However, clinical trials and epidemiologic studies reported that supplementation with retinol or other derivatives actually increased the incidence of diseases associated with oxidative stress, such as cancer and cardiovascular PR-171 in vivo diseases (Omenn et al., 1991, Omenn et al., 1996 and The ABC-Cancer, 1994). Indeed, specific

concentrations of retinol increase ROS production in cell cultures, causing damage to lipids and DNA and activating cell signaling pathways associated to cell death and pre-neoplasic transformation, such as the ERK1/2 MAPK and PKC (Dal-Pizzol et al., 2000, Gelain et al., 2006 and Gelain et al., 2007). The receptor for advanced glycation end-products (RAGE) is a membrane protein belonging to the immunoglobulin family of proteins. RAGEs were first characterized in diabetes, where the gradual accumulation Obeticholic Acid in vitro of advanced glycation end-products

(AGE) was observed to trigger signaling responses inside cells (Yan et al., 1997). These responses included gene expression modulation, free radicals production and release of pro-inflammatory cytokines that ultimately enhance many of the complications related to this disease (Lukic et al., 2008 and Maczurek et al., 2008). RAGE activation is involved in the promotion of either cell death or survival, depending on cell type and experimental conditions. This dual function of RAGE is essential during development, when a fine control of cell proliferation and apoptosis is needed. In adult life, RAGE is Myosin downregulated, but its expression may be enhanced by inflammatory mediators or accumulation of RAGE ligands (Bopp

et al., 2008). RAGE activation also triggers its own upregulation, resulting in intensification of free radical production and expression of pro-inflammatory mediators. Modulation of RAGE expression and activation is believed, for these reasons, to rely on the cellular mechanisms of toxicity exerted by different endogenous compounds such as beta-amyloid peptide, or exogenous agents such as several glycated proteins (Creagh-Brown et al., 2010). Sertoli cells are physiological targets for retinol and retinoic acid, and for this reason constitute a suitable model to study cellular functions of vitamin A, since a variety of reproductive-related processes are regulated by RAR/RXR receptors in a constitutive fashion in these cells (Hogarth and Griswold, 2010). We previously observed that Sertoli cells treated with retinol had an increase in RAGE immunocontent, and that co-incubation with antioxidants reversed this effect (Gelain et al., 2008a). Furthermore, the concentrations of retinol that caused this effect were the same concentrations that increased the production of ROS in Sertoli cells, indicating that retinol affected RAGE expression by a mechanism dependent on free radical production.