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Biomedical subjects

G Ragnotti

Publications and source records attributed to G Ragnotti.

At least 55 records · Page 3Linked to original sources
PubMed1984

Early liver alterations induced by the sex-dependent hepatocarcinogen beta-blocker ZAMI 1305.

Liver alterations occurring after 1, 6 or 10 days of treatment with the hepatocarcinogen beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butyl-amino-propan-2-ol (ZAMI 1305) were studied in male and female Wistar rats. In agreement with its sex-dependent oncogenicity, ZAMI 1305 administration causes DNA damage in the liver of the female but not of the male rat, with the only exception of 2 out of 4 males treated for 6 days. In female rat, the amount of DNA damage increases from 1 to 6 days of treatment, being unchanged at 10 days; a small portion of DNA is however damaged. ZAMI 1305 administration to female rat induces also: (i) an increase of the relative liver weight, of the DNA and RNA synthesizing activity; (ii) a decrease of the number of hepatocytes in mitosis; (iii) a minimal oval cell hyperplasia. When the same parameters were studied in ZAMI 1305-treated male rats, they were unaffected or changed to a less extent in respect to female rats.

Adrenergic beta-Antagonists↗
PubMed1984

Optical isomers of the hepatocarcinogenic beta-blocker ZAMI 1305: influence on nucleic acids synthesis and DNA integrity.

The influence on nucleic acids synthesis and DNA integrity of the D-isomer and of the DL-racemic form of the oncogenic beta-blocker 1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305) and of the non-oncogenic beta-blocker propranolol was tested in vitro and in vivo. Both D- and DL-ZAMI 1305, when added in vitro to nuclei isolated from rat liver, cause inhibition of DNA and RNA synthesis and DNA fragmentation, as evaluated by alkaline sucrose gradient analysis, in a similar dose-dependent fashion. D- and DL-ZAMI 1305 also inhibit to a similar extent the activity of DNA polymerase alpha and beta from regenerating rat liver. When administered in vivo to female rats both D and DL-ZAMI 1305 cause a dose-dependent fragmentation of liver DNA. The D-isomer and DL-racemic form of the non-oncogenic beta-blocker propranolol inhibit DNA and RNA synthesis and cause DNA fragmentation when added in vitro to isolated liver nuclei, being instead without effect when administered in vivo.

Adrenergic beta-Antagonists↗
PubMed1984

Age-dependent, seasonal and daily variations of the DNA damaging capacity of the hepatocarcinogen ZAMI 1305 in female rat liver.

A single injection of the sex-dependent hepatocarcinogen DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305) caused age-related DNA damage, as evaluated by alkaline sucrose gradient analysis, in the liver of female Wistar rats. DNA damage reached a maximum at 4-6 weeks of age, about the onset of sexual maturity, and decreased thereafter. In young rats (5-8 weeks of age), the amount of ZAMI 1305-induced DNA damage showed seasonal and daily differences, being higher when the molecule was administered in winter in respect to summer and in the evening in respect to the morning. In older rats (15-22 weeks of age), no seasonal and daily variations were observed.

Aging↗
PubMed1984

Tumor-initiating activity of the beta-blocker ZAMI 1305 in the liver of the female Wistar rat.

A 1-week treatment with the hepatocarcinogen beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305) induces the appearance of preneoplastic liver lesions--oval cell hyperplasia, basophilic and gamma-glutamyltranspeptidase positive (GGT+) foci--in female Wistar rats, as evidenced by the Solt and Farber short-term test of carcinogenesis. ZAMI 1305-treatment also induces liver DNA damage, as evaluated by alkaline sucrose gradient analysis. The data suggest that the oncogenic B-blocker ZAMI 1305 has initiating activity in the liver of the female Wistar rat.

2-Acetylaminofluorene↗
PubMed1984

Thyroid and chemical hepatocarcinogenesis: further insights from the hepatocarcinogen ZAMI 1305.

The beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylaminopropan-2-ol (ZAMI 1305), oncogenic to the liver of the female but not of the male Wistar rat, was used to investigate some aspects of the relationship between liver and thyroid during chemical hepatocarcinogenesis. Thyroidectomy (TDX) strongly reduces the amount of hepatic DNA damage induced by a single administration of ZAMI 1305 in the female Wistar rat. One week of treatment with triiodothyronine (T3) completely restores the susceptibility of the liver of thyroidectomized animals to the genotoxic activity of the molecule. The amount of hepatic DNA damage in intact females varies with the age of the animal, being maximal in rats of 4-8 weeks of age, when T3 serum concentration are also maximal. An increase of relative thyroid weight, coupled with histological hyperplasia of the gland, is observed in female Wistar rats treated for 6 months with ZAMI 1305. Minimal changes of the thyroid are observed in ZAMI 1305-treated male rats. The increase of relative thyroid weight in female rats appears to be related to the severity of preneoplastic and neoplastic liver changes. These findings and several suggestions from the literature lead us to propose a model for the interaction between liver and thyroid during chemical hepatocarcinogenesis.

