TY - JOUR A1 - Schaper, Katrin A1 - Dickhaut, Jeannette A1 - Japtok, Lukasz A1 - Kietzmann, Manfred A1 - Mischke, Reinhard A1 - Kleuser, Burkhard A1 - Bäumer, Wolfgang T1 - Sphingosine-1-phosphate exhibits anti-proliferative and anti-inflammatory effects in mouse models of psoriasis JF - Journal of dermatological scienc N2 - Background: It has been indicated that the sphingolipid sphingosine-1-phosphate (SIP) restrains the ability of dendritic cells to migrate to lymph nodes. Furthermore SIP has been demonstrated to inhibit cell growth in human keratinocytes. However, only little is known about the effect of S1P in hyperproliferative and inflammatory in vivo models. Objective: In this study, locally acting SIP was explored in different experimental mouse models of psoriasis vulgaris. Methods: S1P and FTY720 were tested in the imiquimod-induced psoriasis mouse model, the mouse tail assay and a pilot study of the severe combined immunodeficiency mice (SCID). Results: In the imiquimod model the positive control diflorasone diacetate and S1P, but not FTY720 reduced the imiquimod-induced epidermal hyperproliferation of the ear skin. This effect was confirmed in the SCID model, where S1P treated skin from patients suffering from psoriasis showed a decrease in epidermal thickness compared to vehicle. In the imiquimod model, there was also significant inhibition of ear swelling and a moderate reduction of inflammatory cell influx and oedema formation in ear skin by SIP treatment. The inflammatory response on the back skin was, however, only reduced by diflorasone diacetate. In the mouse tail assay, the influence of S1P and FTY720 in stratum granulosum formation was tested compared to the positive control calcipotriol. Whereas topical administration of calcipotriol led to a low but significant increase of stratum granulosum, S1P and FTY720 lacked such an effect. Conclusion: Taken together, these results imply that topical administration of SIP might be a new option for the treatment of mild to moderate psoriasis lesions. KW - Imiquimod KW - Psoriasis KW - SCID mice KW - Sphingosine-1-phosphate Y1 - 2013 U6 - https://doi.org/10.1016/j.jdermsci.2013.03.006 SN - 0923-1811 VL - 71 IS - 1 SP - 29 EP - 36 PB - Elsevier CY - Clare ER - TY - GEN A1 - Polzin, Amin A1 - Rassaf, Tienush A1 - Boehm, Andreas A1 - Lueth, Anja A1 - Kleuser, Burkhard A1 - Zeus, Tobias A1 - Kelm, Malte A1 - Kroemer, Heyo K. A1 - Schroer, Karsten A1 - Rauch, Bernhard H. T1 - Aspirin inhibits release of platelet-derived sphingosine-1-phosphate in acute myocardial infarction T2 - INTERNATIONAL JOURNAL OF CARDIOLOGY KW - Sphingosine-1-phosphate KW - Acute coronary syndrome KW - Platelets KW - Aspirin Y1 - 2013 U6 - https://doi.org/10.1016/j.ijcard.2013.10.050 SN - 0167-5273 SN - 1874-1754 VL - 170 IS - 2 SP - E23 EP - E24 PB - ELSEVIER IRELAND LTD CY - CLARE ER - TY - JOUR A1 - Lotinun, Sutada A1 - Kiviranta, Riku A1 - Matsubara, Takuma A1 - Alzate, Jorge A. A1 - Neff, Lynn A1 - Lüth, Anja A1 - Koskivirta, Ilpo A1 - Kleuser, Burkhard A1 - Vacher, Jean A1 - Vuorio, Eero A1 - Horne, William C. A1 - Baron, Roland T1 - Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation JF - The journal of clinical investigation N2 - Cathepsin K (CTSK) is secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption. Global deletion of Ctsk in mice decreases bone resorption, leading to osteopetrosis, but also increases the bone formation rate (BFR). To understand how Ctsk deletion increases the BFR, we generated osteoclast- and osteoblast-targeted Ctsk knockout mice using floxed Ctsk alleles. Targeted ablation of Ctsk in hematopoietic cells, or specifically in osteoclasts and cells of the monocyte-osteoclast lineage, resulted in increased bone volume and BFR as well as osteoclast and osteoblast numbers. In contrast, targeted deletion of Ctsk in osteoblasts had no effect on bone