TY  - JOUR
A1  - Gerecke, Christian
A1  - Schumacher, Fabian
A1  - Berndzen, Alide
A1  - Homann, Thomas
A1  - Kleuser, Burkhard
T1  - Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells
JF  - Epigenetics : the official journal of the DNA Methylation Society
N2  - Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity of alpha-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116 IDH1(R132H/+) (harbouring a mutated IDH1 allele) and the parental cells HCT116 IDH1(+/+) (wild type IDH1). Measurement of the oncometabolite indicated a 56-fold higher content of 2-HG in mutated cells compared to wild type cells. A significant reduction of 2-HG was observed in mutated cells after treatment with ML 309, whereas VC produced only minimally changes of the oncometabolite. However, combinatorial treatment with both, ML309 and VC, in mutated cells induced pronounced reduction of 2-HG leading to levels comparable to those in wild type cells. The decreased level of 2-HG in mutated cells after combinatorial treatment was accompanied by an enhanced global DNA hydroxymethylation and an increased gene expression of certain tumour suppressors. Moreover, mutated cells showed an increased percentage of apoptotic cells after treatment with non-cytotoxic concentrations of ML309 and VC. These results suggest that combinatorial therapy is of interest for further investigation to rescue TET activity and treatment of IDH1/2 mutated cancers.
KW  - Vitamin C
KW  - epigenetics
KW  - IDH1
KW  - TET
KW  - cancer cells
Y1  - 2019
U6  - https://doi.org/10.1080/15592294.2019.1666652
SN  - 1559-2294
SN  - 1559-2308
VL  - 15
IS  - 3
SP  - 307
EP  - 322
PB  - Taylor & Francis Group
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Seitz, Aaron P.
A1  - Schumacher, Fabian
A1  - Baker, Jennifer
A1  - Soddemann, Matthias
A1  - Wilker, Barbara
A1  - Caldwell, Charles C.
A1  - Gobble, Ryan M.
A1  - Kamler, Markus
A1  - Becker, Katrin Anne
A1  - Beck, Sascha
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
T1  - Sphingosine-coating of plastic surfaces prevents ventilator-associated pneumonia
JF  - Journal of molecular medicine
N2  - Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in critically ill patients. Here, we employed the broad antibacterial effects of sphingosine to prevent VAP by developing a novel method of coating surfaces of endotracheal tubes with sphingosine and sphingosine analogs. Sphingosine and phytosphingosine coatings of endotracheal tubes prevent adherence and mediate killing of Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus, even in biofilms. Most importantly, sphingosine-coating of endotracheal tubes also prevented P. aeruginosa and S. aureus pneumonia in vivo. Coating of the tubes with sphingosine was stable, without obvious side effects on tracheal epithelial cells and did not induce inflammation. In summary, we describe a novel method to coat plastic surfaces and provide evidence for the application of sphingosine and phytosphingosine as novel antimicrobial coatings to prevent bacterial adherence and induce killing of pathogens on the surface of endotracheal tubes with potential to prevent biofilm formation and VAP.Key messagesNovel dip-coating method to coat plastic surfaces with lipids.Sphingosine and phytosphingosine as novel antimicrobial coatings on plastic surface.Sphingosine coatings of endotracheal tubes prevent bacterial adherence and biofilms.Sphingosine coatings of endotracheal tubes induce killing of pathogens.Sphingosine coatings of endotracheal tubes ventilator-associated pneumonia.
KW  - Coating
KW  - Plastic surfaces
KW  - Sphingosine
KW  - Ventilation
KW  - Acinetobacter baumannii
KW  - Pseudomonas aeruginosa
KW  - Staphylococcus aureus
Y1  - 2019
U6  - https://doi.org/10.1007/s00109-019-01800-1
SN  - 0946-2716
SN  - 1432-1440
VL  - 97
IS  - 8
SP  - 1195
EP  - 1211
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Kachler, Katerina
A1  - Bailer, Maximilian
A1  - Heim, Lisanne
A1  - Schumacher, Fabian
A1  - Reichel, Martin
A1  - Holzinger, Corinna D.
