@article{HalilbasicFuerstHeidenetal.2020,
  author    = {Halilbasic, Emina and Fuerst, Elisabeth and Heiden, Denise and Japtok, Lukasz and Diesner, Susanne C. and Trauner, Michael and Kulu, Askin and Jaksch, Peter and Hoetzenecker, Konrad and Kleuser, Burkhard and Kazemi-Shirazi, Lili and Untersmayr, Eva},
  title     = {Plasma levels of the bioactive sphingolipid metabolite S1P in adult cystic fibrosis patients},
  series = {Nutrients},
  volume    = {12},
  journal   = {Nutrients},
  number    = {3},
  publisher = {MDPI},
  address   = {Basel},
  issn      = {2072-6643},
  doi       = {10.3390/nu12030765},
  pages     = {11},
  year      = {2020},
  abstract  = {Recent research has linked sphingolipid (SL) metabolism with cystic fibrosis transmembrane conductance regulator (CFTR) activity, affecting bioactive lipid mediator sphingosine-1-phosphate (S1P). We hypothesize that loss of CFTR function in cystic fibrosis (CF) patients influenced plasma S1P levels. Total and unbound plasma S1P levels were measured in 20 lung-transplanted adult CF patients and 20 healthy controls by mass spectrometry and enzyme-linked immunosorbent assay (ELISA). S1P levels were correlated with CFTR genotype, routine laboratory parameters, lung function and pathogen colonization, and clinical symptoms. Compared to controls, CF patients showed lower unbound plasma S1P, whereas total S1P levels did not differ. A positive correlation of total and unbound S1P levels was found in healthy controls, but not in CF patients. Higher unbound S1P levels were measured in Delta F508-homozygous compared to Delta F508-heterozygous CF patients (p = 0.038), accompanied by higher levels of HDL in Delta F508-heterozygous patients. Gastrointestinal symptoms were more common in Delta F508 heterozygotes compared to Delta F508 homozygotes. This is the first clinical study linking plasma S1P levels with CFTR function and clinical presentation in adult CF patients. Given the emerging role of immunonutrition in CF, our study might pave the way for using S1P as a novel biomarker and nutritional target in CF.},
  language  = {en}
}
@article{CencettiBrunoBernacchionietal.2020,
  author    = {Cencetti, Francesca and Bruno, Gennaro and Bernacchioni, Caterina and Japtok, Lukasz and Puliti, Elisa and Donati, Chiara and Bruni, Paola},
  title     = {Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P(2) receptor axis},
  series = {Biochimica et biophysica acta : Molecular and cell biology of lipids},
  volume    = {1865},
  journal   = {Biochimica et biophysica acta : Molecular and cell biology of lipids},
  number    = {9},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {1388-1981},
  doi       = {10.1016/j.bbalip.2020.158759},
  pages     = {9},
  year      = {2020},
  abstract  = {The bioactive sphingolipid sphingosine 1-phosphate (S1P) has emerged in the last three decades as main regulator of key cellular processes including cell proliferation, survival, migration and differentiation. A crucial role for this sphingolipid has been recognized in skeletal muscle cell biology both in vitro and in vivo. S1P lyase (SPL) is responsible for the irreversible degradation of S1P and together with sphingosine kinases, the S1P producing enzymes, regulates cellular S1P levels. In this study is clearly showed that the blockade of SPL by pharmacological or RNA interference approaches induces myogenic differentiation of C2C12 myoblasts. Moreover, down-regulation of the specific S1P transporter spinster homolog 2 (Spns2) abrogates myogenic differentiation brought about by SPL inhibition or down-regulation, pointing at a role of extracellular S1P in the pro-myogenic action induced by SPL blockade. Furthermore, also S1P(2) receptor down-regulation was found to abrogate the pro-myogenic effect of SPL blockade. These results provide further proof that inside-out S1P signaling is critically implicated in skeletal muscle biology and provide support to the concept that the specific targeting of SPL could represent an exploitable strategy to treat skeletal muscle disorders.},
  language  = {en}
}
@article{DerakhshaniKurzJaptoketal.2019,
  author    = {Derakhshani, Shaghayegh and Kurz, Andreas and Japtok, Lukasz and Schumacher, Fabian and Pilgram, Lisa and Steinke, Maria and Kleuser, Burkhard and Sauer, Markus and Schneider-Schaulies, Sibylle and Avota, Elita},
  title     = {Measles Virus Infection Fosters Dendritic Cell Motility in a 3D Environment to Enhance Transmission to Target Cells in the Respiratory Epithelium},
  series = {Frontiers in immunology},
  volume    = {10},
  journal   = {Frontiers in immunology},
  publisher = {Frontiers Research Foundation},
  address   = {Lausanne},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2019.01294},
