospholipids other than phosphoinositides can also be hydrolysed by PLC to give rise to DAG. Studies have shown that IL-1 does not activate the IP pathway, but it primarily stimulates a PLC linked to phosphatidylethanolamine in cultured rat mesangial cells, and a PLC linked to PC in Jurkart cells. We have stimulated human monocytes with IL-1 and calcium ionophore A23187 and we have observed their effect on the phospholipase system. The results indicate that IL-1 does not activate the formation of IPs in cells labeled with [3H]myo-inositol. In contrast, in cells labeled with [3H]AA, IL-1 causes the formation of DAG associated with the hydrolysis of PC. Moreover, after stimulation with IL-1 there is no accumulation of free AA which would indicate that there has been no activation of PLA2, which occurs instead with A23187 stimulation. These data suggest that, in monocytes, IL-1 does not directly stimulate a PLA2 or a PLC active on phosphatidylinositol; instead it primarily stimulates a PLC active on PC.

Calcimycin↗
PubMed1992

Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridaemia.

The effects of bezafibrate 400 mg/day (slow release formulation) on plasma lipids/lipoproteins and on selected haemostatic parameters were evaluated in a double blind cross-over study in patients with Type IIb and IV hyperlipoproteinaemia. Placebo treatment did not influence any of those parameters, but the drug significantly reduced plasma triglycerides (-45%) and VLDL cholesterol, as well as causing a 12% fall in total cholesterol and a 20% increase in HDL cholesterol. Apo AI levels were significantly increased following bezafibrate and Apo B was reduced by about 20%. In addition to changes in the plasma lipid profile, bezafibrate reduced the sensitivity of platelets to the aggregatory effect of collagen, with no effect on TXB2 production. Fibrinogen levels after bezafibrate treatment were significantly lowered, the effect being more marked in patients with hyperfibrinogenaemia. Bezafibrate did not influence the plasma fibrinolytic profile. It is concluded that bezafibrate, besides its beneficial effects on the plasma lipoprotein profile, can exert beneficial changes on specific haemostatic parameters.

Adult↗
PubMed1992

Treatment with low dose metformin in patients with peripheral vascular disease.

Low dose metformin (500 mg b.i.d.) was tested in 11 patients with symptomatic peripheral vascular disease (PVD) in an open design. At -1, 0, 1, 4, 7 months the major lipid and lipoprotein parameters, arterial function, and fibrinolytic activity were monitored. Arterial function changes were similar to those found with a high dose (850 mg t.i.d.) metformin but plasma lipids did not change to an appreciable extent. Post-ischaemic blood flow, by plethysmography, rose 30%; the exercise capacity, evaluated by treadmill test, also increased significantly by 105.7% for relative and 53.3% for absolute claudication. Total fibrinolytic activity did not change during the treatment but the antigens of two of the major components of the fibrinolytic system, i.e. t-PA and PAI-1, were significantly reduced at the end of the study. This study gave results quite consistent with those obtained with higher metformin doses, associated with a potentially higher risk of lactic acidosis.

Aged↗
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↗
PubMed1992

Hypertriglyceridemia and regulation of fibrinolytic activity.

A relation between elevated triglyceride (TG) levels and alterations of the fibrinolytic system has been recognized in studies of patients with coronary heart disease. In this investigation, the total fibrinolytic activity and the levels of specific components of the fibrinolytic system were evaluated in plasma samples from a highly selected group of patients with type IV hyperlipoproteinemia before and after a dietary treatment aimed at reducing TG levels. The fibrinolytic response of type IV patients was comparable to that of normolipidemic subjects, whereas tissue-type plasminogen activator antigen levels before and after venous occlusion (p less than 0.01) and resting plasminogen activator inhibitor-1 (PAI-1) antigen (p less than 0.01) and activity (p less than 0.01) were significantly higher in hypertriglyceridemic subjects compared with controls. After dietary treatment, a 22% reduction in TG levels was attained in type IV patients, with no appreciable modification of fibrinolytic parameters. The analysis of the single-patient data revealed a tendency toward normalization of PAI-1 levels only in those patients who showed a TG reduction greater than or equal to 20%. Very low density lipoproteins (VLDLs) from both normal and type IV patients concentration-dependently stimulated PAI-1 release by endothelial cells and HepG2 cells, with the effect of VLDL from type IV patients being more pronounced on HepG2 cells. The release of PAI-1 induced by VLDL in competent cells may thus account for the elevated levels of this antifibrinolytic protein that occur in hypertriglyceridemic patients.

