TY - GEN A1 - Prüfer, Nicole A1 - Kleuser, Burkhard A1 - van der Giet, Markus T1 - The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality N2 - The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL’s anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL’s protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL’s biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 340 KW - atherosclerosis KW - high-density lipoprotein (HDL) KW - inflammation KW - serum amyloid A (SAA) KW - sphingosine-1-phosphate (S1P) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-398648 ER - TY - GEN A1 - Zoicas, Iulia A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Reichel, Martin A1 - Gulbins, Erich A1 - Fejtova, Anna A1 - Kornhuber, Johannes A1 - Rhein, Cosima T1 - The forebrain-specific overexpression of acid sphingomyelinase induces depressive-like symptoms in mice T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1186 KW - Smpd1 KW - acid sphingomyelinase KW - forebrain KW - depressive-like behavior KW - anxiety-like behavior KW - ceramide Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-524368 SN - 1866-8372 IS - 5 ER - TY - JOUR A1 - Zoicas, Iulia A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Reichel, Martin A1 - Gulbins, Erich A1 - Fejtova, Anna A1 - Kornhuber, Johannes A1 - Rhein, Cosima T1 - The forebrain-specific overexpression of acid sphingomyelinase induces depressive-like symptoms in mice JF - Cells N2 - Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression. KW - Smpd1 KW - acid sphingomyelinase KW - forebrain KW - depressive-like behavior KW - anxiety-like behavior KW - ceramide Y1 - 2020 VL - 9 IS - 5 PB - MDPI CY - Basel ER - TY - GEN A1 - Kleuser, Burkhard T1 - The enigma of sphingolipids in health and disease T2 - International journal of molecular sciences Y1 - 2018 U6 - https://doi.org/10.3390/ijms19103126 SN - 1422-0067 VL - 19 IS - 10 PB - MDPI CY - Basel ER - TY - GEN A1 - Kleuser, Burkhard T1 - The enigma of sphingolipids in health and disease T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1040 KW - sphingosine-1-phosphate Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-472637 SN - 1866-8372 IS - 1040 ER - TY - JOUR A1 - Zabihi, Fatemeh A1 - Graff, Patrick A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Hedtrich, Sarah A1 - Haag, Rainer T1 - Synthesis of poly(lactide-co-glycerol) as a biodegradable and biocompatible polymer with high loading capacity for dermal drug delivery JF - Nanoscale N2 - Due to the low cutaneous bioavailability of tacrolimus (TAC), penetration enhancers are used to improve its penetration into the skin. However, poor loading capacity, non-biodegradability, toxicity, and in some cases inefficient skin penetration are challenging issues that hamper their applications for the dermal TAC delivery. Here we present poly(lactide-co-glycerol) (PLG) as a water soluble, biodegradable, and biocompatible TAC-carrier with high loading capacity (14.5% w/w for TAC) and high drug delivery efficiencies into the skin. PLG was synthesized by cationic ring-opening copolymerization of a mixture of glycidol and lactide and showed 35 nm and 300 nm average sizes in aqueous solutions before and after loading of TAC, respectively. Delivery experiments on human skin, quantified by fluorescence microscopy and LC-MS/MS, showed a high ability for PLG to deposit Nile red and TAC into the stratum corneum and viable epidermis of skin in comparison with Protopic (R) (0.03% w/w, TAC ointment). The cutaneous distribution profile of delivered TAC proved that 80%, 16%, and 4% of the cutaneous drug level was deposited in the stratum corneum, viable epidermis, and upper dermis, respectively. TAC delivered by PLG was able to efficiently decrease the IL-2 and TSLP expressions in human skin models. Taking advantage of the excellent physicochemical and biological properties of PLG, it can be used for efficient dermal TAC delivery and potential treatment of inflammatory skin diseases. Y1 - 2018 U6 - https://doi.org/10.1039/c8nr05536j SN - 2040-3364 SN - 2040-3372 VL - 10 IS - 35 SP - 16848 EP - 16856 PB - Royal Society of Chemistry CY - Cambridge 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 - Wigger, Dominik A1 - Schumacher, Fabian A1 - Schneider-Schaulies, Sibylle A1 - Kleuser, Burkhard T1 - Sphingosine 1-phosphate metabolism and insulin signaling JF - Cellular signalling N2 - Insulin is the main anabolic hormone secreted by 13-cells of the pancreas stimulating the assimilation and storage of glucose in muscle and fat cells. It modulates the postprandial balance of carbohydrates, lipids and proteins via enhancing lipogenesis, glycogen and protein synthesis and suppressing glucose generation and its release from the liver. Resistance to insulin is a severe metabolic disorder related to a diminished response of peripheral tissues to the insulin action and signaling. This leads to a disturbed glucose homeostasis that precedes the onset of type 2 diabetes (T2D), a disease reaching epidemic proportions. A large number of studies reported an association between elevated circulating fatty acids and the development of insulin resistance. The increased fatty acid lipid flux results in the accumulation of lipid droplets in a variety of tissues. However, lipid intermediates such as diacylglycerols and ceramides are also formed in response to elevated fatty acid levels. These bioactive lipids have been associated with the pathogenesis of insulin resistance. More recently, sphingosine 1-phosphate (S1P), another bioactive sphingolipid