A1  - Trump, Sonja
A1  - Mittler, Susanne
A1  - Monti, Juliana
A1  - Trufa, Denis I.
A1  - Rieker, Ralf J.
A1  - Hartmann, Arndt
A1  - Sirbu, Horia
A1  - Kleuser, Burkhard
A1  - Kornhuber, Johannes
A1  - Finotto, Susetta
T1  - Enhanced acid sphingomyelinase activity drives immune evasion and tumor growth in non-small cell lung carcinoma
JF  - Cancer research
N2  - The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and-extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. (C) 2017 AACR.
Y1  - 2017
U6  - https://doi.org/10.1158/0008-5472.CAN-16-3313
SN  - 0008-5472
SN  - 1538-7445
VL  - 77
IS  - 21
SP  - 5963
EP  - 5976
PB  - American Association for Cancer Research
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Gutbier, Birgitt
A1  - Schönrock, Stefanie M.
A1  - Ehrler, Carolin
A1  - Haberberger, Rainer
A1  - Dietert, Kristina
A1  - Gruber, Achim D.
A1  - Kummer, Wolfgang
A1  - Michalick, Laura
A1  - Kuebler, Wolfgang M.
A1  - Hocke, Andreas C.
A1  - Szymanski, Kolja
A1  - Letsiou, Eleftheria
A1  - Lüth, Anja
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Mitchell, Timothy J.
A1  - Bertrams, Wilhelm
A1  - Schmeck, Bernd
A1  - Treue, Denise
A1  - Klauschen, Frederick
A1  - Bauer, Torsten T.
A1  - Tönnies, Mario
A1  - Weissmann, Norbert
A1  - Hippenstiel, Stefan
A1  - Suttorp, Norbert
A1  - Witzenrath, Martin
T1  - Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2
JF  - Critical care medicine
N2  - Objectives: Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia. Design: Controlled, in vitro, ex vivo, and in vivo laboratory study. Subjects: Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells. Interventions: Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin. Measurements and Main Results: Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1(-/-) mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase. Conclusions: Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury.
KW  - acute lung injury
KW  - pneumococcal pneumonia
KW  - sphingosine kinase 1
KW  - sphingosine-1-phosphate
KW  - sphingosine-1-phosphate receptor 2
Y1  - 2018
U6  - https://doi.org/10.1097/CCM.0000000000002916
SN  - 0090-3493
SN  - 1530-0293
VL  - 46
IS  - 3
SP  - e258
EP  - e267
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Balzus, Benjamin
A1  - Sahle, Fitsum Feleke
A1  - Hönzke, Stefan
A1  - Gerecke, Christian
A1  - Schumacher, Fabian
A1  - Hedtrich, Sarah
A1  - Kleuser, Burkhard
A1  - Bodmeier, Roland
T1  - Formulation and ex vivo evaluation of polymeric nanoparticles for controlled delivery of corticosteroids to the skin and the corneal epithelium
JF  - European journal of pharmaceutics and biopharmaceutics : EJPB ; official journal of the International Association for Pharmaceutical Technology
N2  - Controlled delivery of corticosteroids using nanoparticles to the skin and corneal epithelium may reduce their side effects and maximize treatment effectiveness. Dexamethasone-loaded ethyl cellulose, Eudragit® RS and ethyl cellulose/Eudragit® RS nanoparticles were prepared by the solvent evaporation method. Dexamethasone release from the polymeric nanoparticles was investigated in vitro using Franz diffusion cells. Drug penetration was also assessed ex vivo using excised human skin. Nanoparticle toxicity was determined by MTT and H2DCFDA assays. Eudragit® RS nanoparticles were smaller and positively charged but had a lower dexamethasone loading capacity (0.3–0.7%) than ethyl cellulose nanoparticles (1.4–2.2%). By blending the two polymers (1:1), small (105 nm), positively charged (+37 mV) nanoparticles with sufficient dexamethasone loading (1.3%) were obtained. Dexamethasone release and penetration significantly decreased with decreasing drug to polymer ratio and increased when Eudragit® RS was blended with ethyl cellulose. Ex vivo, drug release and penetration from the nanoparticles was slower than a conventional cream. The nanoparticles bear no toxicity potentials except ethyl cellulose nanoparticles had ROS generation potential at high concentration. In conclusion, the nanoparticles showed great potential to control the release and penetration of corticosteroids on the skin and mucus membrane and maximize treatment effectiveness.
