PubMed Health⌕ Search

Biomedical subjects

R Ashkenazi

Publications and source records attributed to R Ashkenazi.

At least 19 recordsLinked to original sources
PubMed1998

Inhibition of Streptomyces griseus aminopeptidase and effects of calcium ions on catalysis and binding--comparisons with the homologous enzyme Aeromonas proteolytica aminopeptidase.

Streptomyces griseus aminopeptidase is a zinc metalloenzyme containing 2 mol zinc/mol protein, similar to the homologous enzyme Aeromonas proteolytica aminopeptidase. In addition, a unique Ca2+-binding site has been identified in the Streptomyces enzyme, which is absent in the Aeromonas enzyme. Binding of Ca2+ enhances stability of the Streptomyces enzyme and modulates its activity and affinity towards substrates and inhibitors in a structure-dependent manner. Among the three hydrophobic 4-nitroanilides of alanine, valine and leucine, the latter displays the largest overall activation (increase in k(cat)/Km). Large enhancements in affinity (1/Ki) upon Ca2+ binding have been observed for inhibitors with flexible (leucine-like) residues at their N-termini and smaller enhancements for inhibitors with rigid (phenylalanine-like) residues.

Aeromonas↗
PubMed1996

Monitoring blood lead levels in workers overexposed to occupational lead: an analysis of Israeli data.

In a retrospective cohort study, we followed the blood lead [Pb(B)] and zinc protoporphyrin (ZPP) determinations of 292 workers found to have Pb(B) levels above the biological exposure index (BEI) during 1987-1993. The results indicated that (a) 22.6% of these workers were never retested for Pb(B) during the follow-up period; (b) 38.5% of the workers tested in the first year of the follow-up continued to exhibit Pb(B) levels above the BEI (84.7% of them also had ZPP > or = 100 micrograms/dl); (c) about 25% of the remaining cohort had at least one more result above the BEI during the fourth, fifth, and sixth years of follow-up; and (d) the incidence density rate of recurrence of Pb(B) concentrations above the BEI was 0.236. We recommend the establishment of a target value lower than the BEI that should be reached before the reinstatement of the overexposed worker. In our view this target value, combined with an efficient control of industrial hygiene conditions, will decrease the rate of recurrence of overexposure.

Cohort Studies↗
PubMed1996

Biological monitoring of exposure to cadmium, a human carcinogen, as a result of active and passive smoking.

Cadmium (Cd), a known human carcinogen, is one of the components of tobacco and also has many industrial uses. Smoking Cd-contaminated cigarettes at work may cause an increase in blood levels and toxicity of Cd. For a population of nonexposed workers, we compared blood Cd and urine cotinine (Cot) levels as biological markers of exposure to cigarette smoke of active smokers (AS) and passive smokers (PS) with those of unexposed nonsmokers (UNS) in 158 workers. The mean Cd in AS (0.097 microgram%; ie, 0.097 microgram/100 mL whole blood) was significantly higher than in UNS (0.085 microgram%), and was very close to the mean Cd levels in PS (0.093 microgram%). Mean Cd levels in exposed past smokers (0.105 microgram% was higher than in nonexposed past smokers (P < 0.05) and in AS. The mean Cot level was significantly higher in AS than in PS or in UNS. Increased smoking was associated directly with increased blood Cd and urine Cot. Our results supported and proved quantitatively that exposure to cigarette smoke is harmful to both AS and PS, as we show that in both cases there is an increase in blood Cd. According to our results, exposure to cigarette smoke via active and passive smoking increases blood Cd by an average of 0.01 micrograms% over the background (UNS). We conclude that exposure to cigarette smoke is a confounder to be taken into account when carrying out epidemiological studies and surveillance programs on workers exposed to Cd at work.

Biomarkers↗
PubMed1995

Down-regulation of hepatic peripheral-type benzodiazepine receptors caused by acute lead intoxication.

