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Biomedical subjects

P Cerutti

Publications and source records attributed to P Cerutti.

At least 73 records · Page 4Linked to original sources
PubMed1983

DNA binding of aflatoxin B1 by co-oxygenation in mouse embryo fibroblasts C3H/10T1/2.

The mechanism of activation of aflatoxin B1 to ultimate metabolites capable of DNA binding was investigated in mouse embryo fibroblasts C3H/10T1/2. The contribution of co-oxygenation reactions which are coupled to arachidonic acid metabolism was assessed by the use of inhibitors of prostaglandin endoperoxide synthetase and lipoxygenase. Indomethacin and 5,8,11,14-icosatetraynoic acid inhibited AFB1-binding to maximally 60%. The antioxidant glutathione was also inhibitory while CuZn superoxide dismutase had no effect or slightly stimulated binding at high concentrations. These results indicate that co-oxygenation plays a major role in AFB1-metabolism in 10T1/2 cells. The observation that the phospholipase A2 inhibitor p-bromophenacylbromide diminished AFB1-DNA binding supports the notion that AFB1, because it is membrane-active, may enhance its own co-oxidative metabolism by stimulating the arachidonic acid cascade.

Aflatoxin B1↗
PubMed1983

Suppression of tumor promoter phorbolmyristate acetate-induced chromosome breakage by antioxidants and inhibitors of arachidonic acid metabolism.

To gain insight into the mechanism of formation of chromosomal aberrations by the tumor promoter phorbolmyristate acetate (PMA) in human lymphocytes, we investigated the effect of antioxidants and inhibitors of arachidonic acid metabolism. Among the antioxidants bovine erythrocyte CuZn superoxide dismutase, glutathione peroxidase, mannitol (a scavenger of hydroxyl radicals), butylated hydroxytoluene and butylated hydroxyanisole were anticlastogenic while catalase and dimethylfuran (a scavenger of singlet oxygen) were inactive. These results show that the induction of aberrations by PMA occurs via indirect action, i.e. the intermediacy of superoxide and hydroxyl radicals. The following inhibitors of arachidonic acid metabolism were strongly anticlastogenic: the cyclo-oxygenase inhibitors indomethacin and flufenamic acid and the lipoxygenase inhibitor BN1015. Imidazole, nordihydroguaiaretic acid BN1048 and 5,8,11,14-eicosatetraynoic acid were moderately active. The inhibitor of phospholipase A2, fluocinolone acetonide, was also anticlastogenic. We conclude that the oxidative metabolism of arachidonic acid is involved in the induction of chromosomal aberrations by PMA in human lymphocytes. However, because of the limited selectivity of these drugs, it is not yet possible to identify unambiguously the step(s) in the arachidonic acid cascade responsible for PMA clastogenicity.

Anti-Inflammatory Agents↗
PubMed1983

Clastogenic action of tumor promoter phorbol-12-myristate-13 acetate in mixed human leukocyte cultures.

The tumor promoter phorbol-12-myristate-13-acetate (PMA) induces chromosomal aberrations in mitogen stimulated human lymphocyte cultures containing monocytes, polymorphonuclear cells (PMN) and platelets. Such cultures produce a diffusible clastogenic factor (CF) in response to PMA which causes aberrations in fresh blood cultures which have not been exposed to PMA. We have studied the contribution of monocytes, PMN and platelets to CF formation. 'Pure' lymphocyte cultures (containing no platelets and maximally 1% PMN and 2% monocytes) only produced CF when they were in contact with 1 to 1.8 X 10(6) monocytes attached to plastic during PMA treatment (18.5 +/- 5.3% mitosis with aberrations for CF produced in the presence of monocytes relative to 6.0 +/- 4% in their absence). They also produced CF of increasing potency upon addition of 0.25 to 5 X 10(6) PMN (20.5 +/- 5.9% mitosis with aberrations for CF produced in the presence of 5 X 10(6) PMN). Cultures containing 5-10 platelets/lymphocyte also formed CF upon PMA treatment. Cultures of purified monocytes and PMN were capable of producing CF in the absence of lymphocytes. The presence of bovine erythrocyte CuZn superoxide dismutase during PMA treatment decreased the activity of the resulting CF under all conditions. Catalase prevented CF production from PMN. It is concluded that the presence of monocytes, PMN or platelets is a prerequisite for CF formation by PMA. Neoplastic tissue is usually surrounded by inflammatory leukocytes. CF produced by these cells in response to tumor promoters such as PMA may induce chromosomal damage in the neighboring tumor cells.

Blood Platelets↗
PubMed1983

The induction of ornithine decarboxylase by phorbol 12-myristate 13-acetate or by serum is inhibited by antioxidants.

The mechanism of action of tumor promoters may involve the modulation of gene expression, e.g., the induction of ornithine decarboxylase (ODC). The tumor promoter phorbol-13-myristate-12-acetate (PMA) induces chromosomal damage via the intermediacy of active oxygen species which may trigger the activation of certain genes. Therefore, we have studied the effect of antioxidants on the induction of ODC by PMA, medium change only and medium change plus PMA in mouse mammary tumor cells Mm5mt/C1. CuZn-superoxide dismutase (SOD, a scavenger of superoxide radicals), catalase (CAT, a scavenger of hydrogen peroxide) and mannitol (a scavenger of hydroxyl radicals) suppressed ODC induction under all three conditions. The relative inhibitory potency of the antioxidants was always SOD less than CAT less than mannitol less than SOD + CAT. Maximal suppression by SOD + CAT was approximately 50%. It is concluded that active oxygen species play a role in ODC induction by factors contained in serum and by PMA.

