Food-grade titanium dioxide decreases hematocrit and hemoglobin and increases compulsive-like behavior in male mice

Food-grade titanium dioxide (E171) is widely used as a food additive, and it is known that after oral consumption, E171 is translocated into the bloodstream reaching the highest titanium level at 6 h. E171 is accumulated in some organs triggering toxicity, but the effects on the blood parameters after oral consumption have been less studied. Recently, evidence shows that oral exposure to E171 induces behavioral signs of anxiety and depression. The relation between blood alterations and psychiatric disorders has been previously demonstrated. However, the oral exposure to E171 effects on alterations in blood parameters and effects linked to alterations in animal behavior has not been explored. In this short communication, we aimed to investigate the effects of E171 on specific blood parameters (hematocrit, hemoglobin, number of erythrocytes, and leukocytes) and anxiety and compulsive-like behavior in males and females orally exposed to ~5 mg/kg for 4 weeks. The results showed that E171 decreased hematocrit and hemoglobin in male but not in female mice while leukocyte and erythrocyte count remained unaltered. Oral consumption of E171 decreased the levels of anxiety-like behavior in females but not in male mice, while compulsive-like behavior was increased in both male and female mice.     

Pangenomic Classification of Pituitary Neuroendocrine Tumors

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Ocular findings in familial adenomatous polyposis

Background: Retinal pigment epithelium (RPE)lesions are predictive congenital phenotypic markersfor familial adenomatous polyposis (FAP). Thisprospective screening study aims at assessing theincidence and significance of these lesions in FAPpatients and their family members.Methods: Sixty-two members from three familiesincluding five patients with the diagnosis of FAP havebeen ophthalmologically surveyed. All RPE lesions weredocumented with fundus photography and fluoresceinangiography was performed in 13 subjects.Sigmoidoscopy and/or radiological examination wereperformed annually in 9 family members with typicalRPE lesions during 4 years to allow early diagnosis ofFAP.Results: Typical RPE lesions were present infive FAP patients and 15 family members.Telangiectatic dilatations in the retinal peripherywith small dot-like hemorrhages were detected in 6subjects from 3 families These lesions wereparticularly evident on fluorescein angiography.Annual colon analysis showed polyps in 3 out of 9subjects who were positive for RPE lesions.Conclusion: RPE lesions are valuable as aclinical marker in predicting FAP. The co-existingperipheral vascular alterations which have not beenreported before, are probably related to FAP.     

Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats

Summary The aim of this study was to investigate imipramine-induced alterations of cytochrome P-450 and to determine whether prolonged concomitant administration of imipramine and lithium results in a pharmacokinetic interaction.Male Wistar rats received imipramine (10 mg/kg i. p.) at 12 h intervals or lithium chloride (100 mg/kg in drinking water) or they were treated with the combination of these drugs for 2 weeks. The long term treatment with imipramine produced a very complex alteration of cytochrome P-450: imipramine increased the level of the cytochrome, but it decreased the rate of its own aromatic hydroxylation in position 2. The rate of N-demethylation in the side chain was not changed. Consequently, in the case of both hydroxylation and demethylation, calculated molecular activities were decreased to 48% and 70% respectively. This differential change in activities corresponded well to the observed decrease of absorption in difference spectra (type I) produced in microsomes by imipramine. Carbamazepine-induced type I difference spectra were also decreased by imipramine pretreatment, but to a lesser extent. In contrast, hexobarbital type I binding was increased by imipramine treatment while type II difference spectra produced by metyrapone were not affected. The preliminary SDS-PAGE analysis of cytochrome P-450 isoenzymes of control and imipramine treated rats showed that the investigated antidepressant markedly intensified a protein band at 50.11 kD while bands at 51.28 kD, 56.20 kD and 56.88 kD were less intensive. These results indicate that the alteration of cytochrome P-450 by imipramine treatment is not only of quantitative but also of qualitative character. Lithium alone given to rats affected neither the concentration of cytochrome P-450 in microsomal protein nor the rate of imipramine metabolism in vitro. Lithium given jointly with imipramine reduced imipramine-induced elevation of cytochrome P-450. This, however, did not cause any change in the rate of imipramine metabolism in vitro and accordingly in imipramine pharmacokinetics in vivo. The concentration of lithium in the blood plasma tended to increase by concurrent administration of imipramine.Send offprint requests to K. J. Netter at the above address     