Animals↗
PubMed1983

Thyroid modifications in male and female rats treated with the hepatocarcinogen beta-blocker ZAMI 1305.

The morphology of the thyroid gland from Wistar rats treated for 6 months with the beta-blocker DL-1-(2-nitro-5-methyl-phenoxy)-3-tert-butyl-amino-propan-2-ol (ZAMI 1305), a potent sex-dependent hepatocarcinogen, was studied. A significant high incidence of cases with thyroid hyperplasia is found among female rats, the only sex susceptible to the carcinogenic effect of ZAMI 1305. Thyroid hyperplasia is instead much less evident in male rats. In female rats the increase in the relative thyroid weight is directly related to the gravity of the predominant liver lesion (clear cell foci, neoplastic nodules, hepatocellular carcinomas). The results suggest an influence of the preneoplastic and neoplastic liver on thyroid gland.

Adrenergic beta-Antagonists↗
PubMed1983

Modifications of ganglioside patterns in human meningiomas.

Ganglioside content and distribution were determined in control meninges and in 30 human meningiomas belonging to four different histological types. Irrespective of the histological classification all meningiomas showed a ganglioside content significantly higher than that of control meninges. The analysis of ganglioside distribution in each meningioma showed that in the majority of the cases the increase of ganglioside content was primarily the result of selective accumulation of ganglioside GM3; in the remaining cases ganglioside GM1 was present in a significantly higher amount than in the control dura mater and leptomeninges. A common feature of both types of meningiomas is a simplification of ganglioside pattern, with a shift from the polysialylated to the monosialylated forms. A tentative classification of meningiomas into "GM3-rich" and "GM1-rich" types, together with an explanation for the selective accumulation of these two types of ganglioside, is proposed.

Chromatography, Thin Layer↗
PubMed1983

In vitro and in vivo DNA damage of male and female rat liver nuclei by oncogenic and nononcogenic beta blockers.

The beta blocker DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305), hepatocarcinogenic to the female rat, and the nononcogenic beta blockers DL-1-(2-nitro-5-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1327), DL-propranolol, and DL-atenolol were tested for their capacity to damage liver DNA in vitro and in vivo. As revealed by alkaline sucrose gradient analysis, all the beta blockers tested, with the exception of DL-atenolol, caused a dose-dependent DNA fragmentation when they were added in vitro to nuclei isolated from livers of both male and female Wistar rats. Analysis of the DNA sedimentation patterns in neutral sucrose gradients demonstrated the absence of DNA fragmentation, thus indicating that the drugs did not induce double-strand DNA breaks. When the beta blockers were administered in vivo, liver DNA damage was observed only in female Wistar rats treated with ZAMI 1305. A single injection of ZAMI 1305 caused the onset of two distinct episodes of DNA damage. The first episode occurred within 5 minutes, and the damage was repaired within 1 hour after the injection; the second, apparently spontaneous, episode occurred 14 hours after the injection, and the damage was more pronounced than that seen in the first episode and took a much longer time to subside. However, a second injection of ZAMI 1305 into female Wistar rats 8 hours after the first injection did not induce the immediate short-lived episode of DNA damage but, like the first injection, it caused late DNA damage that peaked about 16 hours after drug administration.

Adrenergic beta-Antagonists↗
PubMed1982

Inhibition in vitro of yeast DNA polymerase I activity by beta-blockers.

The activity of DNA polymerase I from Saccharomyces cerevisiae is inhibited, in a dose-dependent fashion, by the oncogenic beta-blocker 1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305) and by the non-oncogenic beta-blockers 1-(2-nitro-5-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1327), atenolol, and propranolol, the latter having the highest inhibiting activity. The inhibition is due to an interaction of the beta-blockers with the free enzyme and with the enzyme-DNA complex. The degree of inhibition is directly related to the hydrophobicity of the aromatic moiety and to the length and hydrophilicity of the aliphatic chain of the inhibitor. No relation seems to exist between the in vitro inhibition of yeast DNA polymerase I by beta-blockers and their oncogenic activity.

Adrenergic beta-Antagonists↗
PubMed1982

Liver tumors induced by a new beta-adrenoreceptor blocking agent in female rats.

