The role of decreased Mcl 1 levels in ATO induced apoptosis was studied in HL 6

Sphingolipids including Docetaxel sphingosine and sphinganine are ubiquitous but necessary structural and functional aspects of the cell. Furthermore, sphingolipid metabolites including S1P have important biological roles in a variety of pathophysiological as well as physiological events. Sphinganine 1 phosphate in addition to S1P is produced by the ATP dependent phosphorylation of sphinganine by sphingosine kinases. Sphingosine kinase is a protected lipid kinase with two mammalian isoforms. The biological function of S1P has been thoroughly characterized including cell growth and survival and inflammation. Furthermore, S1P provides powerful anti-apoptotic and professional survival signaling in endothelial cells. In contrast to the well characterized biological and physiological functions of S1P, sphinganine 1 phosphate has not been extensively studied and little is known about its function. We abruptly discovered lately that plasma levels of sphinganine 1 phosphate dropped dramatically after liver IR in mice. Furthermore, in our present and previous Retroperitoneal lymph node dissection studies, we demonstrated that exogenous sphinganine 1 phosphate therapy immediately before reperfusion significantly attenuated the elevation of plasma ALT and creatinine levels after hepatic IR. We suggest that sphinganine 1 phosphate is biologically powerful, is depleted after enormous liver IR injury and may have important cytoprotective functions to defend against endothelial cell dysfunction after liver IR. Though sphinganine 1 phosphate is structurally similar to S1P, it lacks the trans double bond in the 4 position and differs from S1P by being cell impenetrable. Liver IR in exhaustion of systemic along with hepatic ATP levels which might reduce the activities and/or advantages of SK. However, it's uncertain why a selective depletion of plasma sphinganine 1 phosphate and not S1P happens after liver IR as both sphinganine 1 phosphate and S1P synthesis depend on the exact same Dub inhibitor enzyme, SK. Preferential synthesis of sphinganine 1 phosphate over S1P has been demonstrated with SK1 overexpression. Berdyshev et al. have shown that SK1 overexpression in several principal cells and cultured cell lines resulted in a main upregulation of sphinganine 1 phosphate activity relative to S1P. In their study, SK1 over-expression preferentially directed the flow of newly formed sphingoid angles from de novo ceramide creation toward the forming of sphinganine 1 phosphate. These studies suggest that SK1 preferentially synthesizes sphinganine 1 phoshate from simple de novo sphingolipids produced whereas development of S1P is via independent and complicated catabolic pathways. While S1P?? S1P receptor signaling has been thoroughly studied, sphinganine 1 phosphate mediated cell signaling hasn't been studied in more detail.