  pages     = {14},
  year      = {2019},
  abstract  = {Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit.},
  language  = {en}
}
@article{MeinersPalmieriKlopfleischetal.2019,
  author    = {Meiners, Jana and Palmieri, Vittoria and Klopfleisch, Robert and Ebel, Jana-Fabienne and Japtok, Lukasz and Schumacher, Fabian and Yusuf, Ayan Mohamud and Becker, Katrin Anne and Z{\"o}ller, Julia and Hose, Matthias and Kleuser, Burkhard and Hermann, Dirk Matthias and Kolesnick, Richard N. and Buer, Jan and Hansen, Wiebke and Westendorf, Astrid M.},
  title     = {Intestinal acid sphingomyelinase protects from severe Pathogen-Driven Colitis},
  series = {Frontiers in immunology},
  volume    = {10},
  journal   = {Frontiers in immunology},
  publisher = {Frontiers Research Foundation},
  address   = {Lausanne},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2019.01386},
  pages     = {14},
  year      = {2019},
  abstract  = {Inflammatory diseases of the gastrointestinal tract are emerging as a global problem with increased evidence and prevalence in numerous countries. A dysregulated sphingolipid metabolism occurs in patients with ulcerative colitis and is discussed to contribute to its pathogenesis. In the present study, we determined the impact of acid sphingomyelinase (Asm), which catalyzes the hydrolysis of sphingomyelin to ceramide, on the course of Citrobacter (C.) rodentium-driven colitis. C. rodentium is an enteric pathogen and induces colonic inflammation very similar to the pathology in patients with ulcerative colitis. We found that mice with Asm deficiency or Asm inhibition were strongly susceptible to C. rodentium infection. These mice showed increased levels of C. rodentium in the feces and were prone to bacterial spreading to the systemic organs. In addition, mice lacking Asm activity showed an uncontrolled inflammatory T(h)1 and T(h)17 response, which was accompanied by a stronger colonic pathology compared to infected wild type mice. These findings identified Asm as an essential regulator of mucosal immunity to the enteric pathogen C. rodentium.},
  language  = {en}
}
@article{GohlkeZagoriyInostrozaetal.2019,
  author    = {Gohlke, Sabrina and Zagoriy, Vyacheslav and Inostroza, Alvaro Cuadros and Meret, Michael and Mancini, Carola and Japtok, Lukasz and Schumacher, Fabian and Kuhlow, Doreen and Graja, Antonia and Stephanowitz, Heike and J{\"a}hnert, Markus and Krause, Eberhard and Wernitz, Andreas and Petzke, Klaus-Juergen and Sch{\"u}rmann, Annette and Kleuser, Burkhard and Schulz, Tim Julius},
  title     = {Identification of functional lipid metabolism biomarkers of brown adipose tissue aging},
  series = {Molecular Metabolism},
  volume    = {24},
  journal   = {Molecular Metabolism},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {2212-8778},
  doi       = {10.1016/j.molmet.2019.03.011},
  pages     = {1 -- 17},
  year      = {2019},
  abstract  = {Objective: Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism. Methods: Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined. Results: Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation. Conclusions: Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions.},
  language  = {en}
}
@misc{ReichelRheinHofmannetal.2018,
  author    = {Reichel, Martin and Rhein, Cosima and Hofmann, Lena M. and Monti, Juliana and Japtok, Lukasz and Langgartner, Dominik and F{\"u}chsl, Andrea M. and Kleuser, Burkhard and Gulbins, Erich and Hellerbrand, Claus and Reber, Stefan O. and Kornhuber, Johannes},
  title     = {Chronic psychosocial stress in mice is associated with increased acid sphingomyelinase activity in liver and serum and with hepatic C16:0-ceramide accumulation},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {1120},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-44624},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-446241},
  pages     = {10},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@misc{PloehnEdelmannJaptoketal.2018,
  author    = {Pl{\"o}hn, Svenja and Edelmann, B{\"a}rbel and Japtok, Lukasz and He, Xingxuan and Hose, Matthias and Hansen, Wiebke and Schuchman, Edward H. and Eckstein, Anja and Berchner-Pfannschmidt, Utta},
  title     = {CD40 enhances sphingolipids in orbital fibroblasts},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {1099},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-46883},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-468837},
  pages     = {9},
  year      = {2018},
  abstract  = {PURPOSE. Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management.},
  language  = {en}
}
@article{ReichelRheinHofmannetal.2018,