In the present study we investigated the influence of acute lead poisoning upon the expression of benzodiazepine receptors. In addition, we examined if administration of PK 11195, an isoquinoline carboxamide derivative, to lead-poisoned rats could modulate the changes in receptor binding properties achieved by lead alone. Lead poisoning was ascertained by determination of urine delta-aminolevulinic acid levels and lead levels in rat livers. Scatchard analysis of saturation curves of [3H]PK 11195 binding to liver membranes of rats treated with lead alone or with both lead and PK 11195 showed and approximately two-fold decrease in receptor density in comparison with control groups. Peripheral benzodiazepine receptor density in kidneys and adrenals of poisoned rats was not changed by lead intoxication per se or by coadministration of PK 11195. Scatchard analysis of saturation curves of [3H]Ro 15-1788 binding in rat cerebral cortex tissue showed no difference in the receptor density between the various groups. The Kd values of all organs were in the nanomolar range (1-4 nM). We conclude that PK 11195 is not a protective agent of hepatic peripheral benzodiazepine receptors in lead intoxication. Moreover, it causes over-accumulation of lead in hepatocytes in an unknown mechanism of action.

Adrenal Glands↗
PubMed1993

Specificity of Streptomyces griseus aminopeptidase and modulation of activity by divalent metal ion binding and substitution.

Streptomyces griseus aminopeptidase is a calcium-activated zinc metalloenzyme characterized by a high enzymic reactivity, high thermal stability and low molecular mass [Spungin, A. and Blumberg, S. (1989) Eur. J. Biochem. 183, 471-477]. A study of the specificity of S. griseus aminopeptidase using amino acid 4-nitroanilide substrates shows that the leucine derivative is the best substrate. Derivatives of other hydrophobic amino acids, methionine and phenylalanine, are also excellent substrates for the enzyme. The 4-nitroanilides of alanine, valine, proline and lysine are good substrates whereas those of the small size glycine and the acidic amino acids are very poor. No hydrolysis of a terminal Xaa residue can be detected with Xaa-proline N-terminal sequences. Calcium ions bind to the enzyme and modulate its activity in a substrate-dependent manner. The catalytically essential zinc of S. griseus aminopeptidase is removed by dialysis against 1,10-phenanthroline and replaced by manganese or cobalt ions, resulting in enzyme derivatives of altered specificities. Thus, whereas the zinc enzyme hydrolyzes leucine 4-nitroanilide at a 10-fold faster rate than the manganese or cobalt enzymes, the cobalt enzyme hydrolyzes alanine 4-nitroanilide at a more than 20-fold faster rate than the zinc or manganese enzymes.

Aminopeptidases↗
PubMed1992

Adverse health effects in workers exposed to cadmium.

One hundred fifty-two workers who had been exposed to different levels of cadmium (Cd) absorption (blood Cd mean 16.34 micrograms/L, median 11.0 micrograms/L) in a factory making nickel-cadmium batteries were studied. A physical evaluation, as well as blood and urine cadmium and N-acetyl-beta-D-glucosaminidase (NAG), and other routine laboratory tests were performed in order to assess the relationship between different levels of exposure to occupational cadmium and potential cadmium-induced renal damage and other adverse health effects. We found significant correlation between levels of cadmium exposure and a selected group of symptoms and signs. The best predictor of this group of symptoms and signs was an indicator called internal dose index (Cd x exposure time). This indicator appears as the strongest, even after control by confounding factors, such as age and smoking. It is concluded that this index can be used for biological monitoring.

Adult↗
PubMed1992

Fatty acids, calcium soaps of fatty acids, and cottonseeds fed to high yielding cows.

We examined the effects of dietary fat as cottonseed, fatty acids, or calcium soaps of fatty acids in the rations of high yielding lactating cows receiving low forage. Experiments were with isoenergetic, isonitrogenous diets containing equal amounts of forage. Inclusion of up to 510 g/d of fatty acids in the ration enhanced FCM yield. With cottonseed, increased FCM was mainly due to increased fat yield. Dietary fatty acids tended to increase milk in mid and late lactation and to decrease fat percentage. Calcium soaps of fatty acids enhanced FCM, particularly in early lactation. Feeding cottonseed and fatty acids together did not enhance yield. Effects described may be attributed in part to changes in ruminal fermentation in which cottonseed increased acetate concentrations and fatty acids decreased the ratio of acetate and butyrate to propionate and in part to enhanced efficiency of milk yield when fat was included in the ration.

