enzymatic action of dehydrogenases present in most animal cells (Ross 1993) For this reason it was thought until recently that most biological effects of retinol were exclusively Syk Inhibitors dependent on its cellular conversion to retinoic acid Nonetheless there has been a growing body of evidence in the last two decades that retinol per se may exert important biological effects especially through mechanisms that involve modulation of redox states and cell signaling (Acin-Perez et al 2010; Gelain et al 2006) .

Here we observed that Akt and p38 phosphorylation took place within 60 min of retinol incubation with phosphorylation peaks in the range of 15C30 min This rapid effect is not Danoprevir compatible to a genomic action that would be dependent on gene transcription activation by RAR/RXR but is more similar to the more recent nongenomic mechanism of action exerted by retinoids widely reported for different authors (Canon et al 2004; Liou et al 2005; Masia et al 2007) It is noteworthy that Akt and p38 were observed in different cell models to be implicated in the process of malignant cell transformation (Castaneda et al 2010; Han and Sun 2007) In previous works we observed that retinol activated cell proliferation induced proliferative focus formation and enhanced MMP-2 activity in Sertoli cells (Dal-Pizzol et al 2001b; Dalmolin et al 2007;

Gelain et al 2006; Klamt et al 2003b) Recently we also observed that p38 inhibition Puncture wounds reverses many of these effects suggesting that p38 activation may be involved in process of induction of transformation caused by pro-oxidant concentrations of retinol (unpublished data manuscript in preparation) Also recently oxidative stress-induced RAGE up-regulation was reported to be important for the survival response of cancer cells to oxidant injury contributing for the increased resistance of transformed cells against apoptosis caused by oxidative damage (Kang et al 2010) It is possible that RAGE upregulation we observed in Sertoli cells may constitute an adaptive response to the pro-oxidant conditions set by retinol which would be important for cell survival during transformation processes triggered by common pathways controlled by cell cycle-related protein kinases such as Akt and p38In 2008 the World Health Organization expanded the classification of myeloproliferative disorders based on increasing amounts of molecular and cytogenetic data .