resorption or BFR, demonstrating that the increased BFR is osteoclast dependent. Deletion of Ctsk in osteoclasts increased their sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts, which contained elevated levels of sphingosine-l-phosphate (S1P), increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P(1,3) receptor antagonist inhibited these responses. Osteoblasts derived from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio, providing a positive feedback loop that increased the number of osteoclasts. Our data provide genetic evidence that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P. Y1 - 2013 U6 - https://doi.org/10.1172/JCI64840 SN - 0021-9738 VL - 123 IS - 2 SP - 666 EP - 681 PB - American Society for Clinical Investigation CY - Ann Arbor ER - TY - JOUR A1 - Gulbins, Erich A1 - Palmada, Monica A1 - Reichel, Martin A1 - Lueth, Anja A1 - Boehmer, Christoph A1 - Amato, Davide A1 - Mueller, Christian P. A1 - Tischbirek, Carsten H. A1 - Groemer, Teja W. A1 - Tabatabai, Ghazaleh A1 - Becker, Katrin Anne A1 - Tripal, Philipp A1 - Staedtler, Sven A1 - Ackermann, Teresa F. A1 - van Brederode, Johannes A1 - Alzheimer, Christian A1 - Weller, Michael A1 - Lang, Undine E. A1 - Kleuser, Burkhard A1 - Grassme, Heike A1 - Kornhuber, Johannes T1 - Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs JF - Nature medicine N2 - Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants. Y1 - 2013 U6 - https://doi.org/10.1038/nm.3214 SN - 1078-8956 VL - 19 IS - 7 SP - 934 EP - + PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Gerecke, Christian A1 - Mascher, Conny A1 - Gottschalk, Uwe A1 - Kleuser, Burkhard A1 - Scholtka, Bettina T1 - Ultrasensitive detection of unknown colon cancer-initiating mutations using the example of the adenomatous polyposis coli gene JF - Cancer prevention research N2 - Detection of cancer precursors contributes to cancer prevention, for example, in the case of colorectal cancer. To record more patients early, ultrasensitive methods are required for the purpose of noninvasive precursor detection in body fluids. Our aim was to develop a method for enrichment and detection of known as well as unknown driver mutations in the Adenomatous polyposis coli (APC) gene. By coupled wild-type blocking (WTB) PCR and high-resolution melting (HRM), referred to as WTB-HRM, a minimum detection limit of 0.01% mutant in excess wild-type was achieved according to as little as 1 pg mutated DNA in the assay. The technique was applied to 80 tissue samples from patients with colorectal cancer (n = 17), adenomas (n = 50), serrated lesions (n = 8), and normal mucosa (n = 5). Any kind of known and unknown APC mutations (deletions, insertions, and base exchanges) being situated inside the mutation cluster region was distinguishable from wild-type DNA. Furthermore, by WTB-HRM, nearly twice as many carcinomas and 1.5 times more precursor lesions were identified to be mutated in APC, as compared with direct sequencing. By analyzing 31 associated stool DNA specimens all but one of the APC mutations could be recovered. Transferability of the WTB-HRM method to other genes was proven using the example of KRAS mutation analysis. In summary, WTB-HRM is a new approach for ultrasensitive detection of cancer-initiating mutations. In this sense, it appears especially applicable for noninvasive detection of colon cancer precursors in body fluids with excess wild-type DNA like stool. Cancer Prev Res; 6(9); 898-907. (C) 2013 AACR. Y1 - 2013 U6 - https://doi.org/10.1158/1940-6207.CAPR-13-0145 SN - 1940-6207 VL - 6 IS - 9 SP - 898 EP - 907 PB - American Association for Cancer Research CY - Philadelphia ER - TY - JOUR A1 - Böhm, Andreas A1 - Flößer, Anja A1 - Ermler, Swen A1 - Fender, Anke C. A1 - Lüth, Anja A1 - Kleuser, Burkhard A1 - Schrör, Karsten A1 - Rauch, Bernhard H. T1 - Factor-Xa-induced mitogenesis and migration require