Acetates↗
PubMed1990

Central catecholaminergic dysfunction and behavioural disorders following hypoxia in adult rats.

Wistar male rats, 3-4 months old, were made to breathe for 6 h a sub-lethal hypoxic atmosphere consisting of 8% oxygen and 92% nitrogen. Following this treatment, these rats were subjected to a series of behavioral and biochemical tests starting 30 days and ending at about 180 days after the hypoxic insult. an age-matched control group was subjected to the same series of tests. The following findings were made at the time interval indicated, relative to controls: (1) At 30-35 days, diurnal (3 h) and nocturnal (12 h) locomotor activities decreased by about 25%. (2) At 40-45 days, amphetamine in the dose range of 0.25-1 mg/kg proved less effective in eliciting an increase in motor activity and stereotypic behavior. (3) At about 50 days, apomorphine in the dose range 0.25-0.5 mg/kg caused an increase in stereotypic behavior. (4) At 60-65 days, alpha-methyl-p-tyrosine at the dose of 50 mg/kg caused a more pronounced hypoactive syndrome and a slower rate of recovery of motor activity. (5) At 75-90 days, performance in the active avoidance test was inferior to that of controls. (6) At 180 days, and one hour after a dose of 200 mg/kg alpha-methyl-p-tyrosine, the turnover rates of hippocampal norepinephrine and caudate-putamen dopamine were much below control. One may tentatively conclude that one of the effects of hypoxia in adult rats is a lesion producing long-term behavioral disorders which are partly ascribed to dopaminergic and, possibly noradrenergic, dysfunction.

Age Factors↗
PubMed1986

Long-term consequence of early iron-deficiency on dopaminergic neurotransmission in rats.

Nutritional iron-deficiency (ID) induced in rats caused a reduction in peripheral as well as central iron metabolism. This effect was markedly greater in the liver than the brain. Although the decrease in the rate of brain non-haem iron was slower than that of serum and liver, significant diminutions of behavioral response to apomorphine (2 mg/kg) and maximum [3H]spiperone binding (Bmax) in caudate nucleus were noted in these animals. These effects of ID can be reserved by iron supplementation in young (21-day-old) and adult (48-day-old) rats. In contrast, if ID is induced in new born (10-day-old) animals, the diminished brain non-haem iron, behavioral response to apomorphine and [3H]-spiperone binding in caudate nucleus will not recover even after 6 weeks of iron supplementation. However, these animals have normal serum iron, haemoglobin and liver iron. These data point to the profound effect early ID can have on the development of dopaminergic neurotransmission, since brain iron concentration increases its maximum in the 4-5 weeks after birth. The implications of the present finding is that the prevalence of ID in children occurs in the first decade of life, when brain iron accumulation reaches values observed in adults. The profound cognitive changes associated with ID in children is thought to be dopamine-dependent and is not always reversible with iron therapy.

Aging↗
PubMed1985

Serotonergic involvement in pharmacological action of the anxiolytic-sedatives thalidomide and supidimide.

The anxiolytic-sedative drugs thalidomide and supidimide inhibited spontaneous motor activity in rats. Both compounds inhibited the serotonin (5-HT) behavioural syndrome induced by tranylcypromine (TCP) plus L-tryptophan (TRP) or clorgyline plus the selective 5-HT uptake blocker, LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) and delayed the behavioural effects of p-chloro-amphetamine, a releaser of 5-HT. The behavioural syndrome induced by the 5-HT agonist, 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT) was unaffected by supidimide pretreatment. Thus supidimide does not possess 5-HT receptor antagonistic properties. This was further substantiated by the unaltered 5-HT-induced platelet aggregation in the presence of supidimide (10(-7)-10(-4) M). A decrease of 5-HT release into the synaptic cleft will lead to a diminished behavioural response to drugs that act presynaptically. Supidimide induced a greater increase in accumulation of brain 5-HT in TCP (5 mg/kg) plus TRP (100 mg/kg)-treated animals as compared to that in the corresponding controls. These data indicate that the behavioural and pharmacological actions of supidimide may be related to its inhibition of 5-HT release.

