Total and specific dietary polyphenol intakes and 6-year anthropometric changes in a middle-aged general population cohort.

BACKGROUND: Dietary polyphenols are suggested antiobesogenic agents. Prospective evidence in general population of an association between polyphenol intakes and anthropometry is lacking. OBJECTIVE: To assess the associations between dietary polyphenol intakes and changes in body mass index (BMI) and waist circumference (WC) over a 6-year period. METHODS: Individual intakes of 264 different polyphenols (mg day-1) were estimated using the Phenol-Explorer database and the mean of 6-17 24-h dietary records collected in 1994-1996. BMI in kg m-2 and WC in cm were measured in 1995-1996, 1998-1999 and 2001-2002. Linear mixed-effect models allowed for the assessment of longitudinal associations between energy-adjusted quartiles of total polyphenol intake as well as intake of 15 polyphenol classes and changes of these respective polyphenol classes in anthropometry over the 6 years of follow-up. Adjustment variables included sex, age, socio-economic status, lifestyle, dietary intakes and health status. RESULTS: Participants in the highest quartile of intake of flavanones (BMI change: -0.28 (-0.43; -0.13), P=0.009), flavones (BMI change: -0.29 (-0.44; -0.14), P=0.008) and lignans (BMI change: -0.28 (-1.63; -0.09), P=0.01) experienced a less notable increase in BMI over time compared with their counterparts in the bottom quartile of intake of the respective polyphenol classes. Participants in the highest quartile of intake of flavanones (WC change: -1.39 (-2.02; -0.92), P=0.001), flavones (WC change: -1.57 (-2.32; -0.92), P=0.001), hydroxycinnamic acids (WC change: -1.27 (-1.92; -0.63), P=0.01), lignans (WC change: -1.16 (-1.80; -0.51), P=0.006) and total polyphenol intake (WC change: -1.39 (-2.05; -0.74), P=0.001) experienced a less notable increase in WC over time compared with their counterparts in the bottom quartile of intake of the respective polyphenols. CONCLUSIONS: Dietary polyphenol intakes may help reduce weight gain over time in the general population. This could have important public health implications because moderate increases in BMI and WC over time have been shown to increase disease risk.

A new genotoxicity assay based on p53 target gene induction.

The p53 tumor suppressor protein has emerged as a universal sensor of genotoxic stress that regulates the transcription of numerous genes required for appropriate cellular response to DNA damage. Therefore, transcriptional induction of p53 target genes can be considered as a global and early indicator of genotoxic stress. By performing expression microarrays and RNA-Seq analysis on wild-type and mutant TP53 human lymphocytes respectively derived from controls and Li-Fraumeni patients and exposed to different classes of genotoxic agents, we first determined a common p53-dependent transcriptional signature of DNA damage. We then derived a simple and fast assay based on the exposure of wild-type TP53 lymphocytes to physical or chemical agents and on the quantitative measurement of selected p53 target gene transcriptional induction. The specificity of the p53 genotoxicity assay can easily be demonstrated by performing the same experiment in control lymphocytes with heterozygous TP53 mutations, which compromise responses to DNA damage. This assay allowed us to show that most of the drugs commonly used in cancer treatment, except the microtubule poisons, are highly genotoxic. The p53 genotoxicity assay should facilitate the measurement of the genotoxic effects of chemical and physical agents and the identification of drugs that are not genotoxic and do not expose patients to the risk of secondary malignancies, especially those with a constitutional defect in response to DNA damage, such as patients with Li-Fraumeni syndrome.

Rapid induction of naive T cell apoptosis by ecto-nicotinamide adenine dinucleotide: requirement for mono(ADP-ribosyl)transferase 2 and a downstream effector.

Lymphocytes express a number of NAD-metabolizing ectoenzymes, including mono(ADP-ribosyl)transferases (ART) and ADP ribosylcyclases. These enzymes may regulate lymphocyte functions following the release of NAD in injured or inflammatory tissues We report here that extracellular NAD induces apoptosis in BALB/c splenic T cells with an IC(50) of 3-5 microM. Annexin V staining of cells was observed already 10 min after treatment with NAD in the absence of any additional signal. Removal of GPI-anchored cell surface proteins by phosphatidylinositol-specific phospholipase C treatment rendered cells resistant to NAD-mediated apoptosis. RT-PCR analyses revealed that resting BALB/c T cells expressed the genes for GPI-anchored ART2.1 and ART2.2 but not ART1. ART2-specific antisera blocked radiolabeling of cell surface proteins with both [(32)P]NAD and NAD-mediated apoptosis. Further analyses revealed that natural knockout mice for Art2.a (C57BL/6) or Art2.b (NZW) were resistant to NAD-mediated apoptosis. Labeling with [(32)P]NAD revealed strong cell surface ART activity on T cells of C57BL/6 and little if any activity on cells of NZW mice. T cells of (C57BL/6 x NZW)F(1) animals showed strong cell surface ART activity and were very sensitive to NAD-induced apoptosis. As in BALB/c T cells, ART2-specific antisera blocked cell surface ART activity and apoptosis in (C57BL/6 x NZW)F(1) T cells. The fact that T cells of F(1) animals are sensitive to rapid NAD-induced apoptosis suggests that this effect requires the complementation of (at least) two genetic components. We propose that one of these is cell surface ART2.2 activity (defective in the NZW parent), the other a downstream effector of ADP-ribosylation (defective in the C57BL/6 parent).

Suppression of asthma-like responses in different mouse strains by oral tolerance.

In this study we examined the effect of oral antigen (Ag) administration on the development of experimental asthma in different mouse strains. We selected BALB/c, BP2, CBA/Ca interleukin (IL)-5 transgenic, and BALB/c T-cell receptor-delta-deficient mouse strains because they exhibit different aspects of the asthma syndrome. Mice exposed to 1% ovalbumin (OVA), dissolved in the drinking water for 5 consecutive days, became unresponsive to subsequent immunogenic OVA challenges. This regimen of OVA administration induced Ag-specific unresponsiveness in all mouse strains tested, including gammadelta-deficient mice that are said to be resistant to tolerance induction. The Ag-specific unresponsiveness was characterized by reduced (almost absent) airway eosinophilic inflammation, airway hyperreactivity, and mucus production; also by low levels of T helper (Th) 2-type cytokines in bronchoalveolar lavage fluid, and decreased immunoglobulin (Ig) G1 and IgE OVA-specific antibody production. The unresponsive state was not associated with increased levels of the suppressive cytokines IL-10 and transforming growth factor (TGF)-beta or with immune deviation toward the Th1 pathway due to increased levels of interferon-gamma and IL-12. Moreover, treatment with anti- TGF-beta antibodies did not abrogate oral tolerance. Oral Ag administration was quite effective in suppressing the development of key features of asthma when initiated after primary immunization (Day 0) or after booster (Day 7), but not after challenge (Day 14) when it increased allergic responses. Collectively, our findings show for the first time the beneficial and detrimental effects of oral Ag administration on the development of experimental asthma.