Gut microflora is a key player in host energy homeostasis

Gut microflora is now considered as a key organ involved in host energy homeostasis. Recent data suggest that the alterations of the gut bacteria ecosystem could contribute to the development of metabolic disorders such as type 2 diabetes and obesity. First, gut microflora may increase energy efficiency of non digested food via the fermentation, thus providing more energy to the host. Secondly, fatty acids flux and storage in the adipose tissue is under the control of the fasting-induced adipocyte factor FIAF, which expression depends on gut microflora. Third, high-fat diet feeding changes gut bacteria profile, leading to a drop in bifidobacteria content, which correlates with a higher LPS plasma levels, thereby participating to the onset of inflammation, insulin resistance and type 2 diabetes associated with obesity. Changing gut microflora composition could be a useful tool to prevent or to treat high-fat/low fibres diet-induced metabolic syndrome. double dagger.     

Socioeconomic Inequalities in Smoking and Smoking Cessation Due to a Smoking Ban: General Population-Based Cross-Sectional Study in Luxembourg

This study aimed to measure changes in socioeconomic inequalities in smoking and smoking cessation due to the 2006 smoking ban in Luxembourg. Data were derived from the PSELL3/EU-SILC (Panel Socio-Economique Liewen Zu Letzebuerg/European Union—Statistic on Income and Living Conditions) survey, which was a representative survey of the general population aged ≥16 years conducted in Luxembourg in 2005, 2007, and 2008. Smoking prevalence and smoking cessation due to the 2006 smoking ban were used as the main smoking outcomes. Two inequality measures were calculated to assess the magnitude and temporal trends of socioeconomic inequalities in smoking: the prevalence ratio and the disparity index. Smoking cessation due to the smoking ban was considered as a positive outcome. Three multiple logistic regression models were used to assess social inequalities in smoking cessation due to the 2006 smoking ban. Education level, income, and employment status served as proxies for socioeconomic status. The prevalence of smoking decreased by 22.5% between 2005 and 2008 (from 23.1% in 2005 to 17.9% in 2008), but socioeconomic inequalities in smoking persisted. Smoking prevalence decreased by 24.2% and 20.2% in men and women, respectively; this difference was not statistically significant. Smoking cessation in daily smokers due to the 2006 smoking ban was associated with education level, employment status, and income, with higher percentages of quitters among those with a lower socioeconomic status. The decrease in smoking prevalence after the 2006 law was also associated with a reduction in socioeconomic inequalities, including differences in education level, income, and employment status. Although the smoking ban contributed to a reduction of such inequalities, they still persist, indicating the need for a more targeted approach of smoke-free policies directed toward lower socioeconomic groups.     

Magnesium supplementation and deoxycorticosterone acetate--salt hypertension: effect on arterial mechanical properties and on activity of endothelin-1

The aim of this study was to show whether the decrease in blood pressure induced by Mg supplementation in deoxycorticosterone acetate - salt (DOCA-salt) hypertensive rats is associated with mechanical modifications of blood vessels and (or) changes in tissular production and (or) vasoconstrictor activity to endothelin-1. DOCA-salt treatment increased blood pressure, media thickness, cross-sectional area, and lumen diameter of carotid arteries. Distensibility and incremental elastic modulus versus stress were not altered in carotid arteries, suggesting that the DOCA-salt vessel wall adapts structurally to preserve its blood pressure buffering capacity. Magnesium supplementation attenuated DOCA-salt hypertension. In comparison with normotensive rats, systolic, mean, and pulse pressures were higher whereas diastolic pressure was not different in Mg-supplemented DOCA-salt rats. Magnesium supplementation did not significantly modify the elastic parameters of carotid arteries. In resistance mesenteric arteries, DOCA-salt hypertension induces an inward hypertrophic remodeling. Magnesium supplementation attenuates wall hypertrophy and increases lumen diameter to the normotensive diameter, suggesting a decrease in peripheral resistance. Magnesium supplementation normalizes the altered vasoconstrictor activity of endothelin-1 in mesenteric arteries and attenuates endothelin-1 overproduction in kidney, left ventricle, and aorta of DOCA-salt rats. These findings suggest that Mg supplementation prevents blood pressure elevation by attenuating peripheral resistance and by decreasing hypertrophic effect of endothelin-1 via inhibition of endothelin-1 production.     

Effects of deletion of the prolactin receptor on ovarian gene expression

Prolactin (PRL) exerts pleiotropic physiological effects in various cells and tissues, and is mainly considered as a regulator of reproduction and cell growth. Null mutation of the PRL receptor (R) gene leads to female sterility due to a complete failure of embryo implantation. Pre-implantatory egg development, implantation and decidualization in the mouse appear to be dependent on ovarian rather than uterine PRLR expression, since progesterone replacement permits the rescue of normal implantation and early pregnancy. To better understand PRL receptor deficiency, we analyzed in detail ovarian and corpora lutea development of PRLR-/- females. The present study demonstrates that the ovulation rate is not different between PRLR+/+ and PRLR-/- mice. The corpus luteum is formed but an elevated level of apoptosis and extensive inhibition of angiogenesis occur during the luteal transition in the absence of prolactin signaling. These modifications lead to the decrease of LH receptor expression and consequently to a loss of the enzymatic cascades necessary to produce adequate levels of progesterone which are required for the maintenance of pregnancy.     