Tamoxifen induces ultrastructural alterations in membranes of Bacillus Stearothermophilus

Tamoxifen (TAM), a non-steroid antiestrogen, is the mostly used drug for chemotherapy and chemoprevention of breast cancer. However, the mechanisms by which TAM inhibits cell proliferation in breast cancer are not fully understood. TAM strongly incorporates in biomembranes and a variety of effects have been assigned to biophysical and biochemical interactions with membranes. Therefore, a better understanding of the physicochemical basis of interaction of TAM with biomembranes is essential to elucidate the molecular mechanisms of action. A strain of Bacillus stearothermophilus has been used as a model to clarify the interaction of TAM with the cell membrane. TAM effects on the ultrastructure of membranes of this bacterium were evaluated by electron microscopy. Important ultrastructural alterations were observed in B. stearothermophilus treated with TAM, namely change in the geometry of the membrane profile from asymmetric to symmetric, disaggregation of ribosomes, coagulation of the cytoplasmic matrix, occurrence of mesossomes, appearance of fractures in membranes and the alteration of the ultrastructure of cell wall. These ultrastructural alterations confirm that TAM is a membrane-active drug and that membrane damage may be involved in molecular mechanisms of cell death induced by this drug.     

Tamoxifen induces ultrastructural alterations in membranes of Bacillus Stearothermophilus.

Tamoxifen (TAM), a non-steroid antiestrogen, is the mostly used drug for chemotherapy and chemoprevention of breast cancer. However, the mechanisms by which TAM inhibits cell proliferation in breast cancer are not fully understood. TAM strongly incorporates in biomembranes and a variety of effects have been assigned to biophysical and biochemical interactions with membranes. Therefore, a better understanding of the physicochemical basis of interaction of TAM with biomembranes is essential to elucidate the molecular mechanisms of action. A strain of Bacillus stearothermophilus has been used as a model to clarify the interaction of TAM with the cell membrane. TAM effects on the ultrastructure of membranes of this bacterium were evaluated by electron microscopy. Important ultrastructural alterations were observed in B. stearothermophilus treated with TAM, namely change in the geometry of the membrane profile from asymmetric to symmetric, disaggregation of ribosomes, coagulation of the cytoplasmic matrix, occurrence of mesossomes, appearance of fractures in membranes and the alteration of the ultrastructure of cell wall. These ultrastructural alterations confirm that TAM is a membrane-active drug and that membrane damage may be involved in molecular mechanisms of cell death induced by this drug.     

Quantitative expansion of structural genomic alterations in the spectrum of neuroendocrine lung carcinomas

The pathogenesis and interrelationships of neuroendocrine lung carcinomas are not well understood. Tissue macro-arrays prepared from surgical resection specimens from 35 patients with typical carcinoid (TC), six with atypical carcinoid (AC), 13 with large cell neuroendocrine carcinoma (LCNEC), and 15 with small cell lung carcinoma (SCLC) were investigated by fluorescence in situ hybridization (FISH) and immunohistochemistry. Hybridizations with locus-specific DNA probes demonstrated a high incidence of deletion for the tumour suppressor genes p53 and retinoblastoma (Rb), and for the oncogene cyclin D1, comparable in all carcinoma types. Similarly, an increase of DNA copy number for the Her-2/neu and c-myc oncogenes was noted in all neoplasms. A more detailed quantitative analysis of the results, however, demonstrated increasing numbers of cells harbouring these genomic alterations, from low-grade TC to highly malignant SCLC, with the exception of cyclin D1 deletion. Mutations of the p53 and Rb genes, as assayed by immunohistochemical studies, were observed at high incidence in high-grade carcinomas, compared with a low incidence in the low-grade carcinomas. Conversely, in all carcinoma types, neither membrane-bound Her-2/neu nor nuclear cyclin D1 was detected. It is concluded that structural genomic alterations are frequent in neuroendocrine lung carcinomas and that their occurrence may be underestimated by immunohistochemical studies alone. The quantitative expansion of the Rb, p53, c-myc, and Her-2/neu alterations towards high-grade carcinomas suggests common pathogenetic mechanisms in the spectrum of these neoplasms.     

Multiple genetic alterations in malignant metastatic insulinomas

Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor a (TGFα), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGFα, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGFα overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGFα, and ras genesα plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.