  author    = {Reichel, Martin and Rhein, Cosima and Hofmann, Lena M. and Monti, Juliana and Japtok, Lukasz and Langgartner, Dominik and F{\"u}chsl, Andrea M. and Kleuser, Burkhard and Gulbins, Erich and Hellerbrand, Claus and Reber, Stefan O. and Kornhuber, Johannes},
  title     = {Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation},
  series = {Frontiers in Psychiatry},
  volume    = {9},
  journal   = {Frontiers in Psychiatry},
  publisher = {Frontiers Research Foundation},
  address   = {Lausanne},
  issn      = {1664-0640},
  doi       = {10.3389/fpsyt.2018.00496},
  pages     = {8},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{PloehnEdelmannJaptoketal.2018,
  author    = {Pl{\"o}hn, Svenja and Edelmann, B{\"a}rbel and Japtok, Lukasz and He, Xingxuan and Hose, Matthias and Hansen, Wiebke and Schuchman, Edward H. and Eckstein, Anja and Berchner-Pfannschmidt, Utta},
  title     = {CD40 enhances sphingolipids in orbital fibroblasts},
  series = {Investigative ophthalmology \& visual science},
  volume    = {59},
  journal   = {Investigative ophthalmology \& visual science},
  number    = {13},
  publisher = {Association for Research in Vision and Opthalmology},
  address   = {Rockville},
  issn      = {0146-0404},
  doi       = {10.1167/iovs.18-25466},
  pages     = {5391 -- 5397},
  year      = {2018},
  abstract  = {METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management.},
  language  = {en}
}
@article{LaegerCastanoMartinezWernoetal.2018,
  author    = {Laeger, Thomas and Castano-Martinez, Teresa and Werno, Martin W. and Japtok, Lukasz and Baumeier, Christian and Jonas, Wenke and Kleuser, Burkhard and Sch{\"u}rmann, Annette},
  title     = {Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {61},
  journal   = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  number    = {6},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  doi       = {10.1007/s00125-018-4595-1},
  pages     = {1459 -- 1469},
  year      = {2018},
  abstract  = {Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ\%; CON) or low (4 kJ\%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.},
  language  = {en}
}
@article{McVeyKimTabuchietal.2017,
  author    = {McVey, Mark J. and Kim, Michael and Tabuchi, Arata and Srbely, Victoria and Japtok, Lukasz and Arenz, Christoph and Rotstein, Ori and Kleuser, Burkhard and Semple, John W. and Kuebler, Wolfgang M.},
  title     = {Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets},
  series = {American journal of physiology : Lung cellular and molecular physiology},
  volume    = {312},
  journal   = {American journal of physiology : Lung cellular and molecular physiology},
  number    = {5},
  publisher = {American Physiological Society},
  address   = {Bethesda},
  issn      = {1040-0605},
  doi       = {10.1152/ajplung.00317.2016},
  pages     = {625 -- 637},
  year      = {2017},
  abstract  = {Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.},
  language  = {en}
}
@article{BernacchioniGhiniCencettietal.2017,
  author    = {Bernacchioni, Caterina and Ghini, Veronica and Cencetti, Francesca and Japtok, Lukasz and Donati, Chiara and Bruni, Paola and Turano, Paola},
  title     = {NMR metabolomics highlights sphingosine kinase-1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells},
  series = {Molecular oncology / Federation of European Biochemical Societies},
  volume    = {11},
  journal   = {Molecular oncology / Federation of European Biochemical Societies},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1878-0261},
  doi       = {10.1002/1878-0261.12048},
  pages     = {517 -- 533},
  year      = {2017},
  abstract  = {Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.},
  language  = {en}
}
@article{HoehnJerniganJaptoketal.2017,
  author    = {Hoehn, Richard S. and Jernigan, Peter L. and Japtok, Lukasz and Chang, Alex L. and Midura, Emily F. and Caldwell, Charles C. and Kleuser, Burkhard and Lentsch, Alex B. and Edwards, Michael J. and Gulbins, Erich and Pritts, Timothy A.},
  title     = {Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation},
  series = {Annals of surgery : a monthly review of surgical science and practice},
  volume    = {265},
  journal   = {Annals of surgery : a monthly review of surgical science and practice},
  number    = {1},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0003-4932},
  doi       = {10.1097/SLA.0000000000001648},
  pages     = {218 -- 226},
  year      = {2017},
  abstract  = {Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.},
  language  = {en}
}
@article{FolkessonVorkapicGulbinsetal.2017,
  author    = {Folkesson, Maggie and Vorkapic, Emina and Gulbins, Erich and Japtok, Lukasz and Kleuser, Burkhard and Welander, Martin and L{\"a}nne, Toste and W{\aa}gs{\"a}ter, Dick},