KW  - Dermal delivery
KW  - Dexamethasone
KW  - Ethyl cellulose
KW  - Eudragit (R) RS
KW  - Ocular delivery
KW  - Polymeric nanoparticle
Y1  - 2017
U6  - https://doi.org/10.1016/j.ejpb.2017.02.001
SN  - 0939-6411
SN  - 1873-3441
VL  - 115
SP  - 122
EP  - 130
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Pastukhov, Oleksandr
A1  - Schwalm, Stephanie
A1  - Zangemeister-Wittke, Uwe
A1  - Fabbro, Doriano
A1  - Bornancin, Frederic
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Pfeilschifter, Josef
A1  - Huwiler, Andrea
T1  - The ceramide kinase inhibitor NVP-231 inhibits breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death
JF  - British journal of pharmacology : journal of The British Pharmacological Society
N2  - Background and PurposeCeramide kinase (CerK) catalyzes the generation of ceramide-1-phosphate which may regulate various cellular functions, including inflammatory reactions and cell growth. Here, we studied the effect of a recently developed CerK inhibitor, NVP-231, on cancer cell proliferation and viability and investigated the role of cell cycle regulators implicated in these responses.
 Experimental ApproachThe breast and lung cancer cell lines MCF-7 and NCI-H358 were treated with increasing concentrations of NVP-231 and DNA synthesis, colony formation and cell death were determined. Flow cytometry was performed to analyse cell cycle distribution of cells and Western blot analysis was used to detect changes in cell cycle regulator expression and activation.
 Key ResultsIn both cell lines, NVP-231 concentration-dependently reduced cell viability, DNA synthesis and colony formation. Moreover it induced apoptosis, as measured by increased DNA fragmentation and caspase-3 and caspase-9 cleavage. Cell cycle analysis revealed that NVP-231 decreased the number of cells in S phase and induced M phase arrest with an increased mitotic index, as determined by increased histone H3 phosphorylation. The effect on the cell cycle was even more pronounced when NVP-231 treatment was combined with staurosporine. Finally, overexpression of CerK protected, whereas down-regulation of CerK with siRNA sensitized, cells for staurosporine-induced apoptosis.
 Conclusions and ImplicationsOur data demonstrate for the first time a crucial role for CerK in the M phase control in cancer cells and suggest its targeted inhibition, using drugs such as NVP-231, in combination with conventional pro-apoptotic chemotherapy.
Y1  - 2014
U6  - https://doi.org/10.1111/bph.12886
SN  - 0007-1188
SN  - 1476-5381
VL  - 171
IS  - 24
SP  - 5829
EP  - 5844
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Japtok, Lukasz
A1  - Schaper, Katrin
A1  - Bäumer, Wolfgang
A1  - Radeke, Heinfried H.