Animals↗
PubMed1984

Modulation of dopamine receptor in the striatum by iron: behavioral and biochemical correlates.

The present study has shown that in the rat brain iron is unevenly distributed and may be associated with the dopaminergic neuron. The function of the large amounts of iron in certain brain areas, such as the pallidum, caudate nucleus, substantia nigra, nucleus accumbens, and olfactory tubercule, is not known. But it is obvious that by reduction of brain iron, as in the case of nutritional iron deficiency, certain dopamine-mediated behavioral phenomena and biochemical reactions are altered. These changes have been attributed to the selective reduction in dopamine D2 receptors and function in brain areas rich in dopamine neurons and iron. If iron is especially important to dopaminergic modulatory systems in the brain, its deficit might explain the increasing number of reports on behavioral disturbances, EEG, and event-related potentials (ERPs) associated with nutritional iron deficiency in children.

Animals↗
PubMed1983

Long scotophase acclimation increases free urinary catecholamine content in the rat.

1. Acclimation of laboratory rats Rattus norvegicus albino to long scotophase 8L:16D and 4L:20D at an ambient temperature (Ta) of 25 degrees C caused an increase in urinary free catecholamine compared to 12L:12D at Ta = 25 degrees C. 2. Transferring the same individuals from 8L:16D to 12L:12D (at Ta = 25 degrees C) caused a decrease in this factor. 3. The results of this study suggest that acclimation to long scotophase increases sympathetic nervous system and chromaffine cell activities.

Animals↗
PubMed1983

Behavioural hyperactivity in rats treated with selective monoamine oxidase inhibitors and LM 5008, a selective 5-hydroxytryptamine uptake blocker.

The administration of 4-[2-(3-indolyl)ethyl]piperidine (LM 5008), a selective 5-hydroxytryptamine (5-HT) uptake blocker to rats pretreated with tranylcypromine (Tcp) resulted in a behavioural syndrome of locomotor hyperactivity which is indistinguishable from that following combined treatment with Tcp and L-tryptophan. A similar behavioural response was elicited by the administration of LM 5008 to rats pretreated with 5-hydroxytryptophan. The response to LM 5008 after monoamine oxidase (MAO) inhibition was abolished by pretreatment with p-chlorophenylalanine, indicating the involvement of 5-HT in producing the hyperactivity syndrome. The administration of imipramine and chlorimipramine in combination with Tcp also resulted in hyperactivity, but these drugs were much less potent than LM 5008 in producing the syndrome. In contrast to L-tryptophan, which can produce hyperactivity only after the inhibition of both type A and type B MAO, LM 5008 can elicit the syndrome after selective inhibition of MAO type A only but not after inhibition of MAO type B. The behavioural results indicate that when MAO type A is inhibited, LM 5008 treatment elicits hyperactivity by preventing the availability of 5-HT to be metabolized by MAO-B component.

5-Hydroxytryptophan↗
PubMed1983

Effects of LM 5008, a selective inhibitor of 5-hydroxytryptamine uptake, on blood pressure and responses to sympathomimetic amines.

LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) (10, 20 and 50 mg kg-1) had no significant effect on pressor responses to noradrenaline or tyramine in rats anaesthetized with urethane. Desmethylimipramine (1 mg kg-1) blocked the response to tyramine but chlorimipramine (5 mg kg-1) had no significant effect on responses to noradrenaline or tyramine. In the rabbit, anaesthetized with chloralose, LM 5008 (5 mg kg-1) had no effect on pressor responses to noradrenaline, tyramine or angiotensin II, while desmethylimipramine (0.25 mg kg-1) inhibited responses to tyramine and potentiated those to noradrenaline. LM 5008 (10 mg kg-1) had no effect on resting blood pressure of conscious normotensive or DOCA-saline hypertensive rats. Tranylcypromine (5 mg kg-1) produced a fall in blood pressure in conscious normotensive and in DOCA hypertensive rats. Treatment with a combination of LM 5008 (10 mg kg-1) and tranylcypromine (5 mg kg-1) resulted in the appearance of a behavioural hyperactivity syndrome, but blood pressure was not different from that of animals treated with tranylcypromine alone. These results further demonstrate the selectivity of LM 5008 for 5-hydroxytryptamine as opposed to catecholamine uptake.