sphingosine kinase activity and S1P formation in human vascular smooth muscle cells JF - Cardiovascular research N2 - Sphingosine-1-phosphate (S1P) is a cellular signalling lipid generated by sphingosine kinase-1 (SPHK1). The aim of the study was to investigate whether the activated coagulation factor-X (FXa) regulates SPHK1 transcription and the formation of S1P and subsequent mitogenesis and migration of human vascular smooth muscle cells (SMC). FXa induced a time- (36 h) and concentration-dependent (330 nmol/L) increase of SPHK1 mRNA and protein expression in human aortic SMC, resulting in an increased synthesis of S1P. FXa-stimulated transcription of SPHK1 was mediated by the protease-activated receptor-1 (PAR-1) and PAR-2. In human carotid artery plaques, expression of SPHK1 was observed at SMC-rich sites and was co-localized with intraplaque FX/FXa content. FXa-induced SPHK1 transcription was attenuated by inhibitors of Rho kinase (Y27632) and by protein kinase C (PKC) isoforms (GF109203X). In addition, FXa rapidly induced the activation of the small GTPase Rho A. Inhibition of signalling pathways which regulate SPHK1 expression, inhibition of its activity or siRNA-mediated SPHK1 knockdown attenuated the mitogenic and chemotactic response of human SMC to FXa. These data suggest that FXa induces SPHK1 expression and increases S1P formation independent of thrombin and that this involves the activation of Rho A and PKC signalling. In addition to its key function in coagulation, this direct effect of FXa on human SMC may increase cell proliferation and migration at sites of vessel injury and thereby contribute to the progression of vascular lesions. KW - Factor-Xa KW - Atherosclerosis KW - Proliferation KW - Smooth muscle cells KW - Sphingosine kinase-1 Y1 - 2013 U6 - https://doi.org/10.1093/cvr/cvt112 SN - 0008-6363 VL - 99 IS - 3 SP - 505 EP - 513 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Bhabak, Krishna P. A1 - Kleuser, Burkhard A1 - Huwiler, Andrea A1 - Arenz, Christoph T1 - Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues JF - Bioorganic & medicinal chemistry : a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on biomolecular chemistry, medicinal chemistry and related disciplines N2 - Induction of apoptosis mediated by the inhibition of ceramidases has been shown to enhance the efficacy of conventional chemotherapy in several cancer models. Among the inhibitors of ceramidases reported in the literature, B-13 is considered as a lead compound having good in vitro potency towards acid ceramidase. Furthermore, owing to the poor activity of B-13 on lysosoamal acid ceramidase in living cells, LCL-464 a modified derivative of B-13 containing a basic omega-amino group at the fatty acid was reported to have higher potency towards lysosomal acid ceramidase in living cells. In a search for more potent inhibitors of ceramidases, we have designed a series of compounds with structural modifications of B-13 and LCL-464. In this study, we show that the efficacy of B-13 in vitro as well as in intact cells can be enhanced by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed novel promising inhibitors of aCDase and nCDase. In cell culture studies using the breast cancer cell line MDA-MB-231, some of the newly developed compounds elevated endogenous ceramide levels and in parallel, also induced apoptotic cell death. In summary, this study shows that structural modification of the known ceramidase inhibitors B-13 and LCL-464 generates more potent ceramidase inhibitors that are active in intact cells and not only elevates the cellular ceramide levels, but also enhances cell death. KW - Sphingolipids KW - Ceramide KW - Ceramidase inhibitors KW - Structure-activity-relationship Y1 - 2013 U6 - https://doi.org/10.1016/j.bmc.2012.12.014 SN - 0968-0896 VL - 21 IS - 4 SP - 874 EP - 882 PB - Elsevier CY - Oxford ER -