Ubiquitination of the glycosomal matrix protein receptor PEX5 in Trypanosoma brucei by PEX4 displays novel features

Trypanosomatids contain peroxisome-like organelles called glycosomes. Peroxisomal biogenesis involves a cytosolic receptor, PEX5, which, after its insertion into the organellar membrane, delivers proteins to the matrix. In yeasts and mammalian cells, transient PEX5 monoubiquitination at the membrane serves as the signal for its retrieval from the organelle for re-use. When its recycling is impaired, PEX5 is polyubiquitinated for proteasomal degradation. Stably monoubiquitinated TbPEX5 was detected in cytosolic fractions of Trypanosoma brucei, indicative for its role as physiological intermediate in receptor recycling. This modification's resistance to dithiothreitol suggests ubiquitin conjugation of a lysine residue. T. brucei PEX4, the functional homologue of the ubiquitin-conjugating (UBC) enzyme responsible for PEX5 monoubiquitination in yeast, was identified. It is associated with the cytosolic face of the glycosomal membrane, probably anchored by an identified putative TbPEX22. The involvement of TbPEX4 in TbPEX5 ubiquitination was demonstrated using procyclic ?PEX4 trypanosomes. Surprisingly, glycosomal matrix protein import was only mildly affected in this mutant. Since other UBC homologues were upregulated, it might be possible that these have partially rescued PEX4's function in PEX5 ubiquitination. In addition, the altered expression of UBCs, notably of candidates involved in cell-cycle control, could be responsible for observed morphological and motility defects of the ?PEX4 mutant.     

The Interactomes of Influenza Virus NS1 and NS2 Proteins Identify New Host Factors and Provide Insights for ADAR1 Playing a Supportive Role in Virus Replication

Influenza A NS1 and NS2 proteins are encoded by the RNA segment 8 of the viral genome. NS1 is a multifunctional protein and a virulence factor while NS2 is involved in nuclear export of viral ribonucleoprotein complexes. A yeast two-hybrid screening strategy was used to identify host factors supporting NS1 and NS2 functions. More than 560 interactions between 79 cellular proteins and NS1 and NS2 proteins from 9 different influenza virus strains have been identified. These interacting proteins are potentially involved in each step of the infectious process and their contribution to viral replication was tested by RNA interference. Validation of the relevance of these host cell proteins for the viral replication cycle revealed that 7 of the 79 NS1 and/or NS2-interacting proteins positively or negatively controlled virus replication. One of the main factors targeted by NS1 of all virus strains was double-stranded RNA binding domain protein family. In particular, adenosine deaminase acting on RNA 1 (ADAR1) appeared as a pro-viral host factor whose expression is necessary for optimal viral protein synthesis and replication. Surprisingly, ADAR1 also appeared as a pro-viral host factor for dengue virus replication and directly interacted with the viral NS3 protein. ADAR1 editing activity was enhanced by both viruses through dengue virus NS3 and influenza virus NS1 proteins, suggesting a similar virus-host co-evolution.     

8p22 MTUS1 Gene Product ATIP3 Is a Novel Anti-Mitotic Protein Underexpressed in Invasive Breast Carcinoma of Poor Prognosis

Background

Breast cancer is a heterogeneous disease that is not totally eradicated by current therapies. The classification of breast tumors into distinct molecular subtypes by gene profiling and immunodetection of surrogate markers has proven useful for tumor prognosis and prediction of effective targeted treatments. The challenge now is to identify molecular biomarkers that may be of functional relevance for personalized therapy of breast tumors with poor outcome that do not respond to available treatments. The Mitochondrial Tumor Suppressor (MTUS1) gene is an interesting candidate whose expression is reduced in colon, pancreas, ovary and oral cancers. The present study investigates the expression and functional effects of MTUS1 gene products in breast cancer.

Methods and Findings

By means of gene array analysis, real-time RT-PCR and immunohistochemistry, we show here that MTUS1/ATIP3 is significantly down-regulated in a series of 151 infiltrating breast cancer carcinomas as compared to normal breast tissue. Low levels of ATIP3 correlate with high grade of the tumor and the occurrence of distant metastasis. ATIP3 levels are also significantly reduced in triple negative (ER- PR- HER2-) breast carcinomas, a subgroup of highly proliferative tumors with poor outcome and no available targeted therapy. Functional studies indicate that silencing ATIP3 expression by siRNA increases breast cancer cell proliferation. Conversely, restoring endogenous levels of ATIP3 expression leads to reduced cancer cell proliferation, clonogenicity, anchorage-independent growth, and reduces the incidence and size of xenografts grown in vivo. We provide evidence that ATIP3 associates with the microtubule cytoskeleton and localizes at the centrosomes, mitotic spindle and intercellular bridge during cell division. Accordingly, live cell imaging indicates that ATIP3 expression alters the progression of cell division by promoting prolonged metaphase, thereby leading to a reduced number of cells ungergoing active mitosis.

Conclusions

Our results identify for the first time ATIP3 as a novel microtubule-associated protein whose expression is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. ATIP3 re-expression limits tumor cell proliferation in vitro and in vivo, suggesting that this protein may represent a novel useful biomarker and an interesting candidate for future targeted therapies of aggressive breast cancer.