Angiotensin II↗
PubMed1983

Brain iron and dopamine receptor function.

It has been demonstrated that nutritional iron-deficiency induced in rats results in the reduction of DA D2 receptor binding sites, leading to down-regulation of dopaminergic activity similar to that observed in neuroleptic-treated animals. The following observations are common to both conditions: (a) Decreased behavioural response to pre- and post-synaptically DA and serotonin acting drugs, amphetamine, apomorphine and 5-methoxy-N,N-dimethyltryptamine. (b) Inhibition of amphetamine or apomorphine induced hypothermia in rats kept at an ambient temperature of 4 degrees C. (c) Increased sleeping time to phenobarbitone which cannot be attributed to the rate of drug metabolism (5,38). (d) Upregulation of prolactin binding sites in the liver as a result of increased serum prolactin. Additionally, nutritional iron-deficiency lowers brain iron and interferes with protein synthesis in this organ, which could explain the reduction of DA D2 receptor number and function. Given the fact that the highest brain concentrations of iron are found in dopaminergic structures (see 42 for review), and the essential role of intact dopaminergic systems to attentional and learning processes (15b,30), the resultant behavioural changes due to the reduction of dopaminergic activity in iron-deficient animals may go some way to explain the adverse effects on cognition, behavioural patterns, learning and attention, event-related potentials (ERPs) and EEG changes reported in iron-deficient children (19-28,30).

Anemia, Hemolytic↗
PubMed1982

Nutritional iron and dopamine binding sites in the rat brain.

Iron-deficiency (ID) anemia in man is associated with neurological disorders and abnormal behavior. Rats made nutritionally iron-deficient have markedly diminished behavioral responses to centrally-acting drugs (amphetamine and apomorphine) which affect monoaminergic systems. ID has no effect on either the levels of monoamines or on the activities of monoamine-metabolizing enzymes in the brain. We have investigated the possibility that ID may affect postsynaptic events at the level of receptor by measuring the specific binding sites of several neurotransmitters in different brain areas. The results clearly show that ID causes a significant (40-60%) reduction of the DA D2 binding sites in the caudate. DA-sensitive adenylate cyclase, alpha- and beta-adrenergic, muscarinic cholinergic and the benzodiazepine binding sites were not affected by ID. The effects of ID on DA D2 binding sites and the behavioral responses to apomorphine can be reversed when iron-deficient rats are placed for 8 days on an iron-deficient diet supplemented with iron. Chronic hemolytic anemia produced by repeated phenylhydrazine injections caused no change in serum iron and had no effect on either apomorphine-induced hyperactivity or 3H-spiroperidol binding in the caudate. Since the highest concentration of iron is found in DA-rich brain areas, it is possible that iron may be crucial to either the synthesis or coupling of the DA D2 binding site. The possibility that the DA supersensitivity induced by neuroleptics may be related to iron metabolism in the brain has been investigated.

Anemia, Hemolytic↗
PubMed1978

Changes in brain catecholamine turnover and receptor sensitivity induced by social deprivation in rats.

Catecholamine turnover was compared in two brain areas of rats housed under different social conditions. Rats reared in isolation for 6-8 weeks had a significantly lower noradrenaline turnover in the brainstem and lower noradrenaline and dopamine turnover in a brain segment comprising all other areas except the cerebellum, pineal gland, thalamus, and subthalamus. In the open-field test, isolated rats were much more active than group-housed animals. Noradrenaline turnover increased in both brain areas of isolated rats but not in grouped animals after exposure to the open field. Hyperactivity was selectively reduced in isolated rats by chronic oral treatment with d-amphetamine, 5 mg/kg/24 h. It was also reduced 15 min after pretreatment with alpha-methyl-p-tyrosine 200 mg/kg. It is suggested that a prolonged period of reduced noradrenaline release may sensitise post synaptic receptors in isolated rats. Hyperactivity appears to be associated with an increase in transmitter release onto sensitised receptors.

Animals↗