A1  - Jeong, Se Kyoo
A1  - Kleuser, Burkhard
T1  - Sphingosine 1-Phosphate Modulates Antigen Capture by Murine Langerhans
 Cells via the S1P(2) Receptor Subtype
JF  - PLOS ONE
N2  - Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P(2) receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P(2) not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions. Citation: Japtok L, Schaper K, Baumer W, Radeke HH, Jeong SK, et al. (2012) Sphingosine 1-Phosphate Modulates Antigen Capture by Murine Langerhans Cells via the S1P(2) Receptor Subtype. PLoS ONE 7(11): e49427. doi:10.1371/journal.pone.0049427
Y1  - 2012
U6  - https://doi.org/10.1371/journal.pone.0049427
SN  - 1932-6203
VL  - 7
IS  - 11
PB  - PUBLIC LIBRARY SCIENCE
CY  - SAN FRANCISCO
ER  - 
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  - JOUR
A1  - Pewzner-Jung, Yael
A1  - Tabazavareh, Shaghayegh Tavakoli
A1  - Grassme, Heike
A1  - Becker, Katrin Anne
A1  - Japtok, Lukasz
A1  - Steinmann, Joerg
A1  - Joseph, Tammar
A1  - Lang, Stephan
A1  - Tuemmler, Burkhard
A1  - Schuchman, Edward H.
A1  - Lentsch, Alex B.
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Futerman, Anthony H.
A1  - Gulbins, Erich
T1  - Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa
JF  - EMBO molecular medicine
N2  - Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P.aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P.aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection.
KW  - cystic fibrosis
KW  - long chain base
KW  - lung infection
KW  - Pseudomonas aeruginosa
KW  - sphingosine
Y1  - 2014
U6  - https://doi.org/10.15252/emmm.201404075
SN  - 1757-4676
SN  - 1757-4684
VL  - 6
IS  - 9
SP  - 1205
EP  - 1214
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Fayyaz, Susann
A1  - Henkel, Janin
A1  - Japtok, Lukasz
A1  - Krämer, Stephanie
A1  - Damm, Georg
A1  - Seehofer, Daniel
A1  - Püschel, Gerhard Paul
A1  - Kleuser, Burkhard
T1  - Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P(2) receptor subtype
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.
 The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.
 Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P(2) receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P(2), was not able to inhibit insulin signalling.
 These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P(2) receptor to impair insulin signalling. In particular, S1P(2) inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.
KW  - FTY720
KW  - Insulin signalling
KW  - Palmitate
KW  - S1P receptors
KW  - Sphingolipids
KW  - Sphingosine 1-phosphate
Y1  - 2014
U6  - https://doi.org/10.1007/s00125-013-3123-6
SN  - 0012-186X
SN  - 1432-0428
VL  - 57
IS  - 2
SP  - 373
EP  - 382
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Henry, Brian D.
A1  - Neill, Daniel R.
A1  - Becker, Katrin Anne
A1  - Gore, Suzanna
A1  - Bricio-Moreno, Laura
A1  - Ziobro, Regan
A1  - Edwards, Michael J.
A1  - Muehlemann, Kathrin
A1  - Steinmann, Joerg
A1  - Kleuser, Burkhard
A1  - Japtok, Lukasz
A1  - Luginbuehl, Miriam
A1  - Wolfmeier, Heidi
A1  - Scherag, Andre
A1  - Gulbins, Erich
A1  - Kadioglu, Aras
A1  - Draeger, Annette
A1  - Babiychuk, Eduard B.
T1  - Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice
JF  - Nature biotechnology : the science and business of biotechnology
N2  - Gram-positive bacterial pathogens that secrete cytotoxic pore-forming toxins, such as Staphylococcus aureus and Streptococcus pneumoniae, cause a substantial burden of disease. Inspired by the principles that govern natural toxin-host interactions, we have engineered artificial liposomes that are tailored to effectively compete with host cells for toxin binding. Liposome-bound toxins are unable to lyse mammalian cells in vitro. We use these artificial liposomes as decoy targets to sequester bacterial toxins that are produced during active infection in vivo. Administration of artificial liposomes within 10 h after infection rescues mice from septicemia caused by S. aureus and S. pneumoniae, whereas untreated mice die within 24-33 h. Furthermore, liposomes protect mice against invasive pneumococcal pneumonia. Composed exclusively of naturally occurring lipids, tailored liposomes are not bactericidal and could be used therapeutically either alone or in conjunction with antibiotics to combat bacterial infections and to minimize toxin-induced tissue damage that occurs during bacterial clearance.
