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1.
Genes Nutr ; 1(1): 61-70, 2006 Mar.
Article in English | MEDLINE | ID: mdl-18850221

ABSTRACT

The lethal milk mouse syndrome is caused by a point mutation in the zinc transporter gene ZnT4 resulting in defective zinc secretion in the milk of homozygous mutant dams. Pups of any genotype fed solely on lm milk die within the first two weeks of neonatal life, displaying zinc deficiency symptoms. Homozygous mutant pups survive when foster nursed by wild type dams and show signs of mild zinc deficiency in adulthood. To further investigate the role of ZnT4 in zinc secretion in the intestinal epithelium, we have studied the expression by real time quantitative PCR of mutant ZnT4 and of other zinc transporters of the Zip and ZnT families, in the jejunum of homozygous lm mice and of the isogenic wild type strain C57BL/ 6J. We report in this paper that expression of the mutant ZnT4 mRNA, carrying a premature translational termination codon (ZnT4/lm), is almost absent in tissues from lm mice, probably as a result of degradation by the Nonsense Mediated mRNA Decay (NMD) Pathway. In the jejunum of mutant mice, we also observed decreased expression of the uptake zinc transporter Zip4, paralleled by increased levels of both metallothionein genes MTI and MTII. Zinc supplementation of lm mice in the drinking water did not result in further decrease of Zip4 expression, but led to full induction of MT mRNAs. These results lead us to conclude that, although in the enterocytes of lm mice the absence of the zinc secretion activity mediated by ZnT4 results in increased intracellular zinc concentration, other zinc efflux activities are able to maintain the level of zinc ions below the threshold necessary for full induction of metallothioneins.

2.
J Nutr Biochem ; 13(3): 157-167, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11893480

ABSTRACT

Chitosan is a polycationic compound widely employed as dietary supplement and also present in pharmaceutical preparations. Although it has been approved for human consumption, its possible side effects have not been widely investigated and the available data in the literature are still controversial. Several polycationic substances have been shown to affect tight junction permeability in epithelial cell models in vitro. In this study we have compared the effects of chitosan and other polycations (polyethylenimine, poly-L-lysines of different molecular weights) on the integrity of tight junctions and of the actin cytoskeleton in the human intestinal Caco-2 cell line. We have measured trans-epithelial electrical resistance and paracellular passage of the extracellular marker inulin, and we have localized F-actin and tight junctional proteins (ZO1 and occludin) in cell monolayers treated with various concentrations of each polycation. Fluorescent poly-L-lysines were also employed to determine their association with the cell monolayer. Our results indicate that all polycations investigated are able to induce a reversible increase in tight junction permeability. This effect is concentration and energy dependent, affected by the extracellular concentration of divalent cations (calcium, magnesium and manganese) and it is associated with morphological changes in the F-actin cytoskeleton, as well as in the localization of tight junctional proteins. Chitosan, in particular, was the only cationic polymer that displayed an irreversible effect on tight junctions at the highest concentration tested (0.01%). These results indicate that oral ingestion of chitosan may have more widespread health effects by altering intestinal barrier function, thus allowing the entrance into the circulation of potentially toxic and/or allergenic substances.

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