A newly synthesized beta-adrenoreceptor blocking agent, DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305), administered intragastrically for 6 months induced hepatocellular carcinomas in female outbred Wistar rats in a dose-dependent fashion but was harmless to the livers of male outbred Wistar rats. Experiments with castrated animals confirmed the dependence of the carcinogenic effect of ZAMI 1305 on the hormonal status of the rat. When an isomer of ZAMI 1305, DL-1-(2-nitro-5-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1327), and DL-practolol, which have pharmacologic activities similar to those of ZAMI 1305, were administered by the same experimental technique as used for ZAMI 1305, no liver tumors appeared either in male or female rats.

Adrenergic beta-Antagonists↗
PubMed1981

Quantification of damage to striated muscle after normothermic or hypothermic ischemia.

Muscular ischemia of different duration was induced by use of a tourniquet applied to the rear left leg of rabbits under normothermic or hypothermic conditions, and variations in serum creatine kinase, lactate dehydrogenase, K+, Ca2+, and lactate were determined at various intervals after blood flow was restored. A monocompartmental model analysis applied to the activities of the two enzymes in the serum demonstrated that: (a) the total enzyme activity leaked into the blood is proportional to the duration of normothermic but not of hypothermic ischemia; (b) this enzyme leakage persists until at least the third day after blood flow is restored; (c) a substantial part of the ischemic damage seems to occur as a consequence of re-perfusion, not of the ischemia itself; and (d) hypothermia greatly minimizes the ischemic damage. The data we obtained for K+ and for lactate confirm the protective effect of hypothermia.

Animals↗
PubMed1979

Inhibition of protein synthesis in ischaemic liver from phenobarbitone-treated rat.

Both ribosomal factors and cytosolic inhibitors are involved in the reduction of the rate of protein synthesis which occurs in the ischaemic hepatocyte from control and phenobarbitone-treated livers. Of these 2 factors it is the latter which seems to play a major role in determining the irreversible impairment of protein synthesis. Phenobarbitone administration has no effect on the rate of protein synthesis of ischaemic and post-ischaemic hepatocyte.

Animals↗
PubMed1978

Phenobarbitone-induced stimulation of protein synthesis in liver of diabetic rat.

The effect of phenobarbitone on liver weight, on the rate of protein synthesis and on the sedimentation profiles of polyribosomes from livers was studied in diabetic rats. The rate of protein synthesis by isolated postmitochondrial supernatants from diabetic rats is lower than that from normal animals. The analysis of polyribosome profiles and the effect of Sephadex chromatography on protein synthesis demonstrated that the reduction was dependent in part on polyribosomal disaggregation and in part on the presence in the cytosol of low molecular weight inhibitor(s). Phenobarbitone administration had the same effect in either diabetic or normal rats in that it increased, (a) the degree of polyribosomal aggregation, (b) the rate of protein synthesis by the isolated postmitochondrial supernatants, (c) liver weight and (d) the activity of the inducible enzyme, NADPH-cytochrome c reductase. Both polyribosomal and soluble factors appear to be involved in the phenobarbitone effect. As the diabetic rats do not secret insulin the results suggest that insulin is not involved in the control of protein synthesis by phenobarbitone. It is suggested that the intracellular redox state has a major influence on the rate of protein synthesis.

Animals↗
PubMed1975

The effect of phenobarbitone on protein synthesis by liver polyribosomes in fed and starved rats.

1. The effect of phenobarbitone on the rate of protein synthesis and on the sedimentation patterns of various liver subcellular fractions containing ribosomes was studied in rats. 2. Phenobarbitone treatment increased the incorporation of [114C]leucine into protein by all preparations, provided they had not been subjected to preliminary treatment with Sephadex G-25. The phenobarbitone-induced effect on incorporation was associated with a gain in liver weight and a higher degree of polyribosomal aggregation. 3. Preparations that were treated with Sephadex G-25 incorporated more radioactivity into protein, but did not show the response to phenobarbitone treatment. 4. When the influence of starvation and phenobarbitone was studied separately on membrane-bound and membrane-free polyribosomes, it was shown that whereas both classes of polyribosomes were affected by starvation, apparently only the former class was susceptible to phenobarbitone stimulation of protein synthesis. 5. The decreased capacity for protein synthesis of polyribosomes from starved rats was independent of their association with the membranes of the endoplasmic reticulum, but resulted from polyribosomal disaggregation, from an intrinsic defect of the polyribosomes themselves and from changes in composition of the cell cap. 6. The results are discussed in relation to the problem of the control of protein biosynthesis and of the functional separation of membrane-bound and membrane-free polyribosomes.

Animals↗