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Biomedical subjects

M Salmona

Publications and source records attributed to M Salmona.

At least 109 records · Page 6Linked to original sources
PubMed1991

Interspecies and interstrain studies on the increased susceptibility to metrazol-induced convulsions in animals given aspartame.

The ability of aspartame (APM) to increase the susceptibility to metrazol-induced convulsions was studied in two strains of mice (CD1 and DBA/2J) and in guinea-pigs. Rats were included as known positive controls. Plasma and brain levels of phenylalanine (Phe) and tyrosine (Tyr) were measured in CD1 mice and guinea-pigs at various intervals after a dose of 1 g APM/kg body weight (administered orally to mice and ip to guinea-pigs). In mice, peak levels of Phe and Tyr were observed in plasma after 30 min and in brain after 60 min. In guinea-pigs peak plasma levels of Phe and Tyr occurred 30 min after treatment. Phe was at a maximum in guinea-pig brain after 30 min, while Tyr levels reached a peak at 120 min. In further experiments Phe and Tyr levels were measured 1 hr after APM doses of 0.5, 0.75 or 1 g/kg. In CD1 mice, plasma Phe and Tyr levels were increased significantly only at the highest dose, whereas in brain, Tyr concentrations were significantly increased by 0.75 or 1 g APM/kg and Phe was significantly increased by all three doses. In the guinea-pig, plasma Phe and Tyr were increased significantly only by 1 g APM/kg and in brain this dose significantly raised only the Phe levels. Monoamine and metabolite levels were determined in the brain striata of CD1 and DBA/2J mice 1 hr after the oral administration of 1 or 2 g APM/kg body weight; no differences from control values were found in either strain. The studies of potentiation of metrazol-induced convulsions showed that APM, at doses of up to 2 g/kg body weight, had no such effect in mice or guinea-pigs. In contrast, as expected, the potentiation was significant in the rat at 1 g/kg.

Animals↗
PubMed1991

Effect of iodinated contrast media on the synthesis and metabolism of leukotriene B4.

To investigate whether the endogenous vasoactive substrate, leukotriene B4 (LTB4), was induced in adverse reactions observed after intravenous injection of iodinated contrast media (CM), the authors measured the in vitro production and metabolism of LTB4 by human polymorphonuclear leukocytes (PMNs) after stimulation with different doses of commercial CM preparations: iopamidol, 300 mg I/mL; iodamide, 300 mg I/mL; iohexol, 300 mg I/mL; ioxaglate, 320 mg I/mL; and the experimental preparation, iomeprolo. This study showed that the CM studied do not stimulate the production or metabolism of LTB4 by isolated human blood PMNs. All of the CM studied except iodamide do not inhibit the production or metabolism of LTB4 in PMNs stimulated by A23187. The in vitro hepatic microsomal oxidation of exogenous LTB4 to (omega-1)OH LTB4 and omega-OH LTB4 was inhibited by all the CM studied. LTB4 production by PMNs seems not to play a major role in anaphylactoid reactions observed after iodinated CM. However, a transient blockade by CM of LTB4 metabolism, leading to an increase of steady-state concentrations of LTB4, could not be excluded by these experiments.

Animals↗
PubMed1991

Effect of hypothyroidism induced in adult rats on brain membrane fluidity and lipid content and composition.

This study was designed to establish whether fluidity and lipid composition of brain membranes were affected by hypothyroidism, in the hope of clarifying the mechanism through which thyroid hormone deficiency might influence nerve cell functions. Rats were made hypothyroid by injections of PTU (dissolved in 0.005 M NaOH, 50 mg/kg, ip, daily for 28 days). Membrane fluidity, cholesterol (chol) and phospholipids (PL) content, and PL and their fatty acid composition were measured in plasma, erythrocyte plasma membranes, liver microsomes and brain subcellular fractions. P2 pellets from brains of hypothyroid animals were less fluid than those of euthyroid ones; subcellular fractionation showed that mitochondrial membranes were responsible for the rigidity observed. Similar changes were found in erythrocyte "ghosts". The reduced fluidity seemed to be related more to alterations in the ratios between phosphatidylcholine, sphingomyelin and phosphatidylethanolamine, than to those of chol/PL, protein/PL or fatty acid unsaturation index. The well known alteration in hypothyroidism-induced desaturase activity, which in peripheral tissue leads to a reduction of 20:4n-6 and to an increase in its precursors (18:2n-6 and 20:3n-6), is barely detectable in brain membranes. Only in phosphatidylcholine of synaptosomes and myelin did slight changes in percentages of the n-6 family fatty acids result in a significant alteration of 20:4n-6/20:3n-6 ratios.