Animals↗
PubMed1981

N-Acetoxy-acetylaminofluorene reacts preferentially with a control region of intracellular SV40 chromosome.

Many chemical carcinogens or their metabolites react with DNA; thus it is of interest to determine what effect chromosomal structure has on these reactions. The chromosome of simian virus 40 (SV40) is well suited for such studies; like chromatin of eukaryotic cells, it is organized into nucleosomes. The nucleotide sequence of SV40 is known, together with much about the pattern of viral gene expression and DNA replication, and the structure of the viral chromosome. We have investigated the binding of the ultimate carcinogen, N-acetoxy-acetylaminofluorene (AAAF), to specific regions of the SV40 chromosome in situ in the intact infected cell. The results, reported here, indicate that a region containing regulatory functions on the intracellular SV40 chromosome has unique structural properties which render it more susceptible to attack by AAAF than the rest of the SV40 genome. The preferential binding of AAAF to regulatory regions of chromatin may have implications for the mechanism of action of this and similar carcinogens.

2-Acetylaminofluorene↗
PubMed1981

Clastogenic activity from Bloom syndrome fibroblast cultures.

Media from cultures of fibroblasts of six patients with the autosomal recessive disease Bloom syndrome (BS) and from four normal fibroblast strains were analyzed for clastogenic activity towards phytohemagglutinin-stimulated human blood lymphocytes from healthy donors. Clastogenic activity was detected in concentrated ultrafiltrates of media from all six BS strains but none of the normal fibroblast strains. The frequencies of chromosomal aberrations that were induced depended on the concentration of the ultrafiltrates. Addition of bovine superoxide dismutase to the blood lymphocyte cultures strongly suppressed the clastogenic potency of the ultrafiltrates. Unconcentrated conditioned BS media were inactive. From the pore size of the ultrafilters and Sephadex G-10 chromatography it is concluded that the clastogenic material is in the molecular weight range of 1000 to 10,000. The concentrated ultrafiltrates of BS culture media also possessed the capacity to induce sister chromatid exchanges in normal human blood lymphocytes, but with relatively low efficiency. On the basis of these results and by analogy to certain collagen diseases such as systemic lupus erythematosus, we speculate that BS cells are deficient in the detoxification of active oxygen species.

Cells, Cultured↗
PubMed1979

[Fragments of linear unintegrated Rous sarcoma virus DNA, resulting from digestion with SmaI restriction endonuclease].

Linear unintegrated DNA of Schmidt-Ruppin Rous sarcoma virus, subgroup D (SR-RSV-D), was digested with SmaI restriction endonuclease, analyzed by agarose gel electrophoresis, "blotted" by Southern's method and hybridized with a viral 32P cDNA. SmaI cleaves this DNA at five sites, two of which are localized at the ends of the provirus. Src and env genes seem not to be restrictied by SmaI cleavage.

Animals↗
PubMed1979

Effects of metabolite VIII of bromexine (Na 872) on type II epithelium of the lung: an experimental and morphological study with reference to surfactant secretion.

50 Wistar rats were divided into 5 groups: 4 experimental and 1 control group. The experimental groups A and B received, per os, a daily dose of 100 mg of Na 872 (metabolite VIII of Bromexine) for 3 or 6 days and were killed 1 day later. The experimental groups C and D received 200 mg of the same substance according to the same experimental procedure and for the same periods. The lungs were fixed in situ by perfusion, examined by light and electron microscopy using morphometric methods. No manifest lesions occurred in alveolar tissue. Morphometric analysis showed an increase in the volume ratio of type II epithelial cells and of lamellated body volume in respect to total alveolar tissue volume. Furthermore, our findings suggested an increase in lamellated bodies in respect to type II cell volume, particularly in group C (200 mg/3 days); they showed the existence of a hypertrophy of type II cells, particularly at 6 days.

Ambroxol↗
PubMed1979

Distribution and function of cytoskeletal proteins in lung cells with particular reference to 'contractile interstitial cells'.

Cytoskeletal proteins are demonstrated in the interstitial cells of the lungs. These proteins appear in the cytoplasm as bundles of microfilaments, the individual filaments measuring 40--80 A in diameter. The presence of actin and myosin in these cells is demonstrated by immunofluorescence. Antiactin antibodies (AAA) obtained from patients with chronic aggressive hepatitis, as well as AAA and antimyosin antibodies prepared in the rabbit, are used. The major difference between the cytoskeletal proteins of interstitial cells and other cells of the alveolar tissue (type II epithelium, pericytes, and near the junctional complexes of endothelial cells) is that the microfilaments within the interstitial cells are organized into bundles forming tiny intracytoplasmic 'muscles'. Furthermore, they appear to be much more abundant and seem to anchor the cell on the alveolar basement membrane by hemidesmosome-like structures. These peculiar cytological features provide these cells with an important functional capacity. Being located in the 'pillars' which cross the capillary space, the contraction of interstitial cells may modify the alveolocapillary configuration in some circumstances. The physiological importance of such an 'active' alveolar motility is to provide the lung with a mechanism of autoregulation of the ventilation/perfusion (V/Q) ratio at alveolar level.

Actins↗