Y1  - 2015
U6  - https://doi.org/10.1038/nbt.3037
SN  - 1087-0156
SN  - 1546-1696
VL  - 33
IS  - 1
SP  - 81
EP  - U295
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Japtok, Lukasz
A1  - Schmitz, Elisabeth I.
A1  - Fayyaz, Susann
A1  - Krämer, Stephanie
A1  - Hsu, Leigh J.
A1  - Kleuser, Burkhard
T1  - Sphingosine 1-phosphate counteracts insulin signaling in pancreatic beta-cells via the sphingosine 1-phosphate receptor subtype 2
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - Glucolipotoxic stress has been identified as a key player in the progression of pancreatic beta-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic beta-cells but also regulate beta-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in beta-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P(2)) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P(2) axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by beta-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P(2), the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued beta-cell damage clearly indicating an important role of the S1P(2) in beta-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish beta-cell dysfunction and the development of T2D.
KW  - type 2 diabetes mellitus
KW  - sphingolipids
KW  - survival
KW  - proliferation
KW  - Akt signaling
Y1  - 2015
U6  - https://doi.org/10.1096/fj.14-263194
SN  - 0892-6638
SN  - 1530-6860
VL  - 29
IS  - 8
SP  - 3357
EP  - 3369
PB  - Federation of American Societies for Experimental Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Michels, Meta
A1  - Japtok, Lukasz
A1  - Alisjahbana, Bachti
A1  - Wisaksana, Rudi
A1  - Sumardi, Uun
A1  - Puspita, Mita
A1  - Kleuser, Burkhard
A1  - de Mast, Quirijn
A1  - van der Ven, Andre J. A. M.
T1  - Decreased plasma levels of the endothelial protective sphingosine-1-phosphate are associated with dengue-induced plasma leakage
JF  - Journal of infection
N2  - Background: A transient endothelial hyperpermeability is a hallmark of severe dengue infections. Sphingosine-1-phosphate (S1P) maintains vascular integrity and protects against plasma leakage. We related plasma S1P levels to dengue-induced plasma leakage and studied mechanisms that may underlie the decrease in S1P levels in dengue.
 Methods: We determined circulating levels of S1P in 44 Indonesian adults with acute dengue and related levels to plasma leakage, as determined by daily ultrasonography, and to levels of its chaperone apolipoprotein M, other lipoproteins and platelets.
 Results: Plasma S1P levels were decreased during dengue and patients with plasma leakage had lower median levels compared to those without (638 vs. 745 nM; p < 0.01). ApoM and other lipoprotein levels were also decreased during dengue, but did not correlate to S1P levels. Platelet counts correlated positively with S1P levels, but S1P levels were not higher in frozen-thawed platelet rich plasma, arguing against platelets as an important cellular source of S1P in dengue.
 Conclusions: Decreased plasma S1P levels during dengue are associated with plasma leakage. We speculate that decreased levels of ApoM underlies the lower S1P levels. Modulation of S1P levels and its receptors may be a novel therapeutic intervention to prevent plasma leakage in dengue. (C) 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
KW  - Sphingosine 1phosphate
KW  - Dengue
KW  - APOM protein
KW  - Human
KW  - Blood platelets
Y1  - 2015
U6  - https://doi.org/10.1016/j.jinf.2015.06.014
SN  - 0163-4453
SN  - 1532-2742
VL  - 71
IS  - 4
SP  - 480
EP  - 487
PB  - Elsevier
CY  - London
ER  - 
TY  - JOUR
A1  - Carpinteiro, Alexander
A1  - Becker, Katrin Anne
A1  - Japtok, Lukasz
A1  - Hessler, Gabriele
A1  - Keitsch, Simone
A1  - Pozgajova, Miroslava
A1  - Schmid, Kurt W.
