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1-Alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) is known to play an important physiological
role on growth and differentiation in a variety of nonmalignant and malignant cell
types through classical actions, mediated by its specific receptor (VDR), and nongenomic
actions resulting in the activation of specific signalling pathways. Due to the broad distribution
of Vitamin D Receptor (VDR) in many tissues and the ability of 1,25(OH)2D3 to
regulate fundamental processes, such as cell proliferation and differentiation, this steroid
hormone has been suggested in the treatment of different diseases, from cancer to neurodegenerative
diseases. In fact, structural 1,25(OH)2D3 analogues, with weaker collateral
effects, have recently entered in clinical trials. Other interesting molecules due to their
pleiotropic actions are the bioactive sphingolipids (SLs), in particular ceramide (Cer) and
sphingosine 1-phosphate (S1P). Cells maintain a dynamic balance of these metabolites
since Cer and sphingoid bases mediate cell death, while S1P exerts mitogenic effects and
promotes differentiation of several cell types including osteogenic and neural cells. The
biological actions of 1,25(OH)2D3 and SLs, in particular S1P, share many common effectors,
including calcium regulation, growth factor expression, inflammatory cytokines,
etc., but whether they could act synergistically is still unknown and deserves further
investigation
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