Disease relevance of sphingosine

• The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis [1].
• OCH, a sphingosine-truncated analog of alpha-galactosylceramide (alphaGC), is a potential therapeutic reagent for a variety of Th1-mediated autoimmune diseases through its selective induction of Th2 cytokines from natural killer T (NKT) cells [2].
• The intracellular flow and fate of two fluorescently labeled sphingolipids, 6-[N-(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]hexanoyl glucosyl sphingosine (C6-NBD-glucosylceramide) and C6-NBD-sphingomyelin, was examined in the human colon adenocarcinoma cell line HT29 [3].
• This acute toxicity could be prevented by a lyso-GM1 ganglioside with N-acetylated sphingosine [4].
• Gaucher disease types 1, 2, and 3: differential mutations of the acid beta-glucosidase active site identified with conduritol B epoxide derivatives and sphingosine [5].

Psychiatry related information on sphingosine

• As one sphingolipid metabolite, sphingosine is known to exert a potent antimicrobial effect on S. aureus at physiologic levels, and it may play a significant role in bacterial defense mechanisms of healthy normal skin [6].

High impact information on sphingosine

• The sphingosine analogue, D-L-threo-dihydrosphingosine (DHS), inhibits the SK enzyme competitively with a dissociation constant, K1, of 5 to 18 microM [7].
• Sphingolipid breakdown products, sphingosine and lysosphingolipids, inhibit protein kinase C, a pivotal enzyme in cell regulation and signal transduction [8].
• Cells were first incubated with liposomes containing N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproyl sphingosine (C6-NBD-ceramide), or with a bovine serum albumin complex of the fluorescent lipid, and then examined by fluorescence microscopy [9].
• In contrast to GLTP, ACD11 accelerates the transfer of sphingosine, but not of glycosphingolipids, between membranes in vitro [10].
• Knockout of Arabidopsis accelerated-cell-death11 encoding a sphingosine transfer protein causes activation of programmed cell death and defense [10].

Chemical compound and disease context of sphingosine

• Our data suggest that the relative levels of sphingolipid metabolites may play a role in determining the radiosensitivity of prostate cancer cells, and that the enhancement of ceramide and sphingosine generation could be of therapeutic value [11].
• We present data showing that rhabdomyosarcoma cell lines, independent of lineage (alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma), are particularly sensitive to the induction of apoptosis as a result of an elevation in the cellular levels of sphingosine (D-erythro-sphingosine) [12].
• Furthermore, dl-threo-dihydrosphingosine and B-5354c, isolated from a novel marine bacterium, both sphingosine kinase inhibitors, blocked the toxin-induced hemolysis and production of S1P and caused sphingosine to accumulate [13].
• Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases [14].
• A specific enhancing effect of N,N-dimethylsphingosine on epidermal growth factor receptor autophosphorylation. Demonstration of its endogenous occurrence (and the virtual absence of unsubstituted sphingosine) in human epidermoid carcinoma A431 cells [15].

Biological context of sphingosine

• It appears that sphingosine affects TNF alpha-induced PGE2 production via a mechanism that is independent of PKC involvement, and that sphingosine may function as an endogenous second messenger capable of modulating the responsiveness of the cell to external stimuli [16].
• Down-regulation of PKC by overnight incubation of cells with PMA or inhibition of PKC with the PKC inhibitor sphingosine blocked the stimulation of MAP kinase by epinephrine and, correspondingly, epinephrine-promoted AA release was inhibited under these conditions [17].
• The capacity of drugs that act on type 1 sphingosine 1-phosphate receptors to suppress organ graft rejection in humans and autoimmunity in animal models without apparent impairment of host defenses against infections suggests that this system is a promising target for new forms of immunotherapy [18].
• Transfection-mediated upregulation of p27kip1 decreases sphingosine-induced cell death in alpha-catenin-deficient cells [19].
• Adding TPA (100 nM) before insemination caused a reduction in the frequency of HRs at fertilization, but neither TPA nor sphingosine affected the frequency or size of HRs when they were added after the start of fertilization [20].

Anatomical context of sphingosine

• Division of labor: specialization of sphingosine kinases in mast cells [21].
• Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses [22].
• Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement [23].
• The protein kinase C inhibitors H7 and sphingosine inhibit neurite outgrowth on laminin in a reversible and dose-dependent manner [24].
• T and B lymphocytes, as well as endothelial cells, express distinctive profiles of G protein-coupled receptors for sphingosine 1-phosphate, which is a major regulator of T cell development, B and T cell recirculation, tissue homing patterns, and chemotactic responses to chemokines [18].

Associations of sphingosine with other chemical compounds

• Stimulation of mast cells by allergens induces two mammalian sphingosine kinases (Sphk1 and Sphk2) to produce sphingosine-1-phosphate (S1P) [1].
• Short-term (1 min) exposure of cells to sphingosine dramatically increased TNF alpha-induced PGE2 production [16].
• The sphingosine analogues stearylamine and stearoyl-D-sphingosine had little or no effect on TNF alpha-mediated PGE2 production, supporting a specific role for sphingosine in the activation process [16].
• A recent paper has expanded the regulation of the enzyme to the realm of sphingolipid signaling, specifically implicating that sphingosine 1-phosphate, endothelial differentiation gene (Edg) receptors and Akt kinase induce a signal transduction pathway via phosphorylation of a serine residue in eNOS [25].
• FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity [26].

Gene context of sphingosine

• Sphingosine kinase (SK) 1 catalyzes the formation of the bioactive lipid sphingosine 1-phosphate, and has been implicated in several biological processes in mammalian cells, including enhanced proliferation, inhibition of apoptosis, and oncogenesis [27].
• These data are consistent with the interpretation that sphingosine regulates ERK1 and ERK2 phosphorylation through inhibition of PKCdelta, and this in turn leads to inhibition of Raf-1 translocation to the plasma membrane [28].
• The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug [29].
• Differential phospholipase D activation by bradykinin and sphingosine 1-phosphate in NIH 3T3 fibroblasts overexpressing gelsolin [30].
• TNF-alpha also stimulates sphingosine kinase, the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (SPP), a further metabolite of ceramide [31].

Analytical, diagnostic and therapeutic context of sphingosine

• Microinjection of S1P has no effect, neither has addition of sphingosine or ceramide [32].
• The immunofluorescence data were correlated with establishment of functional tight junctions as measured by transepithelial resistance and back-exchange of the cell surface, labeled with metabolites of the fluorescent lipid analogue N-(7-[4-nitrobenzo-2-oxa-1,3-diazole]) aminocaproyl sphingosine [33].
• Western blotting demonstrated that sphingosine inhibited the translocation of Raf-1 and PKCdelta from PMN cytosol to the plasma membrane during phagocytosis [28].
• The effects of C8-cer and sphingosine were similar by three separate criteria, phosphoamino acid analysis, anti-phosphotyrosine antibody immunoblotting, and phosphopeptide mapping by high performance liquid chromatography [34].
• Initial dephosphorylation was observed as early as 1 h after treatment of hematopoietic cells with sphingosine, whereas complete shift to the dephosphorylated form was seen 4 h after treatment [35].

References