A1  - Adams, Constantin
A1  - Müller, Stefan
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Grassme, Heike
A1  - Helfrich, Iris
A1  - Gulbins, Erich
T1  - Regulation of hematogenous tumor metastasis by acid sphingomyelinase
JF  - EMBO molecular medicine
N2  - Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of 51 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C-16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing 1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis.
KW  - acid sphingomyelinase
KW  - ceramide
KW  - integrins
KW  - platelets
KW  - tumor-metastasis
Y1  - 2015
SN  - 1757-4676
SN  - 1757-4684
VL  - 7
IS  - 6
SP  - 714
EP  - 734
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Huston, Joseph P.
A1  - Kornhuber, Johannes
A1  - Muehle, Christiane
A1  - Japtok, Lukasz
A1  - Komorowski, Mara
A1  - Mattern, Claudia
A1  - Reichel, Martin
A1  - Gulbins, Erich
A1  - Kleuser, Burkhard
A1  - Topic, Bianca
A1  - Silva, Maria A. De Souza
A1  - Mueller, Christian P.
T1  - A sphingolipid mechanism for behavioral extinction
JF  - Journal of neurochemistry
N2  - Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions.
KW  - acid sphingomyelinase
KW  - ceramide
KW  - extinction
KW  - hippocampus
KW  - operant behavior
KW  - sphingomyelin
Y1  - 2016
U6  - https://doi.org/10.1111/jnc.13537
SN  - 0022-3042
SN  - 1471-4159
VL  - 137
SP  - 589
EP  - 603
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Hollmann, Claudia
A1  - Werner, Sandra
A1  - Avota, Elita
A1  - Reuter, Dajana
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Becker, Katrin Anne
A1  - Schneider-Schaulies, Jürgen
A1  - Beyersdorf, Niklas
T1  - Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4(+) Conventional versus Foxp3(+) Regulatory T Cells
JF  - The journal of immunology
N2  - CD4(+) Foxp3(+) regulatory T cells (Tregs) depend on CD28 signaling for their survival and function, a receptor that has been previously shown to activate the acid sphingomyelinase (Asm)/ceramide system. In this article, we show that the basal and CD28-induced Asm activity is higher in Tregs than in conventional CD4(+) T cells (Tconvs) of wild-type (wt) mice. In Asm-deficient (Smpd1(-/-); Asm(-/-)) mice, as compared with wt mice, the frequency of Tregs among CD4(+) T cells, turnover of the effector molecule CTLA-4, and their suppressive activity in vitro were increased. The biological significance of these findings was confirmed in our Treg-sensitive mouse model of measles virus (MV) CNS infection, in which we observed more infected neurons and less MV-specific CD8(+) T cells in brains of Asm(-/-) mice compared with wt mice. In addition to genetic deficiency, treatment of wt mice with the Asm inhibitor amitriptyline recapitulated the phenotype of Asm-deficient mice because it also increased the frequency of Tregs among CD4(+) T cells. Reduced absolute cell numbers of Tconvs after inhibitor treatment in vivo and extensive in vitro experiments revealed that Tregs are more resistant toward Asm inhibitor-induced cell death than Tconvs. Mechanistically, IL-2 was capable of providing crucial survival signals to the Tregs upon inhibitor treatment in vitro, shifting the Treg/Tconv ratio to the Treg side. Thus, our data indicate that Asm-inhibiting drugs should be further evaluated for the therapy of inflammatory and autoimmune disorders.
Y1  - 2016
U6  - https://doi.org/10.4049/jimmunol.1600691
SN  - 0022-1767
SN  - 1550-6606
VL  - 197
SP  - 3130
EP  - 3141
PB  - American Assoc. of Immunologists
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Nojima, Hiroyuki
A1  - Konishi, Takanori
A1  - Freeman, Christopher M.