Adult↗
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↗
PubMed1990

Evaluation of atherosclerotic lesions using NMR microimaging.

Magnetic resonance imaging (MRI) has been proposed as a potential tool in the evaluation of atherosclerotic lesions. However, two basic difficulties have to date prevented the full exploitation of the potentials of this technique: the poor spatial resolution of the conventional tomographs and the wide variety of the lesions as well as their intrinsic dishomogeneity. In this study the in vitro morphology of normal and atherosclerotic vascular tissue specimens has been evaluated using a high resolution spectometer equipped with a microimaging device. Morphological features of the vessel walls as small as 10(-1) mm have been detected and the distribution of lipids and of calcified or necrotic regions has been evidenced in atherosclerotic plaques. Different techniques, such as local spectroscopy performed on volumes of 1 mm3 and localized magnetization recovery measurements, have been employed to characterize specific regions of the vessel walls from the chemical and the physical point of view. The good agreement of NMR findings with histological data allows us to conclude that NMR microimaging represents a suitable technique for the in vitro detection and characterization of atheromatous lesions.

Adolescent↗
PubMed1990

Dietary n-9, n-6, and n-3 fatty acids modify linoleic acid more than arachidonic acid levels in plasma and platelet lipids and minimally affect platelet thromboxane formation in the rabbit.

We have studied the effects of semisynthetic diets containing 5% by weight (12% of the energy) of either olive oil (70% oleic acid, OA) or corn oil (58% linoleic acid), or fish oil (Max EPA, containing about 30% eicosapentaenoic, EPA C 20:5 n-3, plus docosahexaenoic, DHA C 22:6 n-3, acids, and less than 2% linoleic acid), fed to male rabbits for a period of five weeks, on plasma and platelet fatty acids and platelet thromboxane formation. Aim of the study was to quantitate the absolute changes of n-6 and n-3 fatty acid levels in plasma and platelet lipid pools after dietary manipulations and to correlate the effects on eicosanoid-precursor fatty acids with those on platelet thromboxane formation. The major differences were found when comparing the group fed fish oil and depleted linoleic acid vs the other groups. The accumulation of n-3 fatty acids in various lipid classes was associated with modifications in the distribution of linoleic acid and arachidonic acid in different lipid pools. In platelets maximal incorporation of n-3 fatty acids occurred in phosphatidyl ethanolamine, which also participated in most of the total arachidonic acid reduction occurring in platelets, and linoleic acid, more than archidonic acid, was replaced by n-3 fatty acids in various phospholipids. The archidonic acid content of phosphatidyl choline was unaffected and that of phosphatidyl inositol only marginally reduced. Thromboxane formation by thrombin stimulated platelets did not differ among the three groups, and this may be related to the minimal changes of arachidonic acid in phosphatidyl choline and phosphatidyl inositol.

Journal Article↗
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

Dietary fatty acids, serum lipids, platelet biochemistry and function.

Dietary fatty acids of the n-6 mainly linoleic acid (LA) series, and of the n-3, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) series both reduce plasma cholesterol levels and platelet responses to aggregating agents. The potency of n-3 fatty acids, which are present in relatively high concentrations in fish oils, is at least one order of magnitude greater than that of LA. The effects of fish oils appear to be related to the incorporation of EPA into plasma lipoproteins and cell phospholipid pools, thus modulating metabolic processes within specific lipid pools. Inhibition of platelet function and modifications of the activity of other blood cells, such as leukocytes, is attributed to interference with the eicosanoid system. Competition of EPA with arachidonic acid (AA) for the oxygenases and/or generation of less active metabolites from this precursor are the major mechanisms of action. Feeding studies in experimental animals indicate that exogenously administered n-3 fatty acids undergo distribution among the major plasma lipid classes and platelet phospholipids quite different to that of endogenous AA. In addition, the generation of inositolphosphates by stimulated platelets is decreased by dietary n-3 fatty acids in a manner independent of the effects on the eicosanoid system. It appears that polyunsaturated fatty acids (PUFA) of the n-6 and n-3 series are differently handled in various lipid pools and that early steps of cell activation, in addition to the generation of eicosanoids, are affected by dietary fatty acids. This indicates that fatty acids modulate key steps in the regulation of cell function and biochemistry.(ABSTRACT TRUNCATED AT 250 WORDS)

Arteriosclerosis↗