Céline Boby

Adipocyte/breast cancer cell crosstalk in obesity interferes with the anti-proliferative efficacy of tamoxifen

Background Obesity is a well-known risk factor of breast cancer in post-menopausal women that also correlates with a diminished therapeutic response. The influence of adipocytes and their secretome, i.e. adipokines, on the efficacy of hormone therapy has yet to be elucidated. Methods We investigated, ex vivo, whether mature adipocytes, differentiated from adipose stem cells of normal-weight (MA20) or obese (MA30) women, and their secretions, were able to counteract the effects of tamoxifen (Tx) which is known to decrease neoplastic cell proliferation. Results In a tridimensional model and in a model of co-culture, the anti-proliferative effect of Tx on MCF-7 cancer cells was counteracted by MA30. These two models highlighted two different specific gene expression profiles for genes encoding cytokines or involved in angiogenesis based on the adipocyte microenvironment and the treatment. Thus it notably showed altered expression of genes such as TNFα that correlated with IL-6. In addition, leptin, IL-6 and TNFα, at concentrations reflecting plasma concentrations in obese patients, decreased the anti-proliferative efficacy of 4-hydroxytamoxifen (a major active metabolite of Tx). Conclusions These findings bring insights on adipocytes and mammary cancer cell interactions in Tx therapy, particularly in overweight/obese people. Indeed, patient’ adipokine status would give valuable information for developing individual strategies and avoid resistance to treatment.

Substantial Variability Across Individuals in the Vascular and Nutrigenomic Response to an Acute Intake of Curcumin: A Randomised Controlled Trial

SCOPE Curcumin exerts biological activities of interest in cardiovascular prevention. However, its vascular protective effect is still poorly investigated in humans. The present study aims to assess vascular effect of an acute intake of curcumin and its nutrigenomic impact in circulating immune cells. METHODS AND RESULTS In a randomized, double-blind, crossover design, 18 healthy smokers consume a placebo or a 5-g curcumin. Before and 2 h after the intake, vascular function measurements are performed by using flow-mediated dilation (FMD). In addition, endothelial function in the microcirculation and blood pressure are evaluated. Plasma curcumin concentrations and changes in gene expression in peripheral blood mononuclear cells (PBMC) are analyzed. No significant effect of curcumin on FMD is observed when considering the entire study population, mainly due to a high interindividual variability. A subgroup analysis according to the gender or the cardiovascular-risk score reveals a significant effect of curcumin on FMD in women and in subjects presenting lower cardiovascular risk. No change in gene expression is observed when data are analyzed for all volunteers but changes in expression are observed when analyzed according to gender. CONCLUSIONS This clinical trial highlights that a substantial variability in efficacy of curcumin exists across individuals.

Anthocyanins and their gut metabolites attenuate monocyte adhesion and transendothelial migration through nutrigenomic mechanisms regulating endothelial cell permeability

Abstract Cardioprotective effects of dietary anthocyanins are partly attributed to their ability to maintain endothelial function. However, the underlying cellular and molecular mechanisms of action are not fully understood. This study aimed to evaluate the effect of anthocyanins and their gut metabolites, at physiologically‐relevant conditions, on endothelial cell (EC) function and decipher the underlying molecular mechanisms of action using integrated omics approaches. Primary EC were treated with a mixture of 0.1 &mgr;M cyanidin‐3‐arabinoside, 0.1 &mgr;M cyanidin‐3‐galactoside, 0.1 &mgr;M cyanidin‐3‐glucoside, 0.1 &mgr;M delphinidin‐3‐glucoside, 0.1 &mgr;M peonidin‐3‐glucoside and 0.5 &mgr;M 4‐hydroxybenzaldehyde for 3 h or a mixture of gut metabolites: 0.2 &mgr;M protocatechuic, 2 &mgr;M vanillic, 1 &mgr;M ferulic and 2 &mgr;M hippuric acids for 18 h. Also, successive exposure of EC to both mixtures was performed to mimic anthocyanin pharmacokinetics following their intake. Inflammatory stress was induced using TNF&agr; and monocytes added to assess adhesion and transmigration. Effects of these mixtures on gene, miRNA expression and their potential interaction with cell signalling were investigated. Anthocyanins and their gut metabolites significantly reduced monocyte adhesion and transendothelial migration. Gene expression analysis, using macroarrays, showed that tested compounds modulated the expression of genes involved in cell‐cell adhesion, cytoskeleton organisation or focal adhesion. Bioinformatics analyses of gene expression data identified potential transcription factors involved in the observed nutrigenomic effects and signalling proteins regulating their activity. Molecular docking revealed cell signalling proteins to which these bioactives may bind to and potentially affect their activity and the activation of downstream signalling, effects that were in agreement with the results of Western blot analyses. Microarray analysis showed that anthocyanins and their gut metabolites affected miRNA expression in EC, especially those involved in regulation of EC permeability, contributing to the observed changes in EC function. Integration of these results revealed endothelial‐protective properties of anthocyanins and their gut metabolites and deciphered new underlying multi‐target and multi‐layered mode of action.