A1  - Schuster, Rebecca M.
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Lentsch, Alex B.
T1  - Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes
JF  - PLoS one
N2  - Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect.
Y1  - 2016
U6  - https://doi.org/10.1371/journal.pone.0161443
SN  - 1932-6203
VL  - 11
SP  - 6900
EP  - +
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Reichel, Martin
A1  - Rhein, Cosima
A1  - Hofmann, Lena M.
A1  - Monti, Juliana
A1  - Japtok, Lukasz
A1  - Langgartner, Dominik
A1  - Füchsl, Andrea M.
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Hellerbrand, Claus
A1  - Reber, Stefan O.
A1  - Kornhuber, Johannes
T1  - Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation
JF  - Frontiers in Psychiatry
N2  - Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28% (P = 0.006) and secretory Asm activity by 47% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-alpha (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders.
KW  - chronic psychosocial stress
KW  - acid sphingomyelinase
KW  - ceramide
KW  - sphingolipid metabolism
KW  - chronic subordinate colony housing (CSC)
KW  - liver metabolism
Y1  - 2018
U6  - https://doi.org/10.3389/fpsyt.2018.00496
SN  - 1664-0640
VL  - 9
PB  - Frontiers Research Foundation
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Nojima, Hiroyuki
A1  - Freeman, Christopher M.
A1  - Schuster, Rebecca M.
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Lentsch, Alex B.
T1  - Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate
JF  - Journal of hepatology
N2  - Background & Aims: Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. Methods: Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. Results: Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. Conclusions: Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
KW  - Liver injury
KW  - Sphingolipids
KW  - Sphingosine kinase
KW  - Ischemia/reperfusion
KW  - Transplantation
Y1  - 2016
U6  - https://doi.org/10.1016/j.jhep.2015.07.030
SN  - 0168-8278
SN  - 1600-0641
VL  - 64
SP  - 60
EP  - 68
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Al Fadel, Frdoos
A1  - Fayyaz, Susann
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
T1  - Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - Background/Aims: Ectopic lipid accumulation in hepatocytes has been identified as a risk factor for the progression of liver fibrosis and is strongly associated with obesity. In particular, the saturated fatty acid palmitate is involved in initiation of liver fibrosis via formation of secondary metabolites by hepatocytes that in turn activate hepatic stellate cells (HSCs) in a paracrine manner Methods: a-smooth muscle actin-expression (alpha-SMA) as a marker of liver fibrosis was investigated via western blot analysis and immunofluorescence microscopy in HSCs (LX-2). Sphingolipid metabolism and the generation of the bioactive secondary metabolite sphingosine I-phosphate (SIP) in response to palmitate were analyzed by LC-MS/MS in hepatocytes (HepG2). To identify the molecular mechanism involved in the progression of liver fibrosis real-time PCR analysis and pharmacological modulation of SIP receptors were performed. Results: Palmitate oversupply increased intra- and extracellular SIP-concentrations in hepatocytes. Conditioned medium from HepG2 cells initiated fibrosis by enhancing alpha-SMA-expression in LX-2 in a S1P-dependent manner In accordance, fibrotic response in the presence of SIP was also observed in HSCs. Pharmacological inhibition of SIP receptors demonstrated that S1P(3) is the crucial receptor subtype involved in this process. Conclusion: SIP is synthesized in hepatocytes in response to palmitate and released into the extracellular environment leading to an activation of HSCs via the S1P(3) receptor (C) 2016 The Author(s) Published by S. Karger AG, Basel
KW  - Palmitate
KW  - Liver fibrosis
KW  - Sphingosine 1-phosphate
KW  - Hepatic stellate cells
KW  - Hepatocytes
KW  - alpha-SMA
Y1  - 2016
U6  - https://doi.org/10.1159/000453213
SN  - 1015-8987
SN  - 1421-9778
VL  - 40
SP  - 1637
EP  - 1645
PB  - Karger
CY  - Basel
ER  -