derivative, has also been shown to increase in T2D and obesity. Although many studies propose a protective role of S1P metabolism on insulin signaling in peripheral tissues, other studies suggest a causal role of S1P on insulin resistance. In this review, we critically summarize the current state of knowledge of S1P metabolism and its modulating role on insulin resistance. A particular emphasis is placed on S1P and insulin signaling in hepatocytes, skeletal muscle cells, adipocytes and pancreatic 13-cells. In particular, modulation of receptors and enzymes that regulate S1P metabolism can be considered as a new therapeutic option for the treatment of insulin resistance and T2D. KW - Insulin resistance KW - Type 2 diabetes KW - Sphingolipids KW - Hepatocytes KW - Adipocytes KW - Skeletal muscle cells Y1 - 2021 U6 - https://doi.org/10.1016/j.cellsig.2021.109959 SN - 0898-6568 SN - 1873-3913 VL - 82 PB - Elsevier Science CY - Amsterdam [u.a.] ER - TY - JOUR A1 - Edlich, Alexander A1 - Gerecke, Christian A1 - Giulbudagian, Michael A1 - Neumann, Falko A1 - Hedtrich, Sarah A1 - Schaefer-Korting, Monika A1 - Ma, Nan A1 - Calderon, Marcelo A1 - Kleuser, Burkhard T1 - Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin JF - European Journal of Pharmaceutics and Biopharmaceutics N2 - Engineered nanogels are of high value for a targeted and controlled transport of compounds due to the ability to change their chemical properties by external stimuli. As it has been indicated that nanogels possess a high ability to penetrate the stratum corneum, it cannot be excluded that nanogels interact with dermal dendritic cells, especially in diseased skin. In this study the potential crosstalk of the thermore-sponsive nanogels (tNGs) with the dendritic cells of the skin was investigated with the aim to determine the immunotoxicological properties of the nanogels. The investigated tNGs were made of dendritic polyglycerol (dPG) and poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)), as polymer conferring thermoresponsive properties. Although the tNGs were taken up, they displayed neither cytotoxic and genotoxic effects nor any induction of reactive oxygen species in the tested cells. Interestingly, specific uptake mechanisms of the tNGs by the dendritic cells were depending on the nanogels cloud point temperature (Tcp), which determines the phase transition of the nanoparticle. The study points to caveolae-mediated endocytosis as being the major tNGs uptake mechanism at 37 degrees C, which is above the Tcp of the tNGs. Remarkably, an additional uptake mechanism, beside caveolae-mediated endocytosis, was observed at 29 degrees C, which is the Tcp of the tNGs. At this temperature, which is characterized by two different states of the tNGs, macropinocytosis was involved as well. In summary, our study highlights the impact of thermoresponsivity on the cellular uptake mechanisms which has to be taken into account if the tNGs are used as a drug delivery system. KW - Dendritic cells KW - Drug delivery systems KW - Nanogel KW - Nanoparticle KW - Nanoparticle uptake KW - Nanotoxicology Y1 - 2017 U6 - https://doi.org/10.1016/j.ejpb.2016.12.016 SN - 0939-6411 SN - 1873-3441 VL - 116 SP - 155 EP - 163 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Börtlein, Charlene A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Dölken, Lars A1 - Avota, Elita T1 - Role of Neutral Sphingomyelinase-2 (NSM 2) in the Control of T Cell Plasma Membrane Lipid Composition and Cholesterol Homeostasis JF - Frontiers in cell and developmental biology N2 - The activity of neutral sphingomyelinase-2 (NSM2) to catalyze the conversion of sphingomyelin (SM) to ceramide and phosphocholine at the cytosolic leaflet of plasma membrane (PM) is important in T cell receptor (TCR) signaling. We recently identified PKC zeta as a major NSM2 downstream effector which regulates microtubular polarization. It remained, however, unclear to what extent NSM2 activity affected overall composition of PM lipids and downstream effector lipids in antigen stimulated T cells. Here, we provide a detailed lipidomics analyses on PM fractions isolated from TCR stimulated wild type and NSM2 deficient (Delta NSM) Jurkat T cells. This revealed that in addition to that of sphingolipids, NSM2 depletion also affected concentrations of many other lipids. In particular, NSM2 ablation resulted in increase of lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) which both govern PM biophysical properties. Crucially, TCR dependent upregulation of the important T cell signaling lipid diacylglycerol (DAG), which is fundamental for activation of conventional and novel PKCs, was abolished in Delta NSM cells. Moreover, NSM2 activity was found to play an important role in PM cholesterol transport to the endoplasmic reticulum (ER) and production of cholesteryl esters (CE) there. Most importantly, CE accumulation was essential to sustain human T cell proliferation. Accordingly, inhibition of CE generating enzymes, the cholesterol acetyltransferases ACAT1/SOAT1 and ACAT2/SOAT2, impaired TCR driven expansion of both CD4(+) and CD8(+) T cells. In summary, our study reveals an important role of NSM2 in regulating T cell functions by its multiple effects on PM lipids and cholesterol homeostasis. KW - neutral sphingomyelinase-2 KW - T cell receptor KW - plasma membrane KW - lyso-phospholipids KW - diacylglycerol KW - cholesteryl ester Y1 - 2019 U6 - https://doi.org/10.3389/fcell.2019.00226 SN - 2296-634X VL - 7 PB - Frontiers Research Foundation CY - Lausanne ER -