Animals↗
PubMed1990

Role of cell cholesterol in modulating antineoplastic ether lipid uptake, membrane effects and cytotoxicity.

Membrane-interactive ether lipids (EL) exert toxic and antiproliferative effects on cancer cells in vitro. They appear to be selectively more toxic to cancer cells than to normal cells and thus they are ideal candidates for bone-marrow purging procedures. However, no conclusive explanation has yet been provided for this property. We now present some data indicating that the cholesterol concentration in the incubation medium modulates EL toxicity against the HL60 leukemic cell line in vitro. Furthermore, model membranes richer in cholesterol take up EL more slowly, and cell cholesterol enrichment of HL60 cells counteracts EL biophysical membrane interaction, but not toxicity, in our experimental model. However, the K562 cell line, a leukemia line less sensitive to EL toxic action, has higher levels of cell cholesterol. Our data provide evidence to explain differences in sensitivity to EL among different cell types and contribute to the understanding of the mechanism of action of EL.

Antineoplastic Agents↗
PubMed1990

Determination of argininosuccinate lyase and arginase activities with an amino acid analyzer.

The measurement of argininosuccinate lyase (ASase) and arginase, both in liver and erythrocytes, was developed by using a commercial amino acid analyzer. The method is based upon the use of two different substrates, argininosuccinate and arginine for ASase and arginase, respectively, and the measurement of only one final metabolite: ornithine. The use of ornithine as a marker of biological activity of ASase is related to the fact that in the urea cycle, the specific activity of arginase is much higher than that of ASase; thus, during in vitro determinations, arginine, which is the product of ASase, is rapidly converted to ornithine. The sensitivity of the methods is very high since we were able to detect both activities using very diluted rat liver homogenates (0.10 mg protein/ml) or few microliters of human blood. In rat liver the Vmax for ASase and arginase were respectively 0.54 and 140 mumol/h/mg protein; the apparent Km values 1.25 and 13.5 mM. In human erythrocytes the Vmax for the same enzymes were 7.2 and 170 nmol/h/mg Hb and the apparent Km values were 0.66 and 9.5 mM. In 10 healthy volunteers the specific activity of ASase and arginase determined in blood were respectively 8.60 +/- 0.46 and 124.1 +/- 14.5 nmol/h/mg Hb. The results obtained from 2 patients suffering from argininosuccinic aciduria were also reported. In these latter cases while ASase was not detectable in blood, arginase activity was at the lowest end of the confidence limits determined in healthy volunteers.

Amino Acids↗
PubMed1990

Plasma and brain kinetics of large neutral amino acids and of striatum monoamines in rats given aspartame.

Two doses (250 and 1000 mg/kg body weight) of aspartame were administered orally to male rats, and plasma and brain phenylalanine and tyrosine kinetic profiles were studied. In both plasma and brain the maximum increase in phenylalanine and tyrosine levels was reached 60 min after treatment. The changes in brain levels of phenylalanine or tyrosine 0, 60, 120 or 180 min after treatment with 1000 mg AMP/kg were directly correlated with the ratio of the plasma concentration of phenylalanine or tyrosine to the overall plasma concentration of the other large neutral amino acids. The time course of monoamine and metabolite concentrations, in the corpora striatum of the brain, was studied after an oral dose of 500 mg phenylalanine/kg. No significant modifications of monoamine levels were found at any of the times studied, up to 5 hr after dosing.

Animals↗
PubMed1990

Oral zeranol shortens the prolonged bleeding time of uremic rats.

