No abstract

This study evaluated the gut and peripheral immune response to genetically modified (GM) maize in mice in vulnerable conditions. Weaning and old mice were fed a diet containing MON810 or its parental control maize or a pellet diet containing a GM-free maize for 30 and 90 days. The immunophenotype of intestinal intraepithelial, spleen, and blood lymphocytes of control maize fed mice was similar to that of pellet fed mice. As compared to control maize, MON810 maize induced alterations in the percentage of T and B cells and of CD4(+), CD8(+), gammadeltaT, and alphabetaT subpopulations of weaning and old mice fed for 30 or 90 days, respectively, at the gut and peripheral sites. An increase of serum IL-6, IL-13, IL-12p70, and MIP-1beta after MON810 feeding was also found. These results suggest the importance of the gut and peripheral immune response to GM crop ingestion as well as the age of the consumer in the GMO safety evaluation.

Vitamin E is a generic term used to indicate all tocopherol (TOC) and tocotrienol (TT) derivates. In the last few years, several papers have shown that a TT-rich fraction (TTRF) extracted from palm oil inhibits proliferation and induces apoptosis in a large number of cancer cells. However, the molecular mechanism(s) involved in TT action is still unclear. In the present study, we proposed for the first time a novel mechanism for TT activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicated a high affinity of TTs for ER␤ but not for ER␣. In addition, in ER␤-containing MDA-MB-231 breast cancer cells, we demonstrated that TTs increase the ER␤ translocation into the nucleus, which in turn activates estrogen-responsive genes (MIC-1, EGR-1 and cathepsin D), as demonstrated by cell preincubation with the ER inhibitor ICI-182,780. Finally, we observed that TT treatment is associated with alteration of cell morphology, DNA fragmentation, and caspase-3 activation. Altogether, these experiments elucidated the molecular mechanism underling ␥-and ␦-TT effects.estrogen receptor-␤; breast cancer; apoptosis; tocopherol; nuclear receptor TOCOTRIENOLS (TTs) are usually included together with tocopherols (TOCs) within the "vitamin E family". TTs have a chemical structure similar to TOCs but present three double bonds at positions 3Ј, 7Ј, and 11Ј of the side chain. Similar to TOCs, TTs have four natural isomers, named as ␣, ␤, ␥, and ␦, that differ by the number and position of methyl groups on the chroman ring. The unsaturation of the side chain is associated with specific chemicophysical characteristics that are attracting growing interest both in the field of nutrition and in pharmacology (7, 62).TOCs are commonly found in high concentrations in vegetable oils, animal fats, grains, vegetables, and fruits (13), whereas TTs are relatively rare in Western diets and found in appreciable levels only in a few specific vegetable fats, such as palm oil and rice bran oil (48). The great bioavailability of TOCs and their high efficiency in acting as antioxidants have attracted the interest of biologists who have disregarded TTs and their properties. Recent investigations have demonstrated that the antioxidant efficacy of TTs in membranes is higher than that of TOCs (59, 66), although their uptake and distribution after oral ingestion are less than that of ␣-TOCs (9, 76). Moreover, TTs have been reported to have many specific activities, such as the suppression of growth and the induction of apoptosis in different human and mouse mammary cancer cells (8, 20, 27, 35, 39 -41, 57, 60, 67-69, 77) and in other human cancer cells (14,15,23,37,42,63,71). In general, TTs have been proposed to possess diverse properties that are often not exhibited by TOCs (58) and are associated with "anticancer" activity that is independent of their antioxidant properties.The molecular mechanisms underlying these beneficial effects are still scarcely understood. In our laboratory, we have previously rep...

It has recently been shown that tocotrienols are the components of vitamin E responsible for inhibiting the growth of human breast cancer cells in vitro, through an estrogen-independent mechanism. Although tocotrienols act on cell proliferation in a dose-dependent manner and can induce programmed cell death, no specific gene regulation has yet been identified. To investigate the molecular basis of the effect of tocotrienols, we injected MCF-7 breast cancer cells into athymic nude mice. Mice were fed orally with 1 mg/d of tocotrienol-rich fraction (TRF) for 20 wk. At end of the 20 wk, there was a significant delay in the onset, incidence, and size of the tumors in nude mice supplemented with TRF compared with the controls. At autopsy, the tumor tissue was excised and analyzed for gene expression by means of a cDNA array technique. Thirty out of 1176 genes were significantly affected. Ten genes were downregulated and 20 genes up-regulated with respect to untreated animals, and some genes in particular were involved in regulating the immune system and its function. The expression of the interferon-inducible transmembrane protein-1 gene was significantly up-regulated in tumors excised from TRF-treated animals compared with control mice. Within the group of genes related to the immune system, we also found that the CD59 glycoprotein precursor gene was up-regulated. Among the functional class of intracellular transducers/effectors/modulators, the c-myc gene was significantly down-regulated in tumors by TRF treatment. Our observations indicate that TRF supplementation significantly and specifically affects MCF-7 cell response after tumor formation in vivo and therefore the host immune function. The observed effect on gene expression is possibly exerted independently from the antioxidant activity typical of this family of molecules.

SummaryEstrogen receptor a (ERa) mediates 17b-estradiol (E2) actions through the transcription of E2-sensitive target genes. In addition, rapid non-genomic signaling (e.g., MAPK/ERK) occurs. It is now well accepted that these rapid membrane-initiated responses account for E2-related cancer. Beside many beneficial effects on human health, nutritional flavonoids exert protective and anticarcinogenic effects on E2-related cancer. The mechanism underlying these effects seems to be related to flavonoids antioxidant properties and/or to their ability to alter signal transduction protein kinases. In addition, an antiestrogenic activity has been proposed but not yet defined. However, the identification and characterization of the responsible mechanisms for flavonoid antitumoral effects is poorly understood. Here, we investigated the possibility that the antimitogenic effects of flavonoids are transduced by modulating ERa-mediated rapid signaling. The ability of two flavonoids, the flavanone naringenin and the flavanol quercetin, with respect of E2, to induce ERa activities has been studied in the human cervix epitheloid carcinoma cell line (HeLa) devoid of any estrogen receptors and rendered E2-sensitive by transient transfection with a human ERa expression vector. Our results indicate that flavonoids act as E2 mimetic on ERa transcriptional activity, whereas they impair the activation of rapid signaling pathways committed to E2-induced proliferation. The resulting decoupling of ERa signal transduction could be proposed as a new mechanism in the protective effects of flavonoids against E2-related cancer.