  title     = {Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms},
  series = {Journal of vascular surgery},
  volume    = {65},
  journal   = {Journal of vascular surgery},
  number    = {4},
  publisher = {Elsevier},
  address   = {New York},
  issn      = {0741-5214},
  doi       = {10.1016/j.jvs.2015.12.056},
  pages     = {1171 -- 1179},
  year      = {2017},
  abstract  = {Background: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study. Methods and Results: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT. Conclusions: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.},
  language  = {en}
}
@misc{HalibasicFuerstHeidenetal.2017,
  author    = {Halibasic, Emina and Fuerst, Elisabeth and Heiden, Denis and Japtok, Lukasz and Diesner, Susanne C. and Hillebrand, P. and Trauner, Michael and Kleuser, Burkhard and Kazemi-Shirazi, Lili and Untersmayr, Eva},
  title     = {Significantly reduced plasma levels of the bioactive sphingolipid S1P in lung transplanted cystic fibrosis patients are associated with gastrointestinal symptoms},
  series = {Allergy},
  volume    = {72},
  journal   = {Allergy},
  number    = {S103},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0105-4538},
  pages     = {195 -- 195},
  year      = {2017},
  language  = {en}
}
@article{FayyazJaptokSchumacheretal.2017,
  author    = {Fayyaz, Susann and Japtok, Lukasz and Schumacher, Fabian and Wigger, Dominik and Schulz, Tim Julius and Haubold, Kathrin and Gulbins, Erich and V{\"o}ller, Heinz and Kleuser, Burkhard},
  title     = {Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity},
  series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  volume    = {43},
  journal   = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1015-8987},
  doi       = {10.1159/000480470},
  pages     = {445 -- 456},
  year      = {2017},
  abstract  = {Background/Aims: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). Methods: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Results: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). Conclusion: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.},
  language  = {en}
}
@misc{NojimaKonishiFreemanetal.2016,
  author    = {Nojima, Hiroyuki and Konishi, Takanori and Freeman, Christopher M. and Schuster, Rebecca M. and Japtok, Lukasz and Kleuser, Burkhard and Edwards, Michael J. and Gulbins, Erich and Lentsch, Alex B.},
  title     = {Chemokine receptors, CXCR1 and CXCR2, differentially regulate exosome release in hepatocytes},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {538},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-41088},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-410885},
  pages     = {15},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@article{HustonKornhuberMuehleetal.2016,
  author    = {Huston, Joseph P. and Kornhuber, Johannes and Muehle, Christiane and Japtok, Lukasz and Komorowski, Mara and Mattern, Claudia and Reichel, Martin and Gulbins, Erich and Kleuser, Burkhard and Topic, Bianca and Silva, Maria A. De Souza and Mueller, Christian P.},
  title     = {A sphingolipid mechanism for behavioral extinction},
  series = {Journal of neurochemistry},
  volume    = {137},
  journal   = {Journal of neurochemistry},
  publisher = {Wiley-Blackwell},
  address   = {Hoboken},
  issn      = {0022-3042},
  doi       = {10.1111/jnc.13537},
  pages     = {589 -- 603},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@article{HollmannWernerAvotaetal.2016,
  author    = {Hollmann, Claudia and Werner, Sandra and Avota, Elita and Reuter, Dajana and Japtok, Lukasz and Kleuser, Burkhard and Gulbins, Erich and Becker, Katrin Anne and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas},
  title     = {Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4(+) Conventional versus Foxp3(+) Regulatory T Cells},
  series = {The journal of immunology},
  volume    = {197},
  journal   = {The journal of immunology},
  publisher = {American Assoc. of Immunologists},
  address   = {Bethesda},
  issn      = {0022-1767},
  doi       = {10.4049/jimmunol.1600691},
  pages     = {3130 -- 3141},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@article{NojimaKonishiFreemanetal.2016,
  author    = {Nojima, Hiroyuki and Konishi, Takanori and Freeman, Christopher M. and Schuster, Rebecca M. and Japtok, Lukasz and Kleuser, Burkhard and Edwards, Michael J. and Gulbins, Erich and Lentsch, Alex B.},
  title     = {Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes},
  series = {PLoS one},
  volume    = {11},
  journal   = {PLoS one},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0161443},
  pages     = {6900 -- +},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}