Intravenous conjugated estrogens reduce the prolonged bleeding time in uremic patients and in a rat model of uremia. However, estrogens have major side effects related to their hormonal activity. We investigated whether a beta-resorcylic acid lactone, zeranol (a compound with close spatial similarity to estrogens but with a weak estrogenic activity), improves primary hemostasis in uremic rats and whether the effect is mediated by estrogen receptors. The results showed that single oral administration of zeranol significantly (P less than 0.01) shortened the bleeding time of uremic rats, 20 mg/kg being the minimum effective dose. This effect was long-lasting (72 hours). The dose of 30 mg/kg zeranol reproduced the pattern observed after 20 mg/kg but bleeding time values were still significantly (P less than 0.01) shortened 96 hours after the administration. No changes in hematocrit, platelet and leukocyte count, and serum creatinine were detected after zeranol administration. When uremic rats were pre-treated orally with two estrogen receptor antagonists, tamoxifen and clomiphene (3 mg/kg), zeranol did not shorten the bleeding time, thus suggesting that the hemostatic effect of zeranol was due to an estrogen receptor-mediated mechanisms. These results might have important future implications for the management of uremic bleeding in humans.

Administration, Oral↗
PubMed1990

Interferon inducers increase O6-alkylguanine-DNA alkyltransferase in the rat liver.

We investigated whether treatment with the interferon inducer polyinosinic-polycytidylic acid and other cytokines (interleukin-1, tumor necrosis factor) or the cytokine inducer lipopolysaccharide modified O6-alkylguanine-DNA alkyltransferase (AT) in rat liver. AT levels were determined in liver extracts using N-[3H]methyl-N-nitrosourea alkylated calf thymus DNA as substrate and an HPLC procedure to measure O6-methylguanine. Doses as low as 0.1 mg/kg i.p. of polyinosinic-polycytidylic acid caused a highly significant increase (P less than 0.01) in AT levels in the liver, evident either 24 or 48 h after treatment. Lipopolysaccharide at the dose of 80 micrograms/kg i.p. also induced AT whereas interleukin-1 (60 micrograms/kg) or tumor necrosis factor (60 micrograms/kg) were inactive. Treatment with human recombinant interferon alpha A/D caused a highly significant increase in AT levels, thus confirming the hypothesis that interferon was probably responsible for the observed effect. These results suggest a link between the immune response and DNA repair mechanisms.

Animals↗
PubMed1990

Disaturated phosphatidylcholine in rabbit eustachian tube surfactant.

A chemical analysis of phospholipids in rabbit Eustachian tube and in its lavages shows phosphatidylcholine (PC) as being the predominating compound, followed by sphingomyelin and phosphatidylethanolamine. As in the lung surfactant, the majority of tubal PC is represented by its disaturated form dipalmitoylphosphatidylcholine (DPPC), known as a powerful surface-active agent. The concentration of PC and DPPC is higher in tubal washing than in the whole tissue, suggesting the existence of an active secretory process. Incubation of tubal mucosa with 14C-choline resulted in the biosynthesis of radiolabelled PC and DPPC at a ratio similar to the lung. These data provide further evidence for the existence of a surface-active agent in the Eustachian tube, chemically similar to the lung surfactant and probably produced through similar metabolic pathways.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1990

Alpha 1-antitrypsin variants produced by recombinant DNA: differences in elastase inhibitory activity and resistance to oxidant agents.

Inherited or "acquired" deficiency of alpha 1-antitrypsin (believed to be the cause of pulmonary emphysema) will probably be treated in the future by replacement with alpha 1-antitrypsin purified from human plasma or produced by recombinant DNA, which seems promising because it permits site-specific mutagenesis in the oxidizable active site of the normal human alpha 1-antitrypsin. The aim of this in-vitro study was to investigate the elastase inhibitory activity and the resistance to oxidizing agents of normal human alpha 1-antitrypsin, a recombinant yeast-produced variant (VAL 358) and a recombinant E. coli-produced variant (LEU 358). The inhibitors were exposed to chemical oxidants (NCS, H2O2, xanthine/xanthine oxidase, chloramine-T) and to PMA-activated neutrophils. The elastase inhibitory activity was assayed on porcine pancreatic elastase and neutrophil elastase. Normal alpha 1-antitrypsin and VAL 358 variant were good inhibitors of both elastases. LEU 358 variant was the best inhibitor for neutrophil elastase, but it poorly inhibited the porcine pancreatic elastase. Normal alpha 1-antitrypsin was affected by all oxidants; both variants were almost totally resistant to chemical oxidants and to activated neutrophils. We conclude that recombinant alpha 1-antitrypsin variants differ in their elastase inhibitory activity and offer increased resistance to oxidant agents.

