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Abstract: In previous studies we demonstrated that resveratrol acts in an antiapoptotic manner on the paclitaxel-treated human neuroblastoma (HN) SH-SY5Y cell line inhibiting the apoptotic pathways induced by the antineoplastic drug. In the present study we evaluated the antiapoptotic effect of resveratrol, studying its activity on cell cycle progression. We determined the mitotic index of cultures exposed to resveratrol and paclitaxel alone or in combination, the cell cycle distribution by flow cytometric analysis (FACS), and the modulation of some relevant cell cycle regulatory proteins. Resveratrol is able to induce S-phase cell arrest and this interference with the cell cycle is associated with an increase of cyclin E and cyclin A, a downregulation of cyclin D1, and no alteration in cyclin B1 and cdk 1 activation. The resveratrol-induced S-phase block prevents SH-SY5Y from entering into mitosis, the phase of the cell cycle in which paclitaxel exerts its activity, explaining the antiapoptotic effect of resveratrol. [Copyright &y& Elsevier]

trans-Resveratrol (3,4′,5-trihydroxystilbene) is able to significantly reduce paclitaxel-induced apoptosis in the human neuroblastoma (HN) SH-SY5Y cell line, acting on several cellular signaling pathways that are involved in paclitaxel-induced apoptosis. trans-Resveratrol reverses phosphorylation of Bcl-2 induced by paclitaxel and concomitantly blocks Raf-1 phosphorylation, also observed after paclitaxel exposure, thus suggesting that Bcl-2 inactivation may be dependent on the activation of the Raf/Ras cascade. trans-Resveratrol also reverses the sustained phosphorylation of JNK/SAPK, which specifically occurs after paclitaxel exposure.Overall, our observations demonstrate that (a) the toxic action of paclitaxel on neuronal-like cells is not only related to the effect of the drug on tubulin, but also to its capacity to activate several intracellular pathways leading to inactivation of Bcl-2, thus causing cells to die by apoptosis, (b) trans-resveratrol significantly reduces paclitaxel-induced apoptosis by modulating the cellular signaling pathways which commit the cell to apoptosis. [Copyright &y& Elsevier]

• Synthesis of PREG in the EAE spinal cord is altered by the pathology in a sex dimorphic way. • Synthesis of PREG in the EAE spinal cord is altered depending on the pathological progression. • The study of neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS. • Metabolism of cholesterol and oxysterol may be interconnected with neuroactive steroid production. Neuroactive steroids, molecules produced from cholesterol in steroidogenic cells (i.e., peripheral glands and nervous system) are physiological modulators and protective agents of nervous function. A possible role for neuroactive steroids in the sex-dimorphic clinical manifestation, onset and progression of Multiple Sclerosis (MS) has been recently suggested. To explore this possibility, we assessed the synthesis of the first steroidogenic product (pregnenolone; PREG) in the spinal cord of experimental autoimmune encephalomyelitis rats, a MS model. Data obtained indicate that the synthesis of PREG in the spinal cord is altered by the pathology in a sex-dimorphic way and depending on the pathological progression. Indeed, in male spinal cord the synthesis was already decreased at the acute phase of the disease (i.e., 14 days post induction - dpi) and maintained low during the chronic phase (i.e., 45 dpi), while in females this effect was observed only at the chronic phase. Substrate availability had also a role in the sex-dimorphic kinetics. Indeed, at the chronic phase, male animals showed a reduction in the levels of free cholesterol coupled to alteration of cholesterol metabolism into oxysterols; these effects were not observed in female animals. These findings suggest that the comprehension of the neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS and to possibly design sex-oriented therapeutic strategies based on neuroactive steroids. [ABSTRACT FROM AUTHOR]