Animals↗
PubMed1989

Membrane fluidity affects tumor-cell motility, invasion and lung-colonizing potential.

Membrane fluidity, determined by steady-state fluorescence polarization measurements, was correlated with metastatic capacity of murine tumor-cell lines. A correlation was observed in cell lines with different metastatic potential, and was confirmed when their lung-colonizing ability was modulated by alteration of either the membrane lipid composition or the culture conditions. Two cellular functions, motility and basement membrane invasion, were affected by the membrane lipid composition, and might explain the role of membrane fluidity observed in cancer metastasis.

Animals↗
PubMed1989

Effects of aspartame and carbohydrate administration on human and rat plasma large neutral amino acid levels and rat brain amino acid and monoamine levels.

Thirty fasted human volunteers were given 0.83 and 8.3 mg aspartame/kg body weight alone, as part of a basal low carbohydrate meal (648 kcal, 10% carbohydrate) or as part of a high energy carbohydrate-rich meal (1290 kcal, 34% carbohydrate). Amino acid concentrations in plasma were determined before and 30, 60 and 180 min after the consumption of aspartame. Under these conditions, which mimic realistic aspartame consumption, aspartame had no significant effect on plasma concentration of any amino acid. In addition, the effect of aspartame alone or with carbohydrates on plasma and brain amino acid levels was studied in rats after acute or subacute (14 d) oral treatment. In subacute dosing experiments aspartame was included in the diet. Brain monoamine concentrations were also measured in the same animals. Plasma concentrations of large neutral amino acids were modified under acute conditions. In contrast, after subacute treatment no significant differences in plasma or brain amino acid concentrations or in brain monoamine concentrations were observed.

Amino Acids↗
PubMed1989

Relationship between changes in alveolar surfactant levels and lung defence mechanisms.

Pulmonary surfactant, besides its mechanical properties, is thought to be involved in lung defence mechanisms. We previously described that: (1) in healthy animals, surfactant synthesis stimulation with ambroxol was accompanied by alveolar macrophage activation and a shift of the alveolar elastase/antielastase balance towards increased antielastase activity, and (2) in bleomycin-treated rats alveolar phospholipidosis was obvious 14 days after drug administration, ambroxol protection reduced the phospholipid peak and the morphological apperance of lung fibrosis at the 14th day of the experiment. The present study found that: (1) in healthy rats, the ambroxol-induced increase of alveolar antielastase activity did not appear due to reactivation of alpha 1-antitrypsin normally oxidized in the alveolar milieu; (2) in bleomycin-induced pulmonary fibrosis, ambroxol protection reduced total long collagen content at day 28, and (3) in paraquat-induced pulmonary fibrosis, alveolar phospholipids were markedly reduced throughout the 21 days of the experiment. On increasing the dose of paraquat, ambroxol protection significantly reduced the animals' death rate.

Ambroxol↗
PubMed1988

A rapid electrochemical assay of lecithin in amniotic fluid using a fluoride ion-sensitive electrode.

An electrochemical method is described for the determination of lecithin in rat and human amniotic fluid. Choline is released from lecithin enzymatically by phospholipase D and the hydrogen peroxide released by the action of choline oxidase is quantitatively determined by peroxidase-catalyzed rupture of the covalent C-F bond of 4-fluorophenol. The concentration of F- ions in solutions is determined by a fluoride sensitive electrode from the resulting cell potential difference recorded before and 10 min after addition of a solution containing phospholipase D, choline oxidase and horseradish peroxidase. Lecithin levels in rat amniotic fluid increased from about 10 mumol/l on the 20th day of gestation to 80 mumol/l on day 21, which corresponds to the time of spontaneous delivery. In human amniotic fluid the lecithin concentrations determined with this new method parallel those already reported. They were approximately 10 to 50 mumol/l between the 15th and 18th weeks of gestation and increased from 5- to 7-fold between the 37th and 41st weeks of pregnancy. This method was only slightly influenced by the presence of blood or meconium contamination in the amniotic fluid.

Amniotic Fluid↗
PubMed1988

Liver DNA alkylation after a single carcinogenic dose of dimethylnitrosamine to newborn and adult CFW Swiss mice.

N-nitrosodimethylamine N-demethylase activity, DNA alkylation, capacity for O6-methylguanine repair and cell proliferation were measured in livers of newborn and adult CFW mice after a single carcinogenic dose of DMNA. DNA alkylation was found in newborn and adult mouse livers but it was significantly higher in the newborn. 6- and 7-methyl substitutions of guanine were identified by HPLC analysis in newborn and in adult mouse livers. Metabolic 14C incorporation into adenine and guanine was observed only in liver DNA of newborns. O6-methylguanine levels were higher in newborn than adult mice after a single i.p. dose of [14C]DNMA. Liver DNA repair capacity measured as O6-meG-DNA methyltransferase was higher in adults than in newborns. De novo liver DNA synthesis was more inhibited by DMNA pretreatment in newborn than in adult mice. The relationship between these parameters and the greater neonatal liver tumor susceptibility is discussed.

Alkylation↗
PubMed1988

Differential effects of benzodiazepines on phospholipid methylation in hippocampus and cerebellum of rats.

To elucidate the relationship between the occupancy of BDZ binding sites and phospholipid methylation in brain, we examined phosphatidylethanolamine-N-methyltransferase (PEMT) activity in synaptosomes of rat hippocampi and cerebella in the presence of BDZ ligands with different modes of action. We found that Ro 5-4864, a specific ligand for "peripheral type" receptors, increased PL methylation in hippocampal and cerebellar synaptosomes. This effect was directly related to receptor occupancy, since the specific antagonist PK 11195 inhibited the rise in PEMT activity induced by Ro 5-4864. Clonazepam, on the other hand, tended to reduce PL production in cerebellum and hippocampus except for hippocampal (3H)-phosphatidyl-N-monomethylethanolamine which was elevated by 40 to 70% at doses ranging from 10(-9) to 10(-6) M. When equimolar concentrations of the antagonist Ro 15-1788 were given in association the clonazepam-induced phosphatidyl-N-monomethylethanolamine increase was reduced by 70%. These data support the involvement of structural and functional membrane alterations in the action of BDZ.

Animals↗
PubMed1988

Effect of aspartame on seizures in various models of experimental epilepsy.

We investigated in rats whether aspartame intake affected the susceptibility to seizures induced chemically (metrazol, quinolinic acid) or electrically (electroshock). Aspartame (0.75-1.0 g/kg), given orally as a single bolus to 16-hr fasted animals 60 min before metrazol, significantly increased the number of animals showing clonic-tonic seizures. At 1.0 g/kg the ED50 for clonic-tonic convulsions was lowered by 23%. A similar increase in seizure susceptibility was observed with 0.25-0.5 g/kg of the aspartame's metabolite phenylalanine. When aspartame was administered to fasted rats in three divided doses (0.33 g/kg) over 120 min or to fed animals after a meal, or overnight with the diet, no significant changes in the incidence of animals showing seizures was observed. One gram per kilogram aspartame and 0.5 g/kg phenylalanine did not modify the CC50 (mA) for tonic hindlimb extension induced by electroshock and the electroencephalographic seizures caused by intrahippocampal injection of 120 nmol quinolinic acid. Plasma and brain levels of phenylalanine and tyrosine significantly raised after both 1 g/kg aspartame as a single bolus (plasma: Phe 285%, Tyr 288%; brain: Phe 146%, Tyr 192%; above controls) or in three divided doses (plasma: Phe 207%, Tyr 315%; brain Phe 103%, Tyr 211%; above controls) and 0.5 g/kg phenylalanine (plasma: Phe 339%, Tyr 410%; brain: Phe 219%, Tyr 192%; above controls), but the ratio Phe/Tyr was not modified. Our data indicate that aspartame cannot be regarded as a general proconvulsant agent. The mechanisms of potentiation of seizures induced by metrazol after the administration of the sweetner in a single